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Salivary Glands

Gross Anatomy and Histology

The mouse, as well as many other species, has three paired salivary glands - submaxillary (submandibular), parotid, and sublingual (Frith and Townsend, 1985). All three major salivary glands are closely associated and located in the subcutaneous tissue of the ventral neck area. The submaxillary are the largest and easiest of the salivary glands to identify grossly. They are lobulated, extend posteriorly to the sternum and clavicle, anteriorly to the hyoid bone, and medially to overlap slightly on the median line. Submaxillary salivary glands of male mice are larger and more opaque than those of females. The much smaller sublingual salivary glands are closely associated with the anterolateral surface of the submaxillary salivary glands. The parotid salivary glands are lobulated and the most diffuse of the three salivary glands. They extend from the base of the ears, where they overlie the morphologically similar exorbital lacrimal gland, posterior to the clavicle.

The parotid salivary glands are classified as serous glands, the sublingual salivary glands as mucous glands and the submaxillary (submandibular) as mixed glands. The salivary glands secrete saliva which has both a chemical and a mechanical function. The mucous secretion aids in swallowing of food and keeping the mouth moist, and the serous secretion adjusts pH, dilutes food, makes it possible to taste food and hydrolyzes the carbohydrates.

Sexual Dimorphism

The submandibular or submaxillary salivary gland is distinctly different morphologically in adult male and female mice. Immature mice of both sexes present a pattern similar to that in adult female mice, suggesting that the difference in adult males is due to the production of testosterone. In the female mouse, the acini are small and epithelial cells have centrally located nuclei and only a few cytoplasmic granules (Fig. 18). In the adult male, the acini are much larger and the tall columnar lining epithelial cells have basally located nuclei and abundant eosinophilic cytoplasmic granules (Fig. 18). Figures 26 and 27 are electron micrographs of the male and female submaxillary salivary glands, respectively, showing the much more prominent secretory granules in the male than in the female.

Lobular Hyperplasia and Atrophy

Lobular hyperplasia and atrophy are seen in both the submaxillary and parotid salivary glands, but are rare in the sublingual. The lesion commonly involves a single lobule in which some acini are atrophied and replaced by hyperplastic ducts (Fig. 19).


Myoepithelioma of the salivary glands is rare in mice except in some strains (Peters et al., 1972; Delaney, 1977). The neoplasm may occur at a low incidence in the BALB/c mouse and is more common in the female. It develops most frequently in the submaxillary or parotid salivary glands and is rare in the sublingual gland. Myoepitheliomas have also been reported in the human parotid gland (Leifer et al., 1974). The myoepithelioma is believed to be derived from the myoepithelial cells in the salivary glands. The tumors become quite large and grossly are often cystic. Microscopically, they are composed of large pleomorphic cells suggesting both an epithelial and a mesenchymal origin (Fig. 20). The larger tumors commonly metastasize to the lung. Normal myoepithelial cells around glands and the tumor cells stain for the intermediate filament proteins, keratin (Fig. 21) and vimentin (Fig. 22).

Ultrastructurally, the cytoplasm of the neoplastic cells contain clumps of fibrils (Fig. 28) and numerous desmosomes are seen at the cell membranes (Fig. 29).

Other Tumors

Spontaneous tumors of the mouse salivary glands other than myoepitheliomas are extremely rare. Figures 23 and 24 are adenomas of the submaxillary salivary gland and Figure 25 is an adenocarcinoma of the parotid salivary gland which metastasized to the lungs. Mouse polyoma virus causes salivary gland tumors including a mesenchymal, an epithelial and a mixed epithelial-mesenchymal type (Dawe, 1979).


Acinar Atrophy and Fatty Replacement

Atrophy of the acinar pancreas with fatty replacement occurs at a low incidence in mice and may be lobular or diffuse. The existing islets appear normal and are embedded in a stroma of adipose tissue (Fig. 30). Occasionally, the adipose tissue contains a chronic inflammatory cell infiltrate. The occurrence of the lesion only in aged mice suggests that it is a true atrophy and not a hypoplasia.

Islet Cell Hyperplasia

Hyperplasia of the pancreatic islets usually involves more than one islet (multifocal), and may involve all islets visible in a histologic section. Certain mouse strains have high incidences of this lesion (Sass et al., 1978). The islets are much enlarged due to an increased number of cells (Fig. 31), which morphologically are similar to those in smaller normal islets. The specified cell type is difficult to identify at the light microscopic level, and the histochemistry and electron microscopy are often needed. Immunoperoxidase staining of the hyperplastic islets has revealed that most of the cells contain insulin (Fig. 32) and some contain somatostatin (Fig. 33). Fig. 34 shows a hyperplastic islet stained for glucagon. Ultrastructural features have rarely been reported in murine islet cells hyperplasia due to the scarcity, as well as the inability to recognize the hyperplasia grossly. Like et al. (1965) reported ultrastructural features of enlarged islets in (C3HfxI)F1 mice. The cells contained increased rough endoplasmic reticulum, polysomes, free ribosomes and mitochondria, enlarged Golgi zones and depletion of beta granules.

Islet Cell Adenoma

Islet cell adenomas in mice commonly involve a single islet within a histologic section (Frith and Sheldon, 1983), are larger than hyperplastic islets and compress adjacent normal pancreas. The cells form ribbons along sinusoidal, thin-walled vessels and the adenomas often appear more vascular (Fig. 35) than hyperplastic islets. The cells stain lightly eosinophilic with hematoxylin and eosin; the nuclei demonstrate a delicate chromatin pattern. The cells are well differentiated, and mitotic figures are few in number.

Islet Cell Carcinoma

Islet cell carcinomas are invariably larger than adenomas and are commonly visible grossly. The cells vary from well-differentiated cells to extremely pleomorphic and anaplastic cells (Frith and Sheldon, 1983). Well-differentiated islet cell carcinomas (Fig. 36) usually invade locally and occasionally metastasize. Most tumors are probably insulinomas. The authors identified one that contained somatostatin (Fig. 37). The cytoplasm of the neoplastic cells is eosinophilic and the nuclei are vesicular. Nucleoli are prominent and may be multiple. Mitotic figures are evident and pleomorphism may be prominent. Some anaplastic carcinomas may be difficult to classify with certainty as islet cell in origin.

Acinar Cell Tumors

Acinar cell tumors have been described in the rat (Boorman and Eustis, 1985), but they are extremely rare in the mouse (Prejan et al., 1973; Cavaliere et al., 1981).


Esophageal Rupture

Rupture of the esophagus is seen in mice as a result of oral intubation and gavage. If the animal survives, an associated inflammatory reaction is present. The lesion is usually fatal.

Papilloma and Squamous Cell Carcinoma

Papillomas and squamous cell carcinomas have been reported in the rat (Cardesa and Ovelar, 1985; Ovelar and Cardesa, 1985), but appear to be rare in the mouse. The experimental production of papillomas has been reported in the mouse (Horie et al., 1985).


Normal Anatomy

The stomach of both the mouse and the rat is divided into a glandular (forestomach) and a nonglandular stomach. The two regions are separated by a ridge around the entrance of the esophagus. The ridge is formed by the thickened lamina propria of the nonglandular stomach. The nonglandular stomach is lined by stratified squamous epithelium, and the glandular stomach is lined by glandular epithelium. The glandular region contains three types of glands: cardiac, pyloric, and fundic.

Glandular Hyperplasia

Hyperplasia of the glandular gastric mucosa may occasionally be seen in mice (Rehm et al., 1987). The lesion may be either focal (Fig. 38) or diffuse in nature.

Adenoma and Adenocarcinoma of the Glandular Stomach

Adenoma and adenocarcinoma of the gastric mucosa are rare in mice. Adenomas are usually well circumscribed and delineated from normal mucosa (Fig. 39). The cells within the adenomas are well differentiated. Gastric adenocarcinomas are invasive and infiltrate into the lamina propria and muscularis (Fig. 40).

Squamous Cell Hyperplasia of the Forestomach

The forestomach (nonglandular stomach) of the mouse is lined by stratified squamous epithelium which may occasionally become hyperplastic (Fig. 41). This lesion may result from the oral administration of toxic irritants.

Squamous Cell Papilloma and Carcinoma of the Forestomach

Squamous cell papilloma and carcinoma occur in the nonglandular stomach. Papillomas are composed of a stalk with a vascular connective tissue core covered by neoplastic squamous epithelium (Figs. 42 and 43). Squamous cell carcinomas are usually relatively well differentiated and produce keratin. They are locally invasive (Fig. 44) and may occasionally metastasize to the lungs (Fig. 45).



Amyloid deposition in the lamina propria of the small intestine is a rare lesion in mice, except in some strains. Amyloid is homogeneous, stains intensely eosinophilic with H & E stains (Fig. 46), and is identified with the use of Congo red, crystal violet or thioflavin T stains (Fig. 47).

Intussusception and Rectal Prolapse

Intussusception may occur in both the large and small intestine (Fig. 48) and may lead to intestinal obstruction, inflammation, necrosis and death. Prolapse of the rectum may be associated with a pinworm infestation or Citrobacter infection (Barthold, 1978); it is characterized by an eversion of the mucosal surface of the rectum exposed through the anus.


Pinworms in mice commonly involve two species Syphacia obvelata and Aspiculuris tetraptera. They are usually found in the colon and sections of the parasite may be seen microscopically in the colonic lumen of infected mice (Fig. 49). Pinworms are not usually associated with any pathologic changes in the large intestine, but occasionally intussusception or rectal prolapse may occur.

Adenoma and Adenocarcinoma

Adenomas of the small intestine are frequently small and may not be detected if the intestine is unopened during gross examination. They are especially common in the duodenum. Microscopically, the adenoma appears as a polypoid epithelial growth projecting into the lumen of the intestine. The epithelium is relatively well differentiated, but usually appears more basophilic than adjacent normal epithelium (Figs. 50 and 51).

Adenocarcinomas are composed of more anaplastic or pleomorphic cells which may project into the lumen as well as infiltrate into and beyond the submucosa and tunica muscularis. Adenocarcinoma frequently are cystic or papillary (Fig. 52) and microscopically show many mitotic figures.

Leiomyoma and Leiomyosarcoma

Smooth muscle tumors of the small intestine are relatively uncommon. Leiomyomas are usually well circumscribed lesions composed of well differentiated smooth muscle cells. Leiomyosarcomas are not well circumscribed and neoplastic smooth muscle cells may infiltrate the submucosa and serosa (Fig. 53).


Extramedullary Hematopoiesis

Extramedullary hematopoiesis (myeloid metaplasia) is normally present in both the fetal and neonatal mouse liver. The lesion may also occur in the adult mouse liver secondary to either an infectious disease or neoplasia. When the predominant cell type is the granulocyte, granulopoietic hyperplasia may be specified (Fig. 54), and if nucleated erythrocytes are the prominent cells, erythropoietic hyperplasia is an appropriate term (Fig. 55). In the mouse liver, the granulocytic activity seems maximal in the sinusoids adjoining the portal vein (Dunn, 1954). Megakaryocytes may be associated with the areas of hematopoiesis.

Fatty Metamorphosis

Fatty metamorphosis may occur in mice as a response to a toxicant. It is also seen in old obese controls and is more common in male than in female mice. The degree of fatty metamorphosis may vary and usually starts with a centrilobular distribution (Figs. 56 and 57). The empty clear vacuoles with the peripherally located compressed nuclei represent lipid which has been removed during tissue processing. The lipid can be confirmed by staining frozen sections with Oil Red O or Sudan Black B.

Lipid Storage Disease

This specific entity represents a genetic homozygous recessive disease identified in BALB/c mice (Morris et al., 1982; Shio et al., 1982). A colony of mice with disease was developed and maintained at NCTR prior to being transferred to The University of Arkansas for Medical Sciences in Little Rock and to NIH. The disease affects both sexes equally and affected mice usually die by 6 weeks of age. Cells within the liver which are believed to be Kupffer's cells are markedly distended with lipid material (Fig. 58). Biochemical studies have identified a number of lipid fractions with sphingomyelin being the most prominent. Other organs commonly involved include the spleen (macrophages), lymph nodes (macrophages), and brain (neurons).


Hemosiderin pigment may be found in Kupffer's cells within the liver. The pigment is distictively granular and golden in color within the cytoplasm of Kupffer's cells (Fig. 59). Occasionally, special stains such as Prussian Blue (Fig. 60) must be used to confirm the presence of iron to differentiate it from other pigments such as bile or ceroid.

Ceroid Pigment

Ceroid is a lipofuscin pigment which is acid fast and periodic acid Schiff (PAS) positive. An increase of ceroid pigmentation has been associated with certain organs in aging mice, including the ovaries and adrenals. Ceroid pigment in the liver may also occur as a result of hepatic toxicants. The pigment is a slightly darker brown than hemosiderin, and is usually present in the cytoplasm of Kupffer's cells (Fig. 61) adjacent to portal areas.


Focal hepatic necrosis is a non-specific entity quite often encountered as an incidental finding in the liver of mice. It can be the result of viruses (mouse hepatitis), bacteria (Clostridium piliforme), toxicants, and ischemia while the etiology is often unknown. It may involve single cells, single or multiple lobules, and it may vary in distribution. Coagulation necrosis with distinct eosinophilic cytoplasm and pyknotic or absent nuclei is the typical morphologic feature (Fig. 62). Cell outlines are usually distinct and an associated inflammatory reaction depends upon the duration of the lesions. Mouse hepatitis virus lesions may have giant cells or hepatocytes with bizarre chromatin patterns (Fig. 63) while lesions of MHV are seen in other tissues. Nude mice often have severe chronic hepatic lesions which leads to a gross appearance of cirrhosis (Ward et al., 1977). Clostridium piliforme causes Tyzzer's disease with hepatic granulomas and intracellular bacteria found within hepatocytes on the edge of the lesion. The Warthin-Starry stain identifies the bacteria (Figure 64).


Amyloidosis may occur in multiple organs including the liver. Amyloid is found in sinusoids beneath the sinusoidal-lining cells, is distinctly homogeneous and eosinophilic (Fig. 65) and stains positively with crystal violet, Congo red (Fig. 66) and thioflavin T stains.

Karyomegaly and Cytomegaly

A striking histological feature of the livers of aged mice is the presence of hepatic cells with enlarged nuclei of variable size. The enlarged nuclei may be rounded or elongated and generally are two or more times normal size. The polyploid cells appear with increasing frequency as aging occurs (Jones, 1967). This increase in nuclear size (karyomegaly) may or may not be associated with an increase in cell size (cytomegaly), and cytomegaly may occur either with (Fig. 67) or without an increase in the size of the nucleus. These changes have also been seen in mice treated with DDT, phenobarbital (Ward et al., 1983), Aroclor 1254 (Kimbrough and Linder, 1974) and other chemicals; and in mouse hepatitis virus infected cells (Ward et al., 1977). Toxins also often induce binucleate and multinucleated hepatocytes as well.


Both intranuclear and intracytoplasmic inclusions are frequently observed within normal and neoplastic mouse hepatocytes. Intranuclear inclusions are round, often filling most of the nucleus, and are distinctly eosinophilic in appearance (Fig. 68). These inclusions have been reported to increase in incidence with age and are usually considered to be invaginations of the cytoplasm into the nucleus (Andrew, 1962; Herbst, 1976).

Cytoplasmic inclusions are somewhat less common, and are most frequently seen in hepatocytes in or adjacent to hepatocellular neoplasms. Intracytoplasmic inclusions are round, vary markedly in size, and are usually eosinophilic (Fig. 69). Some investigators have reported these intracytoplasmic inclusions to be aggregates of smooth endoplasmic reticulum (Hruban et al., 1966), or Mallory bodies. These types of intracytoplasmic inclusions have been reported in mice (Frith and Ward, 1980).

Bile Duct and Ductular Hyperplasia

Proliferation of hepatic bile ducts may occur in response to toxicants and is sometimes associated with an inflammatory reaction. The lesion is usually diffuse and many bile ducts are usually present in portal triads (Fig. 70). Bile ductules (cholangioles, oval cells) may become hyperplastic in response to toxicants as well (Fig. 71). Normal and hyperplastic bile ducts and ductules stain for keratin.

Cholangiofibrosis (Adenofibrosis)

Cholangiofibrosis is characterized by focal areas of basophilic, atypical ducts in a fibrous stroma (Fig. 72). It is rarely seen in control mice. The lesion is controversial and much less commonly induced in the mouse than in the rat. Adenofibrosis in the mouse, induced by Aroclor 1254, has been described (Kimbrough and Linder, 1974).


Hepatic cirrhosis, whether postnecrotic, biliary, pericellular or of some other type, is an uncommon spontaneous occurrence in mice. It may be seen after a variety of toxicants, including carbon tetrachloride and chronic mouse hepatitis infection in nude mice (Ward et al., 1977). It often takes the form of a focal or diffuse increase of fine reticular fibers rather than distinct fibrous collagenous bands (Ward et al., 1979a).


Cholangitis is inflammation of the bile ducts and is characterized by the presence of inflammatory cells (polymorphonuclear leukocytes and/or mononuclear cells) within the ducts and periductular tissue (Fig. 73).

Hepatocellular Foci of Cellular Alteration (Focal Hyperplasia)

Foci of cellular alteration in mice are somewhat similar to those described in the rat (Squire and Levitt, 1975) and may be seen in mice exposed to some carcinogens, including benzidine (Frith and Dooley, 1976), aldrin and dieldrin (Reuber, 1976), N-nitrosodimethylamine, N-nitrosodiethylamine (Ward et al., 1983b; Ward, 1984a) and other chemicals (Frith and Ward, 1980). The primary alteration involves tinctorial qualities and textural appearances of the cytoplasm and size of hepatocytes. There is no obvious disruption of the liver architecture, and the affected hepatocytes merge with adjacent hepatocytes without compressing adjacent normal parenchyma. Foci of cellular alteration may be classified as eosinophilic, basophilic, vacuolated, clear cell, or mixed. They may progress to adenomas and occasionally to carcinomas (Ward, 1984b; Frith et al., 1980a). The cells in the eosinophilic foci can be either the same size or more often larger than adjacent normal hepatocytes. The cytoplasm of the cells in such foci is eosinophilic and has a distinct granular appearance compared to adjacent hepatocytes (Fig. 74). The eosinophilia may be a result of hyperplasia or hypertrophy of smooth endoplasmic reticulum, mitochondria or peroxisomes (Schuller and Ward, 1984). Eosinophilic foci can be found spontaneously but are more commonly induced by carcinogens (Ward, 1984a). Generally, the cells within basophilic foci are smaller but occasionally larger than normal, and their cytoplasm is distinctly basophilic compared with normal adjacent hepatocytes (Fig. 75). The basophilia is usually due to increased amounts of polyribosomes or rough endoplasmic reticulum (Schuller and Ward, 1984). An unusual lesion, induced by N-nitrosodiethylamine, resembling vascular invasion by basophilic foci, has been seen in the livers of mice (Koen et al., 1983a), but no metastases have been seen at this stage of hepatocarcinogenesis. Vacuolated cell foci consist of hepatocytes which contain lipid-laden, distinct cytoplasmic vacuoles of variable size. The nuclei of these vacuolated cells in microscopic sections are either absent or are flattened against the cytoplasmic membrane (Fig. 76). Clear cell foci consist of cells with a clear, ground glass, or sometimes a lacy cytoplasm containing much glycogen. The clear areas stain with PAS stain prior to but not after diatase digestion, suggesting the presence of glycogen (Ward et al., 1983). The nuclei of the affected cells are not flattened against the cell membrane as in the vacuolated cells, but are often located in the center of the involved cells and surrounded by clear cytoplasm (Fig. 77). Often clear cell foci contain many hepatocytes with basophilic or clear cytoplasm. Mixed cell foci contain, in varying proportions, two or more of any of the cell types described in the preceding paragraphs.

Hepatocellular Neoplasms

Hepatocellular Adenoma

The term hepatocellular adenoma is the preferred term for the morphologically and biologically benign liver cell neoplasm (Reuber, 1971; Butler and Newburne, 1975; Gellatly, 1975; Ward and Vlahakis, 1978; Frith and Ward, 1980; Vesselinovitch, 1983; Ward, 1984a). Adenomas are progressively growing focal lesions and may represent early stages in the formation of carcinomas (Stewart, 1975; Ward and Vlahakis, 1978; Frith et al., 1980a). Synonyms for this lesion include benign hepatoma, hyperplastic nodule, nodular hyperplasia (Butler and Newberne, 1975), Type A nodule (Walker et al., 1972), Type 1 or 2 nodule (Gellaty, 1975), liver tumor (Tomatis et al., 1972), neoplastic nodule (Squire and Levitt, 1975) and hepatocellular carcinoma (Stewart, 1975). Hepatocellular adenomas are usually 1-10 mm in diameter, consist of cells resembling relatively normal hepatocytes and usually contain cells similar to those in the foci of cellular alteration. Adenomas exist as distinct nodules which compress adjacent parenchyma and may bulge from the liver surface. Histologically, they are composed of a uniform population of well-differentiated cells which form a solid nodule which may be composed of larger or smaller than normal hepatocytes that have cytoplasm which is basophilic (Fig. 78), eosinophilic (Fig. 79), or vacuolated (Fig. 80). Adenomas may form regular plates one cell thick. They do not invade adjacent parenchyma or vessels, the lesions do not metastasize, and the small nodules have a lower degree of transplantability than do carcinomas (Reuber, 1967; Gellatly, 1975; Williams, 1979). Transplantability is evidence of their neoplastic nature. More recently they have been shown to be of clonal origin (Rabes et al., 1982), and some tumor cells contain alphafetoprotein (Fig. 81), which is also evidence of neoplasia (Koen et al., 1983b). Some chemicals induce either eosinophilic (Ward et al., 1979a; Hoover, et al., 1980; Ward, 1984a) or basophilic adenomas (Vesselinovitch et al., 1978; Ward et al., 1979a). Naturally occurring hepatocellular carcinomas often arise within adenomas (Frith and Dooley, 1976; Ward and Vlahakis, 1978; Ward, 1984b). These foci of carcinoma within adenomas (Fig. 82) appear identical to carcinomas described below.

Hepatocellular Carcinoma

The diagnosis of hepatocellular carcinoma is often made on a distinct trabecular (Fig. 83) or adenoid pattern as well as on cytologic features characteristic of malignancy. Synonyms for this lesion include Type B nodule (Walker et al., 1972), Type 3 nodule (Gellatly, 1975), trabecular carcinoma, and malignant hepatoma. The liver cell plates are more than one cell layer thick, irregular, and composed of well to poorly differentiated hepatocytes. The well-differentiated tumors are composed of uniform cells with a fair amount of cytoplasm (Fig. 84). The moderately well-differentiated hepatocellular carcinomas are composed of larger hepatocytes which vary more in size and shape and form plates or a solid pattern (Fig. 85). The poorly differentiated tumors are composed of cells with less cytoplasm and more immature nuclei forming prominent plates or a solid pattern; some have extremely large anaplastic cells (Fig. 86).

The incidence of metastases has generally been considered very low for mouse hepatocellular tumors, but more recent studies indicate that a thorough examination of step or serial sections of the lung reveals a much higher incidence than previously expected, especially for tumors induced by dimethylnitrosamine (Kyriazis et al., 1974). Metastases are frequently uncommon (0-5 percent) in mice with spontaneous hepatocellular carcinomas (Butler and Newburne, 1975), but may be seen in up to 40% of male B6C3F1 or C3H mice with hepatocellular carcinoma that are allowed to live out their lifespan. Metastases usually occur only when tumors are large (over 10 mm) and increased in weight (Frith et al., 1980b). Some chemicals cause highly metastatic tumors while others cause carcinomas with a low metastatic rate (Ward, 1984a). Figure 87 is a pulmonary metastasis of a hepatocellular carcinoma. Pulmonary metastases may share the trabecular pattern often seen in the primary hepatocellular carcinomas, or they may be more solid in appearance.


Hepatoblastomas have been described in mice as occurring spontaneously and are rarely experimentally induced. Turusov et al. (1973) described liver tumors in mice which resembled human hepatoblastomas. These tumors are almost invariably found within or adjacent to hepatocellular carcinomas, are readily distinguished by their basophilia with H & E stain and metastasize commonly. The tumors frequently consist of organoid structures lined by vascular channels (Fig. 88). The channels are surrounded by several layers of tumor cells arranged either radially or concentrically. In some areas the cells are arranged in rows, rosettes, sheets, or ribbons. Foci of osseous metaplasia are occasionally seen. The cell of origin for this particular mouse neoplasm is uncertain, although it has been suggested that this type is of fetal origin (Turusov et al., 1973). While similar neoplasms occur in children, however, hepatoblastomas only occur in aged mice. Other pathologists have referred to similar lesions as poorly differentiated cholangiocarcinomas (Reuber, 1967) and cholangiomas (Vlahakis and Heston, 1971; Jones and Butler, 1975). The authors recently demonstrated the presence of keratin in hepatoblastomas (Fig. 89) of aged mice but not alphafetoprotein, suggesting their duct or ductular origin rather than their hepatocellular origin (Nonoyama et al., in press.)

Cholangioma and Cholangiocarcinoma

Cholangiomas and cholangiocarcinomas are relatively rare in mice (Reuber, 1967; Vlahakis and Heston, 1971) compared to the common occurrence of hepatocellular neoplasms (Figs. 90 and 91). Some hepatocellular carcinomas assume a distinctly adenoid or glandular pattern suggestive of an adenocarcinoma (Fig. 92), yet, in some cases, when the transition is not evident, it is sometimes difficult to differentiate a hepatocellular adenocarcinoma from a cholangiocarcinoma. Mixed carcinomas, or carcinomas containing distinct areas of both trabecular hepatocellular carcinoma and cholangiocarcinoma, have also been described (Fig. 93).

Hemangioma and Hemangiosarcoma

Hemangiomas are benign tumors and hemangiosarcomas are malignant tumors arising from endothelial cells. Both hemangiomas and hemangiosarcomas may arise as primary neoplasms in a variety of organs and tissues including the liver (Fig. 16). Both are much less common than hepatocellular neoplasms, and hepatic hemangiomas are much less common than hepatic hemangiosarcomas (Frith and Wiley, 1982). Hemagiomas consist of large somewhat irregular vascular channels lined by flattened, normal endothelial cells. Hemangiosarcomas are composed of elongated, flattened, spindle-shaped or polyhedral endothelial cells that line vascular clefts and spaces (Fig. 16) and sometimes form solid sheets. The neoplastic cells may surround hepatocytes which appear to undergo a responsive hypertrophy. Hemangiosarcomas are locally invasive and may metastasize to other organs such as the lungs.

Metastatic Tumors

Metastatic tumors of the liver are rare compared to metastatic tumors of the lung. The most common are the hepatopoietic neoplasms including lymphoblastic lymphoma and follicular center cell lymphoma. Histiocytic sarcoma may occur as either a metastatic or a primary neoplasm of the liver. Metastatic tumors which have been seen in the liver include the alveolar/bronchiolar adenocarcinoma, urinary bladder transitional cell carcinoma, osteosarcoma and pancreatic islet cell carcinoma (Frith, 1983f).

Gall Bladder

Gall Stones

Gall stones are extremely rare in mice. The stones have not been seen frequently enough to be chemically characterized. Stones are present in the lumen and consist of concentric laminations or lamellae (Fig. 94).


Distinct eosinophilic crystals of obscure etiology are occasionally seen in the cytoplasm of the epithelial cells and in the lumen of the gall bladder of mice (Fig. 95). They may be similar in etiology to those described in the lungs, and may be products of the epithelium since the acidophilic cytoplasm of the epithelial cells stains and reacts in the same way as the extracellular crystals (Yang and Campbell, 1964).

Papilloma and Carcinoma

Gall bladder papillomas are rare tumors in the mouse. They consist of papillary projections covering a connective tissue core (Fig. 96). A single gall bladder carcinoma has been seen in a control mouse at NCTR, and a small number have been seen in the NCI-NTP bioassay program (Yoshitomi et al., 1986). The malignant neoplasm from the NCTR was composed of basophilic cells forming a distinct glandular pattern and was infiltrating the liver (Fig. 97).

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