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An unusual feature of the adrenal gland of young mice is the transient X-zone (Fig. 114) that surrounds the medulla. The cytoplasm of the cells in this X-zone is conspicuously more basophilic than the cytoplasm of cells of the zona fasciculata. In males, the X-zone appears at about 10 days postpartum and disappears rapidly without undergoing vacuolization as sexual maturity is reached at approximately five weeks of age. In females, the zone disappears at first pregnancy, but in virgin female mice, it may be visible for up to 30 weeks. The zone undergoes prominent vacuolization in the female (Fig. 115), in contrast to events that occur in the male (Dunn, 1970). It is important to be aware of this entity and not mistakenly consider it a pathologic change. The X-zone appears to be analogous to the fetal cortex in humans (Howard-Miller, 1926). Figure 122 is an electron micrograph of normal mouse adrenal cortex showing prominent mitochondria and lipid droplets, and Figure 123 is an electron micrograph of normal mouse adrenal medulla showing characteristic secretory granules.
Small accessory adrenocortical nodules may sometimes be seen associated with the capsule of the adrenal cortex (Fig. 116). The nodule contains only cortical cells and no medullary tissue.
The adrenal gland of the aged mouse may contain subcapsular focal hyperplastic areas composed of spindle cells (Goodman, 1983). The exact origin of these cells is not known. The spindle cells are basophilic with sparse cytoplasm and indistinct cytoplasmic borders (Fig. 117).
The deposition of ceroid or lipogenic pigment in the adrenal gland is strongly strain and age-related (Frith, 1983d). It initially occurs in cortical epithelial cells and macrophages near the corticomedullary junction and eventually encircles the medulla (Fig. 118). Small amounts of the pigment appear as granular to amorphous yellowish-brown material in the cytoplasm of the epithelial cells and macrophages. When the amount of pigment increases in each cell, the cytoplasm becomes distended, brown and foamy in appearance. Nuclei may become pyknotic and the pigmented cells resemble macrophages. Sometimes the cells fuse to form multi-nucleated giant cells. Occasionally, cells containing the pigment extend into the medulla. The pigment stains red following the periodic acid Schiff reaction (PAS) (Fig. 119) and is also acid fast.
An examination of the ultrastructural aspects of the pigment (Samorajski and Ordy, 1967) revealed cytoplasmic particles of various sizes and electron density. The authors suggested that the pigment originated in cells of the inner cortex and that it was primarily of endogenous origin. It was also reported that the quantity of pigment increased with age and that many of the cells coalesced to form multi-nucleated cells with unusually large pigment inclusions. Reactions specific for lipid pigment included positive staining for sulfatides, peroxidases and vicinal polyhydroxyl groups. Figures 124 and 125 are electron micrographs demonstrating clumps of ceroid pigment in the cytoplasm of adrenal cortical epithelial cells.
Two distinct morphologic types of adrenocortical adenomas occur in mice. Dunn (1970) referred to the cells forming the tumors as Type A and Type B cells. The type A tumors (spindle cell adenomas) are composed of ovoid or spindle to fusiform cells with ovoid nuclei. These tumors appear to develop from the subcapsular spindle cell reaction (Fig. 117), and are commonly reported in mice (Dunn, 1970). The morphologic appearance of these tumors suggests that they may be of mesenchymal rather than epithelial origin. Recent ultrastructural findings, however, suggest that they are of adrenocortical epithelial origin (Frith, 1983c). Adenomas with the morphologic Type A pattern are usually small and are often not seen grossly. They are well delineated from and may compress the adjacent normal cortex (Fig. 120).
Type B adenomas (solid adenomas) are composed of more polygonal cells which are irregular in size and arrangement and may be vacuolated (Dunn, 1970). The cells are similar in appearance to normal adrenocortical cells, making the Type B tumors more easily recognizable as originating from epithelial adrenocortical cells (Fig. 121). The tumors are well delineated from adjacent normal cortex. Mixtures of the Type A and Type B cells may occur in some of these adenomas. Mast cells are often associated with the Type A tumors and are intermingled with the tumor cells. The mitotic index of both types of adenomas is very low.
Carcinomas composed of either the Type A (spindle cell) or Type B (solid cells) also occur (Frith, 1983c). These appear to develop in a continuous spectrum from the adenomas. Type A carcinomas also have small numbers of mast cells mixed with the neoplastic adrenocortical cells (Fig. 126). The tumor cells of carcinomas are larger in size, more pleomorphic and have a higher mitotic index than the adenomas (Fig. 120). The Type B carcinomas (Fig. 127) occasionally metastasize to the lungs (Fig. 128), but the exact frequency of metastases of the two specific types is not known.
Few studies have been conducted on the ultrastructure of adrenocortical tumors of mice. One Type A carcinoma (Frith, 1983c) was large (20 mm) and occurred in a BALB/c female mouse 562 days of age. Large lipid droplets were present in the cytoplasm of the neoplastic cells (Fig. 134), and desmosomes (Fig. 135) were also evident. The presence of the lipid and desmosomes suggests that the Type A cell is both epithelial and adrenocortical in origin.
Hyperplasia of the adrenal medulla may be diffuse or focal. In the diffuse form, the medullary cells are increased in number and volume, resulting in expansion of the entire medulla (Fig. 129). This puts pressure on the surrounding cortex but does not cause recognizable zones of compression. Atrophy of the cortex may result; however, pressure necrosis is not evident. The hyperplastic cells of the medulla may extend into the cortex.
Focal hyperplasia is first recognized by increased basophilia of the cytoplasm and increased size of affected cells, distinguishing them from adjacent medullary secretory cells. The nucleus-to-cytoplasmic ratio may be increased in the hyperplastic cells. These hyperplastic cells may impinge upon cells of the adrenal cortex but do not visibly compress them. Some of these lesions may represent the earliest stage of pheochromocytoma formation.
Pheochromocytomas are composed of relatively uniform polyhedral cells clearly resembling normal medullary secretory cells with central nuclei and finely stippled cytoplasm (Frith, 1983b). The tumor cells are found in cords separated by a delicate stroma into which many capillaries extend. As the tumors become larger, the stroma tends to be less conspicuous and the capillaries are distended with blood. The cytoplasm of the neoplastic cells, stained with H & E, is more basophilic than in normal medullary cells, but the tinctorial characteristics of these cells vary greatly.
These neoplasms originate in the adrenal medulla and may replace a portion of or the entire medulla. They are more sharply delineated from the adjacent medulla than are foci of hyperplasia, possibly due to compression of the normal tissue, but are not usually encapsulated. A pheochromocytoma may be encountered which has grown sufficiently to replace a large portion of the adrenal cortex and to expand or penetrate the adrenal capsule. Some may extend into the perirenal adipose tissue, and into the lumen of blood vessels. Foci of necrosis may occur in the tumor, and bizarre nuclei or distorted cells may appear. The mitotic index varies from one tumor to another and is not a particularly good indicator of malignancy; rather, tumor size is associated with pulmonary metastases. Large, well-differentiated but malignant pheochromocytomas (Fig. 130), may sometimes metastasize to the lungs (Fig. 131). Pheochromocytomas may be bilateral.
Ganglioneuromas occasionally occur in the adrenal medullas of mice. They are characterized by the presence of numerous large neuronal or ganglion cells (Figs. 132 and 133). Ganglioneuromas may sometimes occur in conjunction with pheochromocytomas.
Small cysts may be present primarily in the pars distalis of the pituitary gland. The cysts may be single or multiple. They may be lined by ciliated epithelium and sometimes contain an eosinophilic colloid-like secretion (Fig. 136).
This lesion occurs occasionally in aging controls, but occurs earlier and increases in frequency with increasing doses of natural and synthetic estrogens (Andrews et al., 1980). Focal degeneration and loss of cells in the pars distalis results in small irregular spaces often containing some eosinophilic material administered with cellular debris (Figures 137 and 138). Figures 144 and 145 are electron micrographs showing cellular debris and a lack of an endothelial lining.
Hyperplasia of a variety of cell types may occur in the pituitary, most commonly in the pars distalis, but the specific cell type may be difficult to identify on light microscopy. Immunocytochemistry should be used to identify hormones present in tumor cells when required. The cytoplasm of the affected cells may vary in tinctorial properties. The lesion is focal, but the periphery of the lesion is not well delineated (Figs. 139 and 140). Some of these foci appear to represent the earliest stage of adenoma formation.
Pituitary tumors arising from the pars distalis may occur at a relatively high incidence in some strains of mice (i.e. C57BL/6), and are more common in female mice (Schechter et al., 1981). Pituitary adenomas are much more common than pituitary carcinomas. Adenomas are distinguished from pituitary hyperplasia by being well-delineated and causing compression of adjacent normal cells (Fig. 141). It is generally not possible to identify the specific cell of origin without special stains or immunocytochemistry. Most mouse pituitary tumors in C57BL/6 mice and probably other strains are composed of prolactin (Fig. 142) cells and are thus similar to prolactinomas in humans and rats. Pituitary carcinomas appear much more anaplastic and may invade the base of the brain (Fig. 143). Tumors of the pars intermedia are rare, and are characterized by large cells with pale staining cytoplasm.
Ectopic thyroid tissue in the mouse may be found at the base of the heart in multilocular fat (Frith, 1983e). The tissue consists of a group of isolated thyroid follicles similar in appearance to normal thyroid tissue. The follicles are lined by a single layer of low cuboidal epithelium and are filled with eosinophilic colloid (Fig. 146). Ectopic thyroid tissue results from the failure of all or part of the thyroid anlage to descend from the floor of the pharynx to its cervical location (Ficarra, 1958).
Birefringent crystals are occasionally seen in the lumen of thyroid follicles of mice (Figs. 147 and 148) and have been identified in humans as calcium oxalate.
Focal follicular hyperplasia of thyroid follicles is characterized by a focal increase in the number of and appearance of thyroid follicles. The cytoplasm of the hyperplastic follicles is usually slightly more basophilic, and the epithelium is taller than in normal follicles (Fig. 149). An occasional mitotic figure may be evident. The hyperplastic area is usually focal and not well delineated. Cystic distension of the ultimobranchial bodies, in most mouse strains, may mimic follicular hyperplasia (Rehm et al., 1985a).
Thyroid tumors are usually of follicular or parafollicular (C-cell) origin. C-cell tumors are rare in mice (van Zweiten et al., 1983). Follicular cell adenomas usually occur as single well-delineated lesions within the normal thyroid. Three distinct morphologic types of follicular cell adenomas are seen in the mouse (Frith and Heath, 1983). The most common type is the papillary adenoma. These are usually small and the follicular epithelium presents a distinct papillary pattern which may project into a cystic lumen (Fig. 150). The follicular epithelium is cuboidal, the cytoplasm stains slightly more basophilic than adjacent normal thyroid, and colloid may be present within the lumens of the follicles.
The second type is the micro-follicular adenoma. The cells are similar to the papillary adenoma but distinct follicles are present with little or no papillary pattern (Fig. 151). The neoplastic follicles may contain colloid. The third type is the solid adenoma which is composed of solid sheets of cells with distinctly eosinophilic cytoplasm. Thyroid follicles are rarely formed in the tumor and colloid formation is minimal. Immunoperoxidase staining may be necessary to distinguish the solid adenomas from C-cell adenomas. The mitotic index is extremely low in all three types of thyroid adenomas.
Three general histomorphic types of mouse follicular cell carcinomas have been recognized: solid, papillary and follicular (Heath and Frith, 1983). It should be emphasized that these distinctions are occasionally arbitrary: it is not uncommon for a carcinoma to contain areas of two or perhaps all three of the histologic types, in which case the classification must depend upon which component comprises the major portion of the tumor.
Solid carcinomas consist of solid sheets or closely packed lobules of tumor cells, which invade or occasionally compress the adjacent thyroid follicles or adnexal structures. The size and tinctorial features of the individual cells may vary between tumors, but usually the cell nuclei are rounded and larger than those of normal follicular cells and contain rather densely aggregated chromatin. Mitotic figures may not be numerous except in more anaplastic tumors. The cell cytoplasm is usually more slightly basophilic and may be finely vacuolated. Residual follicles occurring singularly or in groups may be seen among the sheets or packets of tumor cells, and occasionally tumor cells are observed in direct continuity with these isolated follicles. Some solid carcinomas are comprised of larger cells than those described above; they contain more abundant eosinophilic cytoplasm (Fig 152), suggestive of a "hepatoid" appearance or of an oxyphil cell. Immunoperoxidase staining may be necessary to distinguish the solid carcinomas of follicular cell origin from C-cell carcinomas.
Papillary carcinomas consist of tumor cells arranged in irregular papillary infoldings which project into cystic spaces of varying size lined by tumor cells and often containing a faintly eosinophilic colloidal-like material. These infoldings often consist of two or more layers of cells which are larger than normal follicular cells and which may show extensive pleomorphism. Tumors of this type frequently contain confluent or intermingled areas of a "follicular" component, which in some instances may be difficult to distinguish from the papillary portion (Figs. 153 and 154).
Carcinomas of the follicular type are comprised of neoplastic cells which form follicles or follicular structures of varying sizes. The lumina of these structures are often devoid of colloid and are frequently smaller in diameter than those of normal follicles. The individual cells forming the follicles resemble those described in the solid type carcinomas and the area between the follicles contains similar appearing cells. These interfollicular zones, when extensive, often appear indistinguishable from solid type carcinomas. Metastases of thyroid carcinomas are rare in mice.
Three medullary thyroid carcinomas (C-cell carcinoma) have been described in the BALB/c female mouse (van Zweiten, et al., 1983). The neoplasms presented grossly as unilateral spherical masses. Histologically, they were composed of large solid nests of cells separated by delicate connective tissue septa (Figs. 155 and 156). They were similar to solid carcinomas. Cells in all three tumors contained immunoreactive calcitonin (Fig. 157) and two contained somatostatin. Figures 162 and 163 show normal C-cells and Figures 164 and 165 are electron micrographs of a medullary C-cell carcinoma. Note the secretory granules in the cytoplasm in both the normal and neoplastic C-cells.
Ectopic parathyroid tissue in the mouse may be found in the septa or surface connective tissue of the thymus (Frith and Fetters, 1983). It is surrounded by a delicate fibrous capsule which extends into and separates the tissue into small packets (Fig 158). Small capillaries are present in the septa. The packets are composed of polygonal cells with prominent vesicular nuclei and scant lightly basophilic cytoplasm.
The parathyroid of the mouse is so small that it cannot be seen grossly. Consequently, it is not routinely examined microscopically and a true incidence of lesions is not available. Cysts of the parathyroid are occasionally seen (Fig. 159).
These lesions are rare in mice. Figure 160 shows the bilateral enlargement of the parathyroids. This lesion occurs much less frequently in mice than in rats. The most common cause of bilateral hyperplasia is chronic renal disease. Figure 161 shows a rare parathyroid adenoma.
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