AN OBSERVATION OF PRIMARY TUMORS OF THE PITUITARY, OVARIES, AND MAMMARY GLANDS IN A MOUSE

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1 AN OBSERVATION OF PRIMARY TUMORS OF THE PITUITARY, OVARIES, AND MAMMARY GLANDS IN A MOUSE W. U. GARDNER,' L. C. STRONG,' AND G. M. SMITH (Front the Department of Anatomy, Yale Univerdy School of Medicine) Though mammary tumors frequently occur in certain strains of mice, the incidence of primary tumors of other organs is much lower. One reference has been found in the literature to a pituitary tumor in a mouse. Slye, Holmes, and Wells (1931) have reported a pituitary tumor observed in one animal among more than 11,000 examined at autopsy. In this instance a small tumor was observed in a fixed specimen. The incidence of ovarian tumors in mice also appears to be quite low. Slye (1916) reports observing 18 in 11,000 autopsied mice. The writers know of no reports of evidence of physiological activity of ovarian tumors in mice. Simple follicular cysts, usually associated with atrophic genital organs, have occasionally been observed in the ovaries of old mice of our colony. The bilateral ovarian tumors to be reported here were apparently actively secreting female sex hormone. Numerous recent experiments with hormones which induce specific growthstimulating reactions have been attempted to associate hormonal factors with atypical growths or tumors. In view of this the present observation of primary tumors of three glands in one animal, two endocrine and one exocrine, as functionally associated as the pituitary, ovary, and mammary glands, merits recording. OBSERVATIONS AUTOPSY At the time the mouse was sacrified it was described as a very large, thin animal in a poor state of health. It was 695 days old and had given birth to the last of its four litters 371 days previously. Though it had been in breeding cages in contact with males, no pregnancies had been recorded during the last year. (This mouse was No. S88685 and belonged to the EI strain of mice developed by Strong.) Four small tumors were palpated in the left thoracic group of mammary glands after the mouse had been killed. Upon removal of the skin the mammary glands were found to be yellowish in color and very thick, almost as thick as the glands of a lactating female. Four more small nodules were observed, three in the region of the third right thoracic gland, and one in the region of the fourth right gland in the posterior abdominal region. Both ovaries were extremely large, solid, and reddish. The fixed ovaries measured 10 X 8 X 8 mm. and 10 X 6 X 7 mm. The locations and attachments were normal. The uterus was hyperemic and distended with fluid, as 1 National Research Council Fellow. 2 This experiment has been partially supported by a grdnt from the Josiah Macy, Jr. Foundation made to Dr. L C. Strong. 541

2 542 W. U. GARDNER, L. C. STRONG, AND G. M. SMITH is observed in mice at the time of estrus. One area was more distended than the rest. The suprarenals were small but normal in appearance. All other abdominal organs and tissues appeared normal. The thoracic cavity and contents also appeared normal. Upon removing the brain a large pituitary was observed. This had apparently been adherent to the brain, as a torn, bleeding surface was presented. The pituitary, measuring approximately 4 X 3 >< 3 FIG. 1. PIIOTOMICROGRAPtI OF AN AREA OF THE PITUITARY ADENOMA The peripheral cells were compactly arranged in cords and alveoli. At the lower border and nearer the'crnter of the tumor red blood cells were ohserved among the tumor ceiis. A mitotic figure is shown in the lower central region. X 400. nini., was several times the normal size. could not be identified. The posterior lobe of the pituitary HISTOLOGICAL OBSERVATIONS The tissues examined histologically, with the exception of the pituitary, were fixed in Bouin's fluid and stained in hematoxylin and eosin after sectioning at 10 microns. The pituitary was fixed in Zenker's formol fixative and stained with Mallory's triple stain, as well as with hematoxylin-eosin. Pituitary: The pars nervosa and pars intermedia appeared normal. The pars intermedia consisted of uniformly stained, apparently basophilic cells. Between the pars intermedia and pars anterior was a large cleft filled with a uniformly staining colloid-like material. The portion of the pars anterior near the fluid-filled cleft contained definite acidophilic cells and chromophobes and basophilic cells with few granules. Some cells stained yellow with both stains and appeared to be undergoing degeneration. Nuclei in varying stages of degeneration appeared in the yellow cytoplasm.

3 PRIMARY TUMORS IN MOUSE 543 A fairly definite line of demarcation existed between the more normal pars anterior tissue and the tumor tissue. The tumor consisted of chromophobe cells and a very few scattered eosinophilic cells (Fig. 1). At the periphery of the tumor the cells were closely packed and separated by small capillaries. The cells in the central portion tended to lie in cords and were separated by large, incompletely lined blood sinuses. In places it appeared as though diffuse hemorrhage had occurred into the tissues. In some instances charac- FIG. 2. PHOTOMICROGRAPH OF ONE OF THE GRANULOSA-CELL TUMORS OF THE OVARY The cells were arranged in alveoli by delicate connective-tissue septa. Several large ova-like cclls with clear cytoplasm are present. Both ovaries were composed of similar tissue X 265. teristic tumor cells were found lying free in the sinuses. Several mitotic figures were observed. The tumor was considered to be a chromophobe adenoma. Ovaries: No follicles or corpora lutea were observed in either enlarged ovary on gross or microscopic examination. Both ovaries were composed of tumor tissue showing oval or polygonal cells, in irregular alveolar arrangement, supported by a stroma of delicate connective tissue. Occasionally large ova-like cells with a large nuclei and abundant clear cytoplasm were seen. Mitotic figures were numerous. Both ovaries were entirely replaced by tumor tissue resembling granulosa-cell tumors in human ovaries (Fig. 2). Such tumors are frequently associated with uterine endometrial hyperplasia in the human female (Novak, 1934; Bland and Goldstein, 1935). Uterus: A uterine endometrial hyperplasia was observed in this mouse. The glands were well developed and greatly distended. In places it was difficult to distinguish the central lumen of the uterine horns. The one enlarged area of the uterine horn mentioned in the description of the tissue at autopsy was similar in structure to the rest of the organ except that the glands were more distended (Fig. 3). The epithelial cells were cuboidal and closely

4 5 44 W. LJ, GARUNER, L. C. STRONG, AND G. M. SMITH packed. A similar but less extensive uterine hyperplasia has been observed in mice by Parkes (1935) following the continued injection of large amounts (500 m.u. in eighteen days) of trihydroxy-oestrin. The vaginal epithelium did not show stimulation. In was only moderately thickened and composed largely of nucleated epithelial cells invaded by leukocytes. The outer cornified layer was very thin and irregular. The Mammary Glands: The mammary tumors, six in number, were very small. All consisted of closely packed masses, cords, and acini of polygonal epithelial cells with many mitotic figures and evidence of invasion of neighboring areas. The tumors in each instance were regarded as small, actively FIG. 3. PIIOTOGRWII nf TIIR UTERUS, SIXOWING TFIE EXTEXT OF TIIE ENDOMETRIAL GLANDULAR CYSTIC HYPERPLASIA. X 25 growing adenocarcinomata arising in the mammary gland (Fig. 4). Similar mammary tumors have been observed in male mice following extensive treatment with estrogenic hormones (Lacassagne, 1932 ; Burrows, 1935; Bonser, 1935; Gardner, Smith, Allen, and Strong, in press). Besides the mammary cancers mentioned, the remainder of the mammary tissue presented a strange picture (Fig. 5). The thickness of the glands was due largely to the distention of the ducts with a yellowish fluid. Very few alveoli were present and in most of those present the epithelium was undergoing degeneration. The stroma and epithelium in the lobules were infiltrated with leukocytes and lymphocytes as in regressing glands. The epithelium of the distended ducts was flattened, having lost its usual cuboidal or low columnar condition. Following fixation and staining the secretion present in the ducts stained with eosin and showed the presence of concretion-like bodies. Leukocytes were present in the secretion.

5 FIG. 4. PHOTOMICROGRAPH OF OKE oi? THE MAMMARY ADENOCARCIKOMAS. X 245 FIG. 5. PHOTOMICROGRAPH OF AN AREA OF THE MAMMARY GL.4NDS NOT INVOLVED BY TUMOR The congestion of the gland ducts with a non-vacuolated fluid was particularly noticeable. The duct epithelium was very thin and in places completely absent. Few alveoli were present. The stroma showed considerable leukocytic infiltration. X

6 S46 W. U. GARDNER, L. C. STRONG, AND G. M. SMITH SUMMARY A pituitary adenorna, bilateral ovarian granulosa-cell tumors, and multiple mammary adenocarcinoma were observed in one mouse. No definite physiological activity was observed that might be attributed to the pituitary adenoma. A uterine endometrial hyperplasia and a general cystic hyperplastic condition of the mammary glands were observed and ascribed to a hyperovarian state associated with the ovarian tumors. Though it is hazardous at the present time to state that mammary tumors are induced by a hyper-ovarian condition, the r81e of the ovarian hormone in the stimulation of the initial growth of the mammary glands must be a necessary factor. NOTE: The writers wish to express their appreciation to Dr. James Ewing of Memorial Hospital, New York City, for his kindness in examining the slides and for his comments. REFERENCES HLAND, 1. U., AND GOLDSTEIN, L.: Surg., Gpnec. & Obst , BONSER, G. M.: J. Path. & Bact. 41: , BURROWS, H.: Am. J. Cancer 24: , GARDNEK, W. U., SMITH, G. M., ALLEN, E., AND STRONG, L. C.: Arch. Path., in press. LACASSAGNE, A,: Compl. rend. Acatf. d. sc , NOVAE;, E.: Am. J. Surg. 24: , I AKKES, A. S.: Lancet 1: 485, SLYE, M.: J. Cancer Kes. I: , ~LYF, M, HOLMES, H. V., AND WELLS, H. G.: Am. J. Cancer IS: 13Si-1400, 1931.