Mammary Nodular Hyperplasia in Intact R hesus Monkeys

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1 Vet. Path. 10: (1973) Mammary Nodular Hyperplasia in Intact R hesus Monkeys L. W NELSON and L. D. SHOTT Department of Pathology and Toxicology, Mead Johnson Research Center, Evansville, Ind., and Syntex Research, Palo Alto, Calif. Abstrnct. Two control female Rhesus monkeys in long-term toxicity studies had niultiple, palpable nodules in the breast regions. These subcutaneous nodules were 2-7 mni in diameter, firm, and freely movable. No progressive clinical change was observed during a follow-up of 17 or 20 months. Microscopically, one excised nodule consisted of proliferated acinar epithelial cells arranged in lobular patterns. The cells were well differentiated and presented no features of neoplasia. A diagnosis of focal nodular hyperplasia was compatible with the microscopic findings and the clinical follow-up of similar nodules. In the long-term toxicity study of oral contraceptive steroids, tissue alterations in mammary glands are of prime importance. Nodules in breast tissue in either control or test animals must be considered in terms of spontaneous occurrence or of induction by hormonal treatment and evaluated for hyperplastic or neoplastic features. Circumscribed nodules of epithelial hyperplasia and acinar cystic dilatation in the mammary glands of female Rhesus monkeys were previously described and related to castration or ovarian hypofunction [8]. Attempts to produce mammary neoplasia in Rhesus monkeys with carcinogenic hydrocarbons and estrogens were reported [7]. The breasts received the most continuous treatment but remained unresponsive. High dosages of estrogens over periods of as long as 7 years 7 months did not produce neoplastic changes in the mammary glands of monkeys [2]. CHAPMAN [l] reviewed the few reports of mammary neoplasms in subhuman primates and presented a case history of an adenocarcinoma. Recently a mammary adenocarcinoma was reported in a female Rhesus monkey in a study of an oral contraceptive [5]. This report describes the clinical and pathologic findings of subcutaneous nodules in breast regions of untreated control intact female Rhesus monkeys.

2 Monkey NELSON/SHOTT 131 Table I. Mammary nodules in two control Rhesus monkeys Months in study K J II One nodule surgicallv excised during month 4. Report o j Two Cases A long-term toxicity study of an oral contraceptive steroid is being conducted in female Rhesus monkeys according to guidelines of the Food and Drug Administration [3]. After 4 months on study, one control monkey (841 K) had four small subcutaneous nodules in the right mammary gland; each nodule was firm, freely movable, and about 5 nini in diameter. One of these nodules was surgically excised, preserved in 10% buffered formalin, processed for paraffin sections, and stained with hematoxylin and eosin. During subsequent monthly breast examinations, 3-12 nodules were found in this animal (table I). The clinical appearance of other nodules in this monkey was followed for an additional 20 months. Typically, the nodules varied from 2 to 5 mm in diameter, were firm, subcutaneous, and freely movable. Although certain nodules persisted throughout this time and did not vary in clinical features, some nodules regressed or disappeared whereas others were detected in different locations. During the breast examination at 7 months, several nodules were found in a second control monkey (23 J). None of these nodules was biopsied, but the clinical aspects were followed for 17 months. During this period, nodules were detected (table I). The nodules were subcutaneous, firm, freely movable, 3-7 mni in diameter, and otherwise similar to those in the animal described previously. Histologically, the excised nodule consisted of a somewhat circumscribed mass of proliferated acinar epithelial cells separated into lobules by strands of fibrous connective tissue (fig. I). Lobular structure varied, with some lobules composed of solid masses of epithelial cells, some partially subdivided by thin collagenous stroma, and some were acinar-like structures containing homogeneous eosinophilic material of secretory origin (fig. 2). Within the lobules, the cells were regularly stratified with the basalcells well oriented along the basement membrane. Most ducts were lined by single or stratified epithelium. The nuclei of the proliferated acinar cells were uniformly small and oval to round with distinct nucleoli and nuclear membranes. The cytoplasm was generally abundant, eosinophilic, and finely granular, although the cytoplasm of some cells was pale and vacuolated (fig. 3). The above features are compatible with a diagnosis of nodular hyperplasia. Discussion In the toxicologic evaluation of oral contraceptive steroids, mammary glands are target organs and thus receive considerable attention. The lack of

3 132 NELSON/SHOTT Fig. 1. Excised mammary nodule from control female Rhesus monkey. HE. Fig. 2. Part of mammary nodule with acinar epithelial hyperplasia, lobular development and secretory material. HE.

4 Mammary Hyperplasia in Monkeys 133 Fig. 3. Part of mammary nodule with acinar epithelial hyperplasia containing cells with vaciiolated cytoplasm. HE. available and recent reports describing spontaneous nodular mammary lesions in monkeys makes the evaluation and ultimate importance of sporadic nodules in drug-treated monkeys difficult to interpret. Numerous nodules were found in the mammary glands during the monthly breast examinations in two of 20 control monkeys. One nodule was excised early in the study, and the alterations were those of nodular mammary hyperplasia. Repeated clinical examinations have indicated that some of the nodules were transient (i.e. present one month and not palpable in subsequent months), and none of the nodules developed a progressive growth pattern during repeated clinical examinations over 17 or 20 months. The diagnosis of nodular hyperplasia rather than of adenoma or other neoplastic process deserves comment. The large number of nodules, the nonprogressive growth and the transient behavior with regression of some nodules, and the histologic features support this diagnosis. A microscopic indication of the hyperplastic and apparent self-limiting nature of the lesions was the presence of some lobules that contained epithelial cells undergoing vacuolative changes.

5 134 NELSON/SHOTT The hyperplastic nodule described here is somewhat similar to some of the nodules described by SPEERT [8] in castrated female monkeys. The menstrual history of the two monkeys in our study revealed rather regular cycles with no obvious differences from the other control monkeys. For comparative purposes, the nodule described here is somewhat similar to atypical terminal duct hyperplasia as reported by MCDIVITT eta]. [6] and to atypical lobular hyperplasia as reported by HUTTER [4]. Based on the paucity of reported mammary neoplasia in the subhuman primates, even the single occurrence of a neoplasm in a drug-treated monkey causes concern [5]. Historically, the lack of detailed information on breasts of monkeys being studied probably explains the lack of reports on hyperplastic and nodular mammary changes. These nodules should be not only evaluated microscopically but also followed, where possible, to determine the clinical and biological significance. References 1 CHAPMAN, W. L. : Neoplasia in nonhuman primates. J.amer. vet. med. Ass. 153: (1968). 2 GESCHICKTER, C. F. and HARTMAN, C. G. : Mammary response to prolonged estrogenic stimulation in the monkey. Cancer 12: (1959). 3 GOLDENTHAL, E. I.: Current views on the safety evaluation of drugs. FDA Papers 2: (1968). 4 HUTTER, R. V. : The pathologist s role in minimal breast cancer. Cancer 28: (1971). 5 KIRCHSTEIN, R. L.; RABSON, A. S., and RUSTEN, G. W.: Infiltrating duct carcinoma of the mammary gland of a Rhesus monkey after administration of an oral contraceptive. A preliminary report. J. nat. Cancer Inst. 48: (1972). 6 MCDIVITT, R.W.; STEWART, F.W., and BERG, J.W.: Tumors of the breast. Atlas of tumorpathology, second series, vol. 2, pp (Armed ForcesInst. Path., Washington 1968). 7 PFEIFFER, C.A. and ALLEN, E.: Attempts to produce cancer in Rhesus monkeys with carcinogenic hydrocarbons and estrogens. Cancer Res. 8: (1948). 8 SPEERT, H.: Hyperplastic mammary nodules in the castrate female Rhesus monkey. Johns Hopk. Hosp. Bull. 67: (1940). Request reprints from: Dr. L. W. NELSON, Department of Pathology and Toxicology, Mead Johnson Research Center, Evaiisville, IN (USA)