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Thymic cysts have been seen in a number of strains of mice and they generally increase in incidence with age (Frith et al., 1985). The cysts are lined by a simple cuboidal epithelium and the lumen is usually empty. They are more commonly located in the cortex (Fig. 276).
Atrophy of the thymus increases with age and in response to certain toxicants, viruses or irradiation. In the severely atrophic thymus, the distinction between cortex and medulla cannot be made, and all cell types are decreased in number (Fig. 277). In murine Lupus and other similar diseases, the thymus may not atrophy in a normal manner, and lymphoid hyperplasia with follicle formation may be present (Andrews et al., 1978; Ward et al., 1986b).
Ectopic thymus has been reported by investigators adjacent to or in association with the parathyroid gland. The ectopic tissue is predominantly cortical thymic tissue (Fig. 278).
A small accessory spleen is occasionally noted in mice. The accessory spleen is usually near the normal spleen and may be embedded in the pancreas (Fig. 279). Normal red and white pulp may be present.
Amyloidosis of the spleen usually accompanies systemic amyloidosis. It presents a homogeneous eosinophilic appearance (Fig. 280) and stains positively with the Congo red, crystal violet and thioflavin T stains. Early lesions occur in the white pulp and spread to the red pulp.
Both hemosiderin and melanin pigment may occur in the spleens of mice. Hemosiderin is golden brown and usually present in the cytoplasm of macrophages or reticular cells (Fig. 281). It stains positively with iron stains such as Prussian blue. Melanin pigment may occur in the spleen of mice with pigmented skin. It is slightly darker than hemosiderin and has a characteristic elongated or stringy appearance (Fig. 282). It is not associated with macrophages and is iron-negative.
This lesion is rare in mice less than 6 months of age, and no sex differences are noticeable. The incidence also increases slightly with age. Hyperplasia of the lymphoid component (white pulp) of the spleen results in an increase in the number and size of the lymphoid follicles with the enlarged follicles often coalescing (Fig. 283). There is usually an associated increase in the size of the spleen. These lesions may be difficult to distinguish from the early stages of Follicular Center Cell (FCC) Lymphoma.
Extramedullary hematopoiesis (myeloid metaplasia) is normally found in the spleen of mice. The degree of hematopoiesis may vary from strain to strain. The erythropoietic activity is characterized by foci of immature erythrocytic precursors with small, darkly staining nuclei in the red pulp (Fig. 284). Certain neoplastic conditions may markedly stimulate erythropoietic activity.
The erythropoietic activity in the spleen may or may not be associated with an increase in the granulopoietic activity (Fig. 285). A generalized increase in granulopoiesis may be accompanied by granulopoietic elements in a variety of other organs including liver, adrenals and lymph nodes. A marked increase in granulopoietic activity must be distinguished from granulocytic leukemia. In granulopoiesis, the complete series of developing cells including the mature neutrophils are usually present. In granulocytic leukemia, the developing stage of the neoplastic granulocytes may vary from animal to animal but typically a single stage predominates (Dunn, 1954). In addition, marked hyperplasia of granulopoiesis is usually accompanied by lesions responsible for the hyperplasia, including abscesses, ulcerative tumors and other inflammatory lesions.
Megakaryocytes are common in the red pulp of the spleen (Fig. 286) and bone marrow of the mouse, and an increase in the number of megakaryocytes is commonly referred to as megakaryocytosis. Megakaryocytosis occurring concurrently in both the spleen and the bone marrow of mice is rare. It occurs most frequently in mice older than 18 months.
Atrophy of the bone marrow is rare in mice. It may occur spontaneously with an unknown etiology or it may be the result of toxins. Usually all hematopoietic cells are decreased in number and endothelial and fat cells often appear increased (Fig. 287).
Necrosis of lymph nodes is most commonly associated with viral diseases, toxins and lymphoreticular neoplasms. It may rarely occur from infarction. Lymphoid atrophy can be seen during and after toxic lesions, viral infections or certain experimental treatments.
Mineralization of lymph nodes is associated with areas of injury and may be preceded by necrosis. The mineralized deposits are focal and distinctly basophilic. They may present a concentric or laminated appearance and commonly are associated with necrosis.
Accumulations of histiocytes may occur in the subcapsular and medullary sinuses of lymph nodes. The histiocytes have dark basophilic nuclei and abundant distinctly eosinophilic cytoplasm (Fig. 288). They may contain hemosiderin, other pigments, erythrocytes and other phagocytized material.
Hyperplasia of a variety of cell types may occur in hematopoietic tissue of mice. Lymphoid hyperplasia of the lymph nodes is one of the more common lesions, but it is rare in mice under 12 months of age. The incidence increases slightly with age and is slightly greater in females than in males in most strains. Hyperplasia may be seen in the B cell areas (follicles, germinal centers), T cell thymic-dependent areas (paracortex), medullary cords or sinuses. In the common hyperplastic lymph node, the normal corticomedullary division is not usually apparent (paracortical hyperplasia) and the marginal sinus is often filled with lymphocytes (Fig. 289). The lymphocytes are usually small and normal in appearance. The lesion is difficult to distinguish from the lymphoblastic type of malignant lymphoma if only a single node is involved; but if the lymphocytes are mature, few mitotic figures are observed and the "starry sky" effect found in lymphoblastic lymphomas is not seen. Thickening of the medullary cords (Figs. 290 and 291) is often noted and is characterized by the presence of many plasma cells (plasmacytosis), occasionally resembling plasmacytoma. The plasmacytosis is a reaction to chronic inflammatory lesions or tumor antigens.
An increase in mast cells (mastocytosis) may occur in either the spleen or in lymph nodes. Occasionally, focal accumulations of mast cells may occur in other organs such as the ovary or uterus. Investigators have also noted mast cells associated with certain tumors. The number of mast cells normally found in a specific organ may vary from strain to strain (Dunn, 1969).
Dunn (1954) described neoplasms of the reticular system in the mouse as arising from stem cells, granulocytes, lymphocytes, reticular cells and plasmacytes. She recommended that the term "leukemic" be used to denote these lesions irrespective of whether or not malignant cells were found in the peripheral blood. The authors of this monograph would prefer to classify individual neoplasms as either leukemic or non-leukemic, but this designation assumes less importance with the following classification (Table 1) adapted from Pattengale and Frith (1983).
Using immunocytochemical techniques and the newer classification of murine malignant lymphomas (Pattengale and Frith, 1983, 1986; Pattengale and Taylor, 1983; Fredrickson et al., 1985; Frith et al., 1985) the lymphoblastic type is comparable to Dunn's lymphoblastic leukemia. This disease is one of the more common hematopoietic neoplasms in mice and may occur as early as 1 month of age (T-lymphoblastic). It can develop from either T or B lymphocytes and may be spontaneous or induced by retroviruses, chemicals or irradiation. The incidence of lymphoblastic lymphoma usually increases slightly in all strains with age and, at 3-6 months, may have a slight peak (T-lymphoblastic) in some strains such as the BALB/c and a major peak in AKR mice. The incidence is generally higher in the female than in the male mice. Lymphoblastic lymphoma often involves a number of organs, most commonly the liver (Fig. 292), spleen, thymus (Fig. 293), lymph nodes, bone marrow and lungs, but often arises in the thymus (T-lymphoblastic). The disease results in an enlargement of most involved organs due to the proliferation of neoplastic lymphoid cells. Neoplastic lymphocytes are often present in the blood, and in such cases the neoplasm should be classified as leukemic (Fig. 294). The neoplastic lymphocytes have large or small nucleoli, round vesicular nuclei and a small amount of cytoplasm.
Dunn's (1954) reticulum cell sarcoma Type B has been referred to as malignant lymphoma, mixed cell type (Frith and Wiley, 1981) or pleomorphic cell type and more recently has been identified as a follicular center cell lymphoma (FCC) of B cell origin (Pattengale and Frith, 1983; Pattengale and Taylor, 1983; Fredrickson et al. 1985). The spleen, mesenteric lymph nodes and Peyer's patches of the ileum are the most commonly involved sites. The disease is rare before 12 months of age and may increase dramatically in some strains after 18 months. This neoplasm is slightly more common in the female than in the male mouse.
Microscopically, FCC lymphomas present a background of large, pale, transformed B lymphocytes (Fig. 295). In the spleen, the lesion originates in the germinal centers of the follicles in the B cell areas of white pulp and often results in a grossly nodular appearance. FCC may be composed of small follicular cells, large follicular center cells or a mixture of small and large follicular center cells. The small and large cell mixture appears to be the most common type. In lymphomas of small FCC, the cells are cohesive and nuclei are markedly irregular in size and shape with scant cytoplasm. In lymphomas composed of large FCC, the cells are large and cohesive with irregularly shaped, folded and notched nuclei (cleaved) and moderate amounts of cytoplasm. The B cell nature of these cells has been confirmed using immunoperoxidase techniques with Bouin's or B-5 fixed tumors demonstrating the presence of cytoplasmic or cell surface immunoglobulin of the various isotypes (Fig. 296). FCC lymphoma also commonly involves the mesenteric lymph nodes (Fig. 297).
Plasma cell lymphomas occur infrequently in control mice. Lymph nodes, spleen and liver may be involved. The cells are large with amphophilic cytoplasm, some are binucleated, the mitotic index is high and the cells retain a characteristic plasma cell appearance (Fig. 298). Spontaneous plasma cell myelomas are rare, but intraperitoneal plasma cell tumors can be induced with intraperitoneal injections of mineral oil.
Immunoblastic lymphoma of B cell origin is rare in the mouse (Pattengale and Frith, 1983). It is characterized by non-cohesive, large lymphoid cells with round-to-oval vesicular nuclei with prominent and distinct nucleoli (Figs. 299 and 300). In addition, the nuclei are sometimes eccentric and have clumped, peripherally marginated clock-face-like chromatin and the cytoplasm is moderately dense and amphophilic (plasmacytoid features).
The term thymoma is usually used in the mouse to classify a lesion characterized by the presence of a neoplastic epithelial component with or without neoplastic lymphocytes. The epithelial component appears to be derived from the epithelial cells in Hassall's corpuscles or thymic reticular tissue (Fig. 301).
Dunn's (1954) reticulum cell neoplasm Type A or malignant lymphoma (Frith et al., 1981a), histiocytic type, or histiocytic lymphoma, has been recently classified as histiocytic sarcoma (Pattengale and Frith, 1983). Other investigators have described the lesion as endometrial sarcoma (Chouroulinkov et al., 1969; Dawson et al., 1974) or malignant schwannoma (Stewart et al., 1974). Research findings have suggested that the neoplastic cells are derived from histiocytic cells of uncertain origin (tissue histiocytes, Kupffer's cells, macrophages; Frith et al., 1981a). Histiocytic sarcomas are rare until 12 months of age and again slightly more common in females than in males. The liver is the most commonly involved organ in male mice (Figs. 302 and 303); in females the uterus (Fig. 304) and vagina as well as the liver are often involved, suggesting these tissues as sites of origin. Other organs less frequently involved include the spleen, lymph node, bone marrow, lung, kidney and ovaries. Metastatic lesions to the lungs occur in a high percentage of cases with liver involvement. Figures 308 and 309 are transmission electron micrographs showing histiocytic cells which are quite variable in shape. Alpha-1-anti-trypsin (Fig. 303) but not lysozyme is found in some tumor cells.
Mast cell tumors, including benign and malignant tumors (sarcomas) are also rare in mice but have been reported (Deringer and Dunn, 1947; Dunn, 1969; Frith et al., 1976). One case of mast cell sarcoma was seen in an 18-month old C57BL/6 control female mouse, and a small number of cases have been observed in treated mice (Frith et al., 1976). The mast cells are usually disseminated and involve the liver, spleen, and kidneys (Fig. 305). Cytoplasmic granularity may not be evident but can be easily demonstrated with metachromatic stains (Fig. 306).
Granulocytic leukemia is rare in many strains of mice and is seldom evident before 12 months of age (Frith and Wiley, 1981). The disease usually involves the liver (Fig. 307), spleen, kidneys and lymph nodes. The lesion must be distinguished from nonneoplastic granulopoiesis. The neoplastic cells usually represent a single immature or mature developmental stage; while in granulopoiesis, the complete series including ring-form myelocytes, metamyelocytes and adult neutrophils are present (Dunn, 1954). Specific retroviruses can also cause this type of leukemia.
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