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The glomerular tuft of the adult male mouse kidney of certain strains has a unique morphologic characteristic that is not a pathologic lesion. In most animals, the parietal layer of Bowman's capsule is composed of a single layer of flattened epithelium (Fig. 240). In the male mouse, the parietal layer of most of the glomeruli is composed of simple cuboidal epithelium (Fig. 241). The characteristic is seen only in adult male mice and is not present in each glomerulus. The proportion of glomeruli showing this characteristic varies in different strains.
The kidney of the mouse contains a single large renal papilla surrounded by the renal pelvis. Very rarely, a congenital anomaly consisting of a double renal pelvis may occur (Fig. 242).
Renal infarcts in the mouse are morphologically comparable to renal infarcts in other species. They quite commonly appear as triangular shaped areas of coagulation necrosis which extend from the capsular surface through the cortex to or into the medulla (Fig. 243). The tubules may be intensely eosinophilic, and fibrosis may be present in older lesions. The surface of the infarct is depressed below the normal renal surface. In recent lesions, polymorphonuclear leukocytes may infiltrate the border and some tubules may contain hemoglobin casts.
Necrosis of the renal papilla may occur in the mouse kidney (Fig. 244) and is usually associated with renal amyloidosis or toxins.
Hydronephrosis may follow obstruction of one or both ureters or the urethra of the urinary bladder. Causes of hydronephrosis include calculi, tumors or inflammation (Bendele and Carlton, 1986). It may be minimal and result in only a slight dilatation of the renal pelvis (Fig. 245), or it may be severe enough to cause marked compression atrophy of the kidney. Hydroureter may be present proximal to the blockage.
Polycystic kidney is a congenital lesion which may be hereditary in the BALB/c mouse. It affects both sexes and is usually fatal at 3 weeks of age. Grossly, the kidneys are markedly enlarged and microscopically contain multiple cysts of varying size (Fig. 246).
Chronic renal disease (nephropathy) is a common entity in rats but is seen much less frequently in mice. The lesion is characterized by the presence of numerous proteinaceous casts within the tubules and areas of tubular atrophy, regeneration and dilatation, interstitial fibrosis and chronic inflammation (Fig. 247). The degree of nephropathy may be graded as minimal, mild, moderate or severe. The cause is unknown.
This lesion is characterized by proliferation of the mesangial cells of the glomeruli and thickening of glomerular basement membranes. The severity may vary from mild to marked. An eosinophilic homogeneous material is present within the glomeruli (Fig. 248). The etiology of this disease is unknown, but it may be auto-immune or viral in origin. It occurs sporadically in most mouse strains.
This disease is very rare in mice, except in certain strains (Andrews et al., 1978). Various degrees of membranous glomerulonephritis are seen. The capillaries of the renal glomeruli have thickened basement membranes and are distended and filled with fibrin thrombi or hyaline, and dark basophilic material (Fig. 249) staining positive for DNA with the Feulgen stain.
This lesion may be somewhat similar morphologically to membrano-proliferative glomerulonephritis and must be distinguished by special stains. The glomeruli are enlarged and contain focal, nodular or diffuse deposits of eosinophilic homogeneous material (Fig. 250). The amyloid can be confirmed by staining with crystal violet, Congo red or thioflavin T (Fig. 251). Renal amyloidosis may occur only in the kidney or be systematic and occur in many tissues. Renal papillary necrosis is a frequent characteristic of murine renal amyloidosis.
Mineral concretions may occur in the renal pelvis of mice. The lesion is uncommon, and the stones have not been characterized chemically. Calculi consist of concentric laminations of basophilic material (Fig. 252).
Most renal tubular cell adenomas are singular and can be morphologically classified as cystic, papillary, or solid (Shinohara and Frith, 1980). The papillary type is the most common and exhibits a pronounced papillary pattern (Fig. 253). If the pattern appears predominantly cystic without prominent proliferative papillary pattern, the adenoma may be classified as cystic. The cells forming the adenomas are uniformly cuboidal with eosinophilic cytoplasm and relatively small nuclei. Mitotic figures are rare. The cystic and papillary adenomas are usually encaspulated. Some adenomas form a solid pattern and are classified as solid type. They are usually well demarcated from adjacent renal parenchyma, but are not encapsulated. Cells primarily form a solid pattern interspersed with a small amount of fibrous connective tissue containing blood capillaries. The cytoplasm of the cells forming the solid adenomas is usually acidophilic, and the nuclei are small. Adenomas may grow in size and progress to carcinomas (Shinohara and Frith, 1980). They may originate from focal tubular hyperplasia.
Renal cell carcinomas may occur as spontaneous lesions (Frith and Shinohara, 1980) or as induced lesions (Lombard et al., 1974). They may be solid, tubular or anaplastic in morphologic pattern. Tubular cell carcinomas are composed of epithelial cells with either granular eosinophilic- (Fig. 254) or basophilic-staining cytoplasm. The cells vary from small and uniform to large and pleomorphic. The nuclei are usually small and round or oval in the uniform cells, but show various sizes and shapes and prominent nucleoli in the pleomorphic cells. The mitotic index in the tubular cell carcinomas varies from tumor to tumor. The arrangement of tumor cells in these carcinomas shows a basic tubular pattern. Sometimes these tumors form irregular tubular structures composed of tumor cells with various sizes and shapes. Mitoses are frequent, and sometimes, single or multiple cyst-like structures with pale eosinophilic material are seen.
Tubular cell carcinomas may be anaplastic and consist of pleomorphic cells that form irregular tubular structures. Some of these tumors contain areas of sarcomatous change. The nuclei tend to be hyperchromatic and multinucleated giant cells are common. The mitotic index is high, and areas of necrosis and/or hemorrhage are common. Carcinomas occasionally metastasize to the lungs (Fig. 255).
Diverticula are not common in the mouse but have been associated with inflammation and the administration of 4-ethylsulfonylnaphthalene-1-sulfonamide (ENS), acetazolamide, and oxamine (Jackson et al., 1979; Frith et al., 1984). The lesion exists as a down-growth into the urethral wall which may be confused with a carcinoma (Fig. 256). Downgrowth of the surface epithelium may extend through the muscularis to the adventitia. The lesion appears to be associated with the crystalluria produced by ENS.
Histologically, the transitional epithelium of the normal urinary bladder of the mouse consists of three distinct layers (Fig. 257) (Frith, 1979). The cells in the basal layer have clear cytoplasm and are the smallest. The cells of the second layer are slightly larger. The cells forming the surface layer are the largest, have distinctly granular eosinophilic cytoplasm and often extend over and cover a number of cells in the second layer. The nuclei of the surface layer are extremely large, are often binucleated, and have been shown to be polyploid (Walker, 1958). The subepithelial tissue consists of capillaries and lymph vessels in a fibrous stroma that lies directly on the muscular coat. Ultrastructurally, scanning electron microscopy reveals that the surface cells routinely have fix to six sides and are similar in size and shape (Fig. 264; Ayres et al., 1985). With transmission electron microscopy, the urothelial cells contain prominent fusiform vesicles in the cytoplasm which are believed to allow for expansion of the transitional epithelium when the urinary bladder enlarges (Fig. 265).
Crystalluria is often associated with alkaline urine and the administration of such compounds as 4-ethylsufonylnapthalene-1sulfonamide (ENS; Jackson et al., 1979; Frith et al., 1984). Another form of crystalluria has been seen to occur spontaneously with a low incidence in both male and female mice of several strains. These crystalline spherules are more common in the male mouse and are usually associated with distended bladders. The spherical crystals are birefringent (Figs. 258 and 259), acid fast, and PAS positive. Their etiology is currently unknown, although they contain cholesterol.
Urinary calculi may occur spontaneously or may be associated with the administration of such compounds as ENS (Jackson et al., 1979; Frith et al., 1984). The calculi are usually accompanied by a chronic cystitis and may also result in papillary and nodular urothelial hyperplasia (Fig. 260).
Focal lymphoid aggregates may occur in the lamina propria of the urinary bladder (Fig. 261). Their incidence and severity increase with age.
The microscopic evaluation of hyperplasia of the urinary bladder can be better performed in urinary bladders that have been inflated with fixative. The fixative can be instilled through the urethra with a 22-23 gauge needle. It may be necessary to ligate the neck of the bladder after inflation to prevent loss of the fixative. The bladder can be bisected after fixation, examined grossly with a dissecting microscope and then processed for microscopic evaluation.
Hyperplasia of the transitional epithelium of the mouse urinary bladder is a rare spontaneous lesion, but a common finding in animals treated with bladder carcinogens and may be either focal, multifocal, diffuse, simple, papillary, or nodular (Frith, 1979). Hyperplasia may also be associated with chronic cystitis, calculi formation, and in response to such toxic compounds as cyclophosphamide or methyl and ethyl methanesulphonate. Simple hyperplasia may be either focal or diffuse and mild, moderate or marked. Lesions may be classified as mild hyperplasia when the urothelium averages four transitional cell layers in thickness, as moderate hyperplasia when it averages five to six cell layers (Fig. 262), and marked hyperplasia when it averages seven or more cell layers. Figures 266 and 267 are electron micrographs of urothelial hyperplasias showing increases over the normal 3-cell layers.
Papillary hyperplasia differs from simple hyperplasia in that the surface is papillary rather than flattened or squamous. Papillary hyperplasia in mice occurs much less frequently than in rats.
Focal nodular hyperplasia (epithelial downgrowths) may occur in conjunction with either simple or papillary hyperplasia and consists of nodular downgrowths which extend into the lamina propria of the bladder (Fig. 263). It may be focal or multifocal. Nodular hyperplasia is comparable morphologically to von Brunn's nests or cystic cystica in man (Frith, 1979). Although the areas of nodular hyperplasia often appear to have no connection with the surface epithelium, serial sections usually reveal such a connection. The lesion may regress if the etiologic stimulus is removed (Frith and Rule, 1978).
Naturally occurring benign epithelial lesions of the urinary bladder are rare in mice and occur as papillary formations projecting into the lumen. The epithelium shows no pleomorphism, atypia, or anaplasia and is well differentiated. Papillomas induced with 2-acetylaminofluorene (2-AAF) may have a slender narrow stalk (Fig. 268) or a broad base (Fig. 269; Frith et al., 1983b).
Naturally occurring bladder carcinomas are extremely rare in mice (Frith et al., 1980d). Experimentally induced malignant neoplasms of the urothelium are classified according to the histologic pattern, cell type, and depth of invasion (Frith et al., 1980d). Malignant epithelial lesions classified by histologic pattern may be divided into papillary and nonpapillary (solid, polypoid) carcinomas. Papillary carcinomas project into the lumen and may or may not show invasion (Frith et al., 1980d). Non-papillary or solid carcinomas grow down into (invade) the bladder wall.
Bladder carcinomas classified according to histologic cell type are divided into transitional cell (Fig. 270), transitional cell with squamous metaplasia (Fig. 271), squamous, undifferentiated, and adenocarcinoma types. The most common type induced is the transitional cell carcinoma, but this may depend on the type and the dose level of the carcinogen (Frith et al., 1980d).
Transitional cell carcinoma with squamous metaplasia and squamous cell carcinomas tend to be more aggressive and infiltrative than transitional cell carcinomas (Frith et al., 1980d). Urinary bladder carcinomas commonly invade locally but only very occasionally metastasize to the lungs (Fig. 272).
Undifferentiated carcinomas are also rare and may be difficult to distinguish from mesenchymal tumors (Fig. 273). Tumor giant cells and large eosinophilic neoplastic cells with large nuclei and prominent nucleoli may be seen.
Experimentally induced primary mesenchymal tumors of the mouse urinary bladder occur much less frequently than epithelial tumors. The most common are the vascular tumors such as hemangioma (Fig. 274) and hemangiosarcoma (Fig. 275). Hemangiosarcomas may occasionally occur in conjunction with transitional cell carcinomas. Mesenchymal tumors of muscle origin are extremely rare. Occasionally tumors resembling sarcomas are seen, but these may be undifferentiated carcinomas.
Metastatic tumors of the urinary bladder are rare and usually are the result of extension of malignant tumors from adjacent organs, especially from uterine adenocarcinomas and vaginal squamous cell carcinomas. Malignant lymphomas may also occur in the urinary bladder as part of a systemic disease.
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