Female mice become sexually mature at four weeks of age and begin ovulating and cycling sexually every few days. The complete cycle is short and lasts approximately 4-5 days. The vaginal epithelium reflects the various stages of the cycle and turns over rapidly. Proestrus in the mouse is characterized by a prominent layer of large mucous cells lining the vaginal epithelium (Fig. 182). As proestrus is superseded by estrus, the mucous cells are replaced by keratinized epithelium (Fig. 183). Mestestrus is characterized by mucous, cellular debris and large numbers of polymorphonuclear leukocytes in the lumen of the vagina (Fig. 184). In diestrus, the squamous epithelium is thin and atrophic with an occasional neutrophil in the epithelium (Fig. 185).
Vaginal adenosis is a rare lesion in control mice, but is occasionally induced in mice with natural or synthetic estrogens (Highman et al., 1980). The squamous epithelium of the vagina is replaced focally by proliferation of glandular elements which may project into the lamina propria (Fig. 186).
Proliferation of the basal cells of the squamous epithelium lining the vagina is occasionally seen in female mice of certain strains. Small pegs of epithelium extend and project into the lamina propria (Fig. 187). In some cases, the epithelium becomes keratinized.
Granular cell tumors occur very rarely as spontaneous lesions but are induced in the vagina of mice with the administration of natural or synthetic estrogens (Highman et al., 1980). They are usually well circumscribed and composed of large cells with prominent acidophilic cytoplasm. The cytoplasm may present a stippled appearance (Fig. 188) which is more prominent with the PAS stain.
Squamous cell carcinomas may develop spontaneously from the squamous epithelium of the vagina, but they are very rare. They readily invade the stroma of the vagina and may locally invade into the urinary bladder. The more differentiated neoplasms form keratin pearls (Fig. 189).
Hydrometra is the marked dilatation of the horns or body of the uterus. Either one or both horns and the corpus may be involved. The lumen contains a serous proteinaceous material and the wall of the uterus is thin and atrophic because of the luminal distension with fluid (Fig. 190). The cause of the dilatation can often not be determined.
Cystic endometrial hyperplasia is a common spontaneous lesion seen in aged female mice. The endometrial glands are cystic and increased in number (Fig. 191). The condition is probably related to abnormal serum hormone levels.
Uterine adenomyosis is very rare in control mice, but can be induced with both natural and synthetic estrogens (Highman et al., 1980). The lesion is characterized by the downgrowth of hyperplastic glands into the myometrium (Fig. 192). The glands may sometimes extend to the serosal surface of the uterus. It must be differentiated from uterine adenocarcinoma.
Prolapse of the uterus through the cervix into the vagina is a rare lesion but is occasionally seen in female mice (Fig. 193).
A decidual uterine nodule is an idiopathic lesion that is occasionally seen in virgin female mice. The lesion is usually singular, morphologically appears similar to a developing embryo and consists of large trophoblastic-like cells.
Leiomyomas rarely occur in the myometrium of the uterus of mice. They are usually small and consist of a single well-circumscribed tumor of smooth muscle cells. The neoplastic cells are elongated with plump, oval nuclei and form whirling fascicles (Figs. 194 and 195). Uterine leiomyosarcomas are also rare and are composed of less-well differentiated smooth muscle cells producing and whirling pattern (Fig. 196) and invade serosal and epithelial tissues. Some features of anaplasia are present and the mitotic index may be high.
Uterine polyps are extremely common in certain strains of mice such as the BALB/c. They consist of polypoid protrusions of the stroma covered with normal uterine mucosa and may be quite small (Fig. 197), or large (Fig. 198).
These lesions are distinct tumors (Figs. 199 and 200) and must be distinguished from the more common histiocytic sarcoma (Fig. 304). They appear as undifferentiated sarcomas. Some may arise in the stroma of uterine polyps. Their true cell of origin is not known.
Mesotheliomas of the serosal surface of the uterus can be induced with natural and synthetic estrogens (Highman et al., 1980). They form numerous papillary projections and fronds covered by neoplastic mesothelial cells (Fig. 201). The stroma often also contains gland-like structures simulating an adenocarcinoma (Fig. 202). The tumors occasionally invade deeper and may involve all the uterine layers. The neoplasms readily form implants on the viscera and invade other abdominal organs. Occasionally they may metastasize to extra abdominal tissues (Fig. 203).
Uterine adenocarcinoma is a rare spontaneous lesion but may be induced at a low incidence with natural and synthetic estrogens (Highman et al., 1980). The neoplastic glands may be well differentiated (Fig. 204) or show features of anaplasia. The mitotic index may be high. These neoplasms are highly invasive but only rarely metastasize to the lungs (Fig. 205). More rarely, yolk sac carcinomas have also been reported (Stewart et al., 1984), some of which may be of ovarian origin (Majeed et al., 1986).
The mouse has 5 paired sets of mammary glands extending from the ear to the base of the tail. Lesions may occur in any of the individual glands or in all glands. The normal mammary gland of young virgin mice consists of an occasionally isolated gland (acinus) in a stroma of adipose tissue. The glands increase in number and prominence during the estrus stage of the estrous cycle.
Diffuse hyperplasia of the mammary gland becomes especially prominent during late gestation and lactation (Fig. 206), and may be seen in mouse mammary tumor virus infection or in mice without virus infection (Faulkin et al., 1984). The mammary fat pads are completely filled with glands which produce an eosinophilic secretion.
Mammary hyperplastic alveolar nodules (HAN) are focal areas of lobular mammary hyperplasia. These lesions may be single or multiple and consist of a focal collection of hyperplastic glands within an otherwise normal fatty background stroma (Fig. 207); ducts may be distended with eosinophilic secretion. Nodules are visible grossly if large enough, particularly if they are prepared and stained as whole mammary mounts. They are much more common in some strains of mice than others and are believed by some investigators to be precursors of mammary carcinomas, especially in mouse mammary tumor virus infection (Medina, 1973). Occasionally small mammary carcinomas may be present within HAN's (Sass et al., 1982). The incidence of HAN is increased by the prolonged administration of large doses of maternal or synthetic estrogens.
Mammary tumors are commonly classified by Dunn's classification and include mammary adenocarcinoma Type A, B and C; adenoacanthoma; and carcinosarcoma (Dunn, 1959). Other rarer types have been described (Sass et al., 1979). Mammary adenomas and adenocarcinoma Type A (tubular) consist of small uniform glandular (acinar) structures forming a solid pattern (Fig. 208). Adenocarcinoma Type B (papillary-solid) consists of a pleomorphic pattern and often contains numerous cysts filled with secretion (Fig. 209). Adenocarcinoma Type C (mixed) consists of glandular structures embedded in a loose myxomatous structure (Fig. 210), which appears to be myoepithelium. The glands are lined by a single layer of cuboidal epithelium. Adenoacanthomas (adenosquamous carcinomas) consist of a combination of both glandular and squamous patterns in varying proportions (Fig. 211). Carcinosarcoma is composed of a malignant glandular component as well as a malignant mesenchymal component. The mesenchymal portion contains neoplastic spindle cells adjacent to neoplastic glands (Fig. 212). Spindle cells may represent anaplastic epithelium or myoepithelium. Mammary tumors sometimes metastasize to the lung; adenocarcinoma Type B appears most likely to metastasize (Fig. 213).
The incidence and severity of ovarian atrophy increases with age in female mice, and also may be induced with both natural synthetic estrogens (Highman et al., 1977). The atrophic ovary is smaller than the normal counterpart (Figs. 214 and 215), and often contains increased deposits of the lipofuscin pigment, ceroid, which is PAS positive and also acid fast. The atrophy is characterized by a decrease or absence of both follicles and particularly, corpora lutea, and a relative increase in interstitial tissue.
Ovarian cysts may be single or multiple, may vary in size (Fig. 216) and are age-related.
Ectopic pregnancy occurs occasionally in women but appears to be rare in animals. The case illustrated here shows large trophoblasts associated with the ovary of a mouse (Fig. 218), suggesting the past occurrence of an ectopic pregnancy.
Fibrosis of the oviduct may occur occasionally as a spontaneous lesion but is more frequently seen in female mice administered natural or synthetic estrogens (Highman et al., 1977). The mucosa of the oviduct is surrounded by a thickened layer of fibrous connective tissue which stains distinctly eosinophilic and may be partially hyalinized (Fig. 219).
This lesion is characterized by hypertrophied oviductal epithelial cells with prominent eosinophilic cytoplasm (Fig. 220) and nuclei displaced along the luminal surface. The lesion may affect only a few cells or all cells within a single cross section of the oviduct. The lesion rarely occurs spontaneously but can be induced by estrogens (Highman et al., 1977). Figure 222 is an electron micrograph of oviduct hyaline change.
Prominent vacuolization of the epithelial cells lining the oviduct may occur as a spontaneous lesion in aging female mice. The vacuoles are large, clear and occupy nearly the entire cytoplasm of the affected cells (Fig. 221). Figure 223 is an electron micrograph of oviduct vacuolization.
The tubular adenoma (tubular mesothelioma) is the most common naturally occurring ovarian tumor seen in some strains of mice (Frith et al., 1981c; Rehm et al., 1984). This pleomorphic group is characterized by invaginations of mesothelial (or germinal) epithelium into the ovarian stroma, frequently dividing the ovary into multiple lobules. These invaginations usually present as variable sized tubular structures and are lined by simple columnar, cuboidal or occasionally flattened epithelium (Figs. 224 and 225). The much rarer tubular carcinoma is shown in Figure 226.
Serous cystadenomas vary from simple cystic tumors lined by ciliated columnar epithelium to tumors with complex papillary infoldings and slight cellular stratification (Fig 227). The epithelial cells are uniform in appearance, have eosinophilic cytoplasm and oval, basal nuclei. Mitotic figures are rare. These tumors are sometimes associated with tubular adenomas and can be distinguished from them by their cystic pattern and the presence of cilia.
Dysgerminoma is an extremely rare ovarian tumor in the mouse. It consists of solid sheets of polygonal cells subdivided into small fascicles by fine vascularized septa (Fig. 228). The cells have moderately amphophilic cytoplasm and relatively large (20-30 μm diameter) centrally placed nuclei with smooth membranes, a finely granular chromatin pattern and prominent single nucleoli. Mitotic activity is moderate.
Tertomas, usually seen in young mice, are commonly cystic with a mixture of epithelial cell types, including keratinizing squamous epithelium as the most prominent, ciliated tall columnar and small intestinal epithelium. Many of the cyst walls contained compressed corpora lutea and ovarian stroma (Fig. 229). Interspersed between the cysts are variable amounts of well-differentiated nervous tissue resembling that of the cerebral cortex (Fig. 230).
Granulosa cell tumors are characterized by a diversity of morphologic patterns including solid, tubular, diffuse microfollicular and intermediate types. The tumor cells have scanty amphophilic cytoplasm, small ovoid nuclei with coarsely clumped chromatin and single small nucleoli (Fig. 231). Mitoses vary in number from few to numerous. Areas of necrosis may be seen in the large tumors. In the microfollicular type, Cal-Exner-like bodies are seen (Fig. 232). Some granulosa cell tumors contain a prominent thecal component. Granulosa cell tumors are usually unilateral, but they may be bilateral or occur in conjunction with another ovarian tumors. Granulosa cell tumors occasionally metastasize to the lungs (Fig. 233). Some chemicals, especially 7,12-dimethylbenz[a]anthracene, induce granulosa cell tumors after intraperitoneal injection. In SWR/J and SWR/Bm strains, granulosa cell tumors have been found in young untreated mice (Beamer et al., 1985).
Thecomas are a pleomorphic group of ovarian neoplasms and appear to follow a progressive differentiation from purely thecal cells to heavily luteinized cell clusters interspersed between delicate strands of fusiform thecal cells. The principle cell type is fusiform, with an oval nucleus and sparse basophilic cytoplasm (Fig. 234). Luteinization is characterized by increased cell size, faintly eosinophilic, brownish, foamy cytoplasm and a round nucleus with a delicate chromatin pattern (Fig. 235).
Luteomas are generally well circumscribed but not encapsulated, and often involve the entire ovary. They consist of large polygonal cells with a single round nucleus and abundant eosinophilic cytoplasm (Fig. 236) and closely resemble the cells of a normal corpus luteum from which they are in some cases, distinguished with difficulty. The majority of luteomas have few mitotic figures. Mast cells, scattered or in clusters, are common in the luteomas of BALB/c and C57BL/6 strains but less common in those of the C3H strain. There appears to be a transition from the distinctly eosinophilic luteal cells to those with deep brown pigment which give a positive reaction for the pigment ceroid by the periodic acid Schiff (PAS) and acid fast stains.
The Sertoli cell tumor of the ovary is rare and can be distinguished from granulosa cell tumors by the presence of tubules lined by columnar epithelium having basally oriented round nuclei and abundant homogeneous faintly eosinophilic cytoplasm (Fig. 237). These tubules are present in closely set arrays, separated only by thin strands of fibrovascular stroma. Mitotic activity is usually low.
A frequent complication in the diagnosis of vascular tumors in ovaries of mice is the concurrent presence of angiectasis and/or hemorrhagic cysts. An occasional vascular tumor (hemangioma or hemangiosarcoma), is seen in ovaries of mice. The hemangioma consists of capillaries and cavernous vascular channels which contain erythrocytes and are lined by large, plump, pleomorphic endothelial cells (Fig. 238). They differ from angiectasis in that they form nodules or masses.
Hemangiosarcomas are composed of large neoplastic endothelial cells which form small vascular channels as well as solid areas (Fig. 239). Anaplasia may be evident as well as numerous mitotic figures. They occasionally metastasize to the lungs.