42nd Annual Pathology of Laboratory Animals Course AFIP August 1995 DISEASES AND NEOPLASMS OF THE AGING SD RAT James B. Nold, DVM, PhD, Diplomate, ACVP Corning Hazleton (Wisconsin) and George A. Parker, DVM, Diplomate, ACVP Biotechnics, Mountainside, New Jersey General Comments 1. Limited to Sprague-Dawley (CD) and Fischer 344 (F344) rats. 2. Based on information from chemical safety tests: a. Two-week repeated dose range-finding studies. b. 90-day to 120-day subchronic studies. c. 24-month to 30-month chronic toxicity/oncogenicity studies. 3. Rats a. Hsd:Sprague Dawley SD (Harlan Sprague Dawley, Inc.)  Direct descendants of original SD colony b. Crl:CD BR Rat (Charles River Laboratories)  Originated from the outbred SD 40+ years ago. c. Fischer 344 (F344) d. Wistar I. Urinary System A. Kidney 1. Chronic progressive nephropathy Synonyms: Spontaneous degenerative nephropathy Rat nephropathy Chronic nephrosis Glomerulonephrosis a. Most common renal disease of laboratory rats. b. Proteinaceous casts, interstitial inflammation, fibrosis, thickened basement membranes, glomerulosclerosis, crescent formation. c. Basophilic epithelium in early stages of disease. Seen in animals as young as 3-4 months. d. Striking hyaline droplet degeneration. e. More common and more severe in males than females. Incidence in males is reduced if they are castrated. f. Incidence is elevated in rats on a high protein diet. g. Commonly associated systemic lesions in advance CPN include multifocal mineralization (vessels, heart, lung) and fibrous osteodystrophy. 2. Acute hemorrhage in renal sinus a. Acute hemorrhage in renal sinus is relatively common in sacrificed animals. b. Rarely see hematuria in association with hemorrhage, therefore presumed to be an agonal change. 3. Hydronephrosis a. Relatively common in subchronic studies. b. Reported incidence of 2% in Sprague-Dawley breeding colonies. c. Selective breeding resulted in incidence of 33.6% in two generations. d. Right kidney is more commonly involved. e. An anatomic basis has been proposed in one strain of rats (Slonaker-Addis), but this was not confirmed by another study. f. Uroliths, pelvic inflammation, or pelvic mineralization may be present, but often the cause is not evident. g. Cortical tubular cysts commonly seen as a background lesion. 4. Microlithiasis a. Microscopically similar to "dehydration salts" in other species. b. Typically located in a band at the corticomedullary junction. c. More common in females. d. More common in animals that die. 5. Microcalculi in renal sinus a. Sometimes associated with hyperplasia of transitional epithelium of the renal sinus. b. Commonly associated with mild dilatation of the renal sinus. 6. Pigmentation of renal cortical epithelium a. Diffuse, particulate to amorphous, light brown cytoplasmic pigment is compatible with lipofuscin ("aging pigment"). b. Globular, greenish brown pigment in some cases is similar to hemosiderin. 7. Hyaline droplets a. Alpha2 -globulin. b. More common in males. c. Typically indicative of protein reabsorbed from the glomerular filtrate. Involves proximal convoluted tubule and/or pars recta, or collecting ducts. d. Hydrocarbon nephropathy (alpha2 -globulin), histiocytic sarcoma (lysozyme), or Bence Jones protein. 8. Lipomatous foci a. Focal accumulation of lipocytes, typically in renal cortex. b. May be neoplasm or hamartoma. 9. Nephroblastoma (embryonal nephroma) a. Low incidence. 10. Tubular adenomas/adenocarcinomas a. Microscopically similar to other species. b. Associated with hydrocarbon exposure. (1) Tend to be located in the poles of the kidneys. (2) Probably dependent on presence of alpha-2u- globulin. B. Urinary bladder 1. Papillary hyperplasia of urinary bladder epithelium. a. Commonly associated with cystic calculi. Bladder may have been described as thickened at necropsy. b. Calculi are not present in sections, therefore careful review of gross necropsy observations is critical in diagnosis. c. Hyperplasia typically is associated with some degree of inflammation, though often mild. d. Nearly normal polarity and orderly maturation of epithelial cells is present in hyperplasia, in contrast to transitional cell carcinoma. 2. Lymphocytic infiltration in urinary bladder a. Must be differentiated from mononuclear cell leukemia infiltrates in F344 rats. b. The nonneoplastic infiltrates tend to be limited to the submucosa, whereas leukemic infiltrates are throughout the wall of the bladder. c. Cell morphology on standard H&E sections isn't particularly helpful in differentiating between lymphocytic and leukemic infiltrates. d. Multiple organs involvement is most important feature in distinguishing leukemia from inflammatory infiltrates. 3. Calculi a. May be microscopic or macroscopic. b. Usually associated with microcalculi in the renal pelvis. 4. Agonally, may see semen ejaculate in the urinary bladder or urethra. Not to be mistaken for a calculus or occlusion. II. Respiratory System A. Nasal cavity. 1. Incisive fissures in nasal cavity. a. Normal anatomic structure. b. Provides direct communication between oral and nasal cavities. c. Must be distinguished from cleft palate, particularly in teratology studies. 2. Maxillary "sinusitis" a. Correct anatomic term is maxillary recess rather than maxillary sinus. b. Commonly the site of mild suppurative inflammation, sometimes in association with similar inflammation in other parts of the nasal cavity. 3. Rhinitis a. Typically involves neutrophilic infiltration, and sometimes includes erosion or ulceration of the nasal epithelium. b. Etiology unknown. c. Mycotic (aspergillus) rhinitis is seen sporadically. B. Trachea 1. Mineralization of tracheal cartilage. a. Very common as an aging change. b. May represent normal anatomic progression with age. C. Lung 1. Alveolar histiocytosis. a. Multifocal aggregations of alveolar macrophages within alveoli and terminal airways. b. May represent resolved inflammatory foci, or may represent a focal deficit in the pulmonary clearance mechanisms. c. Sialoadenodacryoadenitis virus infection has an associated pneumonitis. 2. Mineralization of pulmonary arteries a. Seen more commonly in F344 than in Sprague-Dawley rats. b. Typically consists of focal or multifocal mineralization beneath the intima or within the muscular wall of the arteries. 3. Hair shaft emboli in intravenous injection studies 4. Murine respiratory mycoplasmosis (Mycoplasma pulmonis) Synonym: Chronic respiratory disease (CRD) a. Used to be the most significant spontaneous lesion in most rat colonies. b. Principally an upper respiratory tract pathogen. Severe lung involvement is common only in advanced cases and/or aged animals. c. Earliest lesions in nares, larynx, and middle ear. (1) Epithelial hyperplasia and metaplasia. (2) Subepithelial lymphoid infiltration. (3) Purulent exudate. d. Lung involvement (1) Lymphoid hyperplasia and infiltration -- considered a characteristic lesion even in the absence of more advanced pathological changes. Note: the rat lung does normally contain some small bronchial associated lymphoid tissue. (2) Bronchiectasis -- large, distended airways filled with large quantities of purulent debris -- an advanced lesion. e. Urogenital (1) Mycoplasmosis also may infect the genital system, producing infertility and histologic changes in the ovaries and oviducts. 5. Pulmonary neoplasms a. Primary pulmonary neoplasms are rare spontaneous neoplasms in the rat. III. Cardiovascular System A. Heart 1. Cardiomyopathy a. Consists of myofiber atrophy and interstitial fibrosis, most commonly beginning in the subintimal myocardium of the left ventricle. b. More common and more severe in males than females. 2. Atrial thrombosis a. May be so severe as to be grossly visible. b. Typically has fibrosis and organization at the base, which continues into the atrial wall. 3. Myocardial mineralization a. Most commonly is secondary to severe nephropathy. 4. Chronic inflammation of base of heart (coronary arteritis) a. Is an uncommon lesion which usually is encountered as an incidental finding. b. Usually not associated with disseminated polyangiitis, and is morphologically different from polyangiitis. 5. Coronary arteriosclerosis a. Uncommonly seen in the larger branches of the coronary arteries. b. Resembles amyloid, but special staining attempts have been unsuccessful. 6. Endocardial hyperplasia/sarcoma (schwannoma) a. Was called fibroelastosis. b. Thickening and cellular proliferation in the subendocardium. c. Infiltrates into the myocardium and expands into the ventricular lumen. d. Size and extent of lesion will be a determining factor in whether to classify this as a hyperplasia or neoplasm. B. Vasculature 1. Polyangiitis (polyarteritis nodosa, panarteritis) a. Grossly visible nodular thickening of mesenteric arteries. But, frequently may be diagnosed microscopically in absence of gross lesions. b. Consists of fibrosis, inflammation and fibrinoid necrosis of muscular arteries in a variety of locations, including mesentery. c. Mesenteric polyangiitis is commonly seen in sections of pancreas. d. Commonly seen in testis and mesenteric arteries. e. Fibrinoid necrosis of the muscular wall of arterioles, with surrounding mixed inflammatory cell infiltration. 2. Aortic mineralization a. Most commonly seen secondary to nephropathy. b. May be so severe as to be grossly noted ("brittle aorta"). 3. Portal vein thrombosis a. Occasional incidental finding. IV. Gastrointestinal System A. Oral cavity 1. General information a. Dental formula: I 1/1, M 3/3. b. Root of upper incisor extends nearly to eye. c. Incisors grow continuously throughout life. 2. Broken teeth a. Incisors may be broken or trimmed to short by caretakers. b. Foreign material from feed may become impacted in pulp cavity and periodontal space. c. May result in endodontitis or periodontitis, sometimes with necrosis of tooth. 3. Odontodystrophy a. May be odontoma but, if neoplastic, does not appear to be an aggressive neoplasm. b. Incidence may approach 10%, though more typically is much lower. c. Consists of a disorderly mass of tooth bud elements. B. Salivary gland 1. Rat salivary glands a. Submaxillary (submandibular) - mixed mucoserous. b. Sublingual - mucous. Attached to anterior pole of submaxillary gland. c. Parotid - primary serous. Plasmacytic infiltrates more common. 2. Acinar atrophy of salivary gland a. Lobular atrophy of glandular cells with fibroplasia in the surrounding interstitium. 3. Focal tinctorial alteration C. Liver 1. Hepatodiaphragmatic nodules in liver a. Nodular protrusion on anterior surface of liver associated with small diaphragmatic hernia. b. Microscopically consist of normal hepatic tissue, with a rounded outer contour. c. Diagnosis depends a great deal on necropsy observation, i.e., location of the nodule on the anterior surface of the liver and in association with a diaphragmatic hernia. d. Must be carefully differentiated from true hepatic neoplasia. 2. Hepatic angiectasis a. Focal or multifocal sinusoidal dilatation. b. Subcapsular foci may be associated with a depression in the surface contour. 3. Ito cell proliferation/hypertrophy a. Resemble angiectasis, except are filled with proteinic material rather than blood. b. Are perisinusoidal fat-storing cells ("Ito cells"). c. Has been called cystic degeneration of hepatocytes. 4. Mitotic figures and multinucleated hepatocytes a. Small number is normal. b. If elevated, may be test material induced. 5. Focal or multifocal inflammation in liver a. Possibly due to bacterial showering from gut. b. Bacteria or overt suppurative inflammation are rarely seen. c. May be acute, subacute or granulomatous. 6. Periportal fatty change in liver a. Spontaneous lesion in older rats. b. May be more common in Sprague-Dawley than F344. c. Must be carefully distinguished from compound-related fatty change. 7. Bile ductule hyperplasia in the liver a. Very common in F344 and Sprague-Dawley rats. b. Consist of hyperplasia and proliferation of bile ductule epithelium, sometimes surrounded by fibroplasia. c. The fibrotic variant has been called cholangiofibrosis. Probably is a chronic form of the purely hyperplastic lesion. 8. Paranuclear vacuoles in liver a. Usually subcapsular. b. Probably some type of artefact. 9. Torsion of liver lobes a. May be seen in any lobe, though the papillary process of the caudate lobe seems to be most prone to torsion. b. Acute torsion has hemorrhagic necrosis with variable neutrophilic infiltration. c. Chronic torsion has fibrosis and a variable degree of necrosis and neutrophilic infiltration. May also have nodular hepatocytic regeneration which must be distinguished from neoplasia. 10. Streamlining in liver a. Blood from different areas of the gastrointestinal tract are concentrated in different lobes of the liver due the phenomenon of streamlining. b. Hepatotoxins which are primarily absorbed from one region of the gut may cause lesions primarily in one lobe of the liver, thus it is essential to take multiple sections of liver on toxicologic pathology studies. 11. Tension lipidosis a. Grossly recognized as a circumscribed pale area. b. Usually occur at periphery of lobe near attachments to adjacent lobes or tissues. 12. Foci of cellular alteration a. Basophilic, eosinophilic, clear cell and mixed foci. b. Omenclature based on tinctorial alteration of hepatocytic cytoplasm. c. Margins blend into the surrounding parenchyma. d. Some foci may compress adjacent parenchyma slightly. e. No disruption of hepatic lobular architecture. f. Hepatocytes within foci may be larger, smaller or same size as hepatocytes in surrounding parenchyma. g. Foci have been shown by special staining techniques to be metabolically different from the surrounding parenchyma. h. Areas of cytoplasmic alteration are same as foci of cytoplasmic alteration, except for size. 13. Hepatocellular hyperplasia a. Usually multifocal nodular lesion associated with previous or concurrent hepatic damage. Regenerative nodule. b. Often accompanies mononuclear cell leukemia in F344. c. Spherical proliferation of hepatocytes without nuclear atypism. d. May have cytoplasmic tinctorial variation, similar to altered foci. e. Hepatic lobular architecture is evident but may be distorted. Portal triads often can be seen. f. May reach a large size, eg. several millimeters. 14. Hepatocellular adenoma a. Nodular proliferations that are sharply demarcated by virtue of definite compression of surrounding parenchyma. b. Usually have distinct cytoplasmic tinctorial changes. c. Hepatic plates in adenoma are not continuous with plates of surrounding parenchyma, but impinge with them at a sharp angle. d. Loss of normal lobular architecture. e. May have increased mitotic rate or cellular atypism. 15. Hepatocellular carcinoma a. Usually larger and more irregular than adenoma. b. Compress or invade surrounding parenchyma. c. Characterized by one or more of the following: cellular atypism, local invasion, haphazard arrangement of cells, broad sheets of cells, trabecular patterns, or glandular patterns. 16. Hepatoblastoma 17. Cholangiocarcinoma 18. Hemangiosarcoma a. Sinusoidal spaces lined by neoplastic endothelial cells. b. May entrap hepatocytes. D. Tongue 1. Papilloma E. Pharynx 1. Papilloma 2. Squamous cell carcinoma F. Stomach 1. General information a. Nonglandular epithelium often is thickened at junction. b. There often is a mild eosinophil infiltration in the submucosa beneath the junction. 2. Cystic dilatation of gastric glands a. Consists of dilatation of the crypts of gastric glands. b. No apparent inflammation or adverse effect is noted. 3. Gastric ulceration and erosion a. Ulceration of the glandular or nonglandular mucosa is commonly seen in aged rats. b. More common in gavage studies, probably due to trauma. c. Edges of ulcers in nonglandular stomach have a variable degree of epithelial hyperplasia. d. Erosion must be differentiated from multifocal autolysis of superficial mucosa. Inflammatory cell infiltration is critical feature of erosion. G. Small intestine 1. Adenocarcinoma H. Large intestine 1. Adenomatous polyp 2. Adenocarcinoma I. Mesentery 1. Mesenteric fat necrosis a. Consist of nodular masses of necrotic, inflamed mesenteric fat. At necropsy is usually described as a mass in the peritoneal cavity or along the testes. b. Appears to be caused by torsion of mesenteric fat. 2. Mesothelioma a. Seen with moderate frequency, especially in F344. b. May consist of very small foci on surface of testis. c. Consist of fibrous tags covered by mesothelial cells. d. May see implants on serosal surface of various abdominal organs. e. Microscopic appearance of benign mesothelioma is similar to malignant mesothelioma. Presence of implants on abdominal organs is evidence of metastasis, therefore malignancy. J. Pancreas 1. Acinar atrophy of the pancreas a. Similar to acinar atrophy of salivary gland. b. Consists of atrophy of acinar elements with persistence of ducts and a variable degree of fibrosis. c. Islets are not affected. 2. Pancreatic vacuoles a. Reported to be an early manifestation of autolysis. b. Consists of clear vacuoles in acinar cells. 3. Hepatocytic islands in pancreas a. Typically located around islets. b. Consist of microscopically normal hepatocytes with Kupffer cells and bile ductules. c. Appears to be functional liver. Toxic changes observed in the liver also are present in the hepatocytes in the pancreas. 4. Acinar cell hyperplasia a. Focal or multifocal hyperplasia is relatively common. b. Consists primarily of focus of tinctorial alteration. 5. Acinar cell adenoma a. Less common than hyperplasia. b. May be associated with corn oil gavage. 6. Tubular adenocarcinoma V. Endocrine System A. Pancreatic islets 1. Islet cell hyperplasia or giant islets a. Great variation in size of islets is commonly noted. b. Probably is normal anatomic variation. 2. Islet cell adenoma/carcinoma a. Adenomas are relatively common in laboratory rats. b. Cell morphology is slightly altered, therefore diagnosis is based on size of lesion and evidence of compression or infiltration. B. Pituitary 1. Pituitary cysts. a. Very common. b. Often have apical cilia on lining cells. c. Probably represent cystic remnants of Rathke's pouch. 2. Focal hyperplasia of the pituitary a. Very common. b. Must be distinguished from adenoma. 3. Pituitary adenoma a. Very common. b. Incidence is 60% in males; 70% in females. c. Chromophobe adenomas are most common. d. Often have bizarre cellular features. e. May cause compression of ventral aspect of brain. Incidence in lower in rats on low protein diet. f. 81/83 stained for prolactin. 14/83 also stained for growth hormone. g. Ovariectomy significantly decreases incidence of pituitary adenomas in female rats. C. Adrenal gland 1. Cortical vacuolation a. Very common. b. Focal/multifocal aggregations of adrenocortical cells which have clear cytoplasmic vacuoles. 2. Cystic degeneration, cortical a. May be part of a continuum from cellular vacuolation to degeneration to large clear- or blood-filled spaces. b. Focal to multifocal areas of degenerative, vacuolated cortical cells being replaced by larger clear-filled or blood-filled spaces. c. More common in females. d. Severely affected glands may grossly appear swollen, soft, dark red, or mass-like. 3. Angiectasis a. Very common. b. More common in cortex, but may also be in medulla. c. Dilatation or coalescence of vascular spaces. d. May be sequelae of cystic degeneration. e. Combinations of cortical vacuolation, angiectasis, and cystic degeneration are very common. Consistency of diagnostic criteria and terminology is critical for purposes of tabulating these changes. 4. Extramedullary hematopoiesis a. Focal or multifocal aggregates of hematopoietic cells. 5. Ectopic adrenocortical tissue a. Most often present outside adrenal capsule. May be seen in kidney. 6. Adrenal medullary and cortical mixing a. Common to see clusters of cortical cells within the medulla. b. Depending on section, medullary tissue may extend out to the capsule. This must be differentiated from medullary hyperplasia. 7. Hyperplasia, cortical a. Distinct cortical foci, usually within the zona fasciculata and zona reticularis. Focal or multifocal. b. Cells may be variably sized, but are well-differentiated. May be vacuolated. c. May be associated with aforementioned degenerative changes. d. Common lesion, but not clear progression to neoplasm. e. Some call these foci of cellular hypertrophy or cellular alteration. 8. Adenoma, cortical a. Well-differentiated, but clearly expansile and compressive. 9. Carcinoma, cortical a. Frequently metastasize. 10. Hyperplasia, medullary a. Must be distinguished from pheochromocytoma. b. Criteria for differentiation based on compression and size. Consistency within a study is important. c. More common in males. d. Basophilic clusters of medullary cells. 11. Pheochromocytoma a. Common in aged rats, particularly males. 12. Ganglioneuroma of adrenal medulla a. Have well differentiated ganglion cells surrounded by well differentiated neuropil. b. Usually (always?) associated with a pheochromocytoma. c. Not common, 28 in 60048 F344 rats from NTP program. D. Thyroid 1. Ultimobranchial cysts or remnants a. Cyst lined by squamous epithelial cells, filled with keratin and cellular debris. b. May be very small, follicle-sized remnants with no cystic dilatation. c. Most commonly seen in the central area of the thyroid. 2. Thyroid colloid concretions a. Basophilic globules in colloid. 3. C-cell hyperplasia 4. C-cell adenoma a. C-cell masses greater than 5 average follicular diameters are classified as adenomas. 5. C-cell carcinoma a. Criteria for malignancy may include size, invasion, cellular pleomorphism, etc. b. May metastasize to lung. 6. Hyperplasia, follicular 7. Adenoma/carcinoma, follicular E. Parathyroid 1. Fibrosis, parathyroid a. Thickening of fibrous trabeculae. 2. Ectopic parathyroid a. Common in mediastinum. 3. Hyperplasia a. Commonly secondary to spontaneous nephropathy. b. Usually diffuse within the gland. 4. Adenoma a. Uncommon. b. Distinguish from hyperplasia by unilateral distribution and remnants of normal parathyroid tissue around the adenoma. VI. Reproductive System and Mammary Gland A. Testis 1. Hypospermatogenesis or tubular atrophy a. May occur as a primary (idiopathic) change or secondary to polyangiitis. Also seen near interstitial cell tumors. 2. Giant cell degeneration a. Multinucleated giant cells in seminiferous tubules. b. Often not associated with tubular atrophy, thus appears to be a distinct pathologic process. 3. Mineralization a. May affect seminiferous tubules or blood vessels. b. Appears grossly as white fibers visible from surface of testis. 4. Sperm granuloma a. Tubule distended by a mass of spermatozoa. b. Usually no associated inflammation. c. May result in secondary tubular atrophy or hypospermatogenesis. 5. Interstitial cell hyperplasia a. Very common in F344, where it is a precursor to interstitial cell tumor. b. Difficult to establish criteria for differentiation between small interstitial cell tumors and large focal hyperplasia. Cellular morphology is similar in both lesions. c. In USA, hyperplasia is no greater than one seminiferous tubule diameter. In Europe, hyperplasia may be up to diameters. 6. Interstitial cell tumor (ICT) a. Up to 95% incidence in 24-month-old F344 rats. Much lower incidence in Sprague-Dawley rats. b. White to yellow foci visible through the tunica vaginalis of the testis. c. Microscopically similar to ICT in other species. B. Prostate 1. Senile atrophy and concretions a. Epithelium is cuboidal or squamoid rather than columnar. b. Lumina contains small, deeply basophilic concretions which are microscopically similar to the "corpora amylacia" of other species. 2. Chronic prostatitis a. Very common in old rats. b. Primarily an interstitial process, though some lumina may be filled with inflammatory cells and cellular debris. 3. Epithelial hyperplasia. a. Seen with moderate frequency. b. Focal or multifocal proliferation of epithelial cells, sometimes filling glandular lumen. 4. Prostatic neoplasms a. Uncommon as spontaneous entity in laboratory rats. C. Preputial and clitoral gland 1. General information a. Are large organs in the rat, eg. 10 mm long x 5 mm wide. b. Consist of a large central duct surrounded by modified sebaceous cells. c. Located on either side of prepuce or vulva. 2. Adenomas may be acinar or squamous 3. Preputial/clitoral gland adenocarcinomas a. Occur in a low incidence as spontaneous entity. b. A few are malignant, and metastasize to the lungs. c. Must be distinguished from inguinal mammary gland neoplasms. d. Most characteristic microscopic feature of acinar preputial/clitoral gland neoplasms is brightly eosinophilic cytoplasmic granules. 4. Duct ectasia a. Consists of dilatation of the central lumen, sometimes with impacted secretory material. May be seen grossly as a discolored focus in the center of the gland. b. Inflammation is variable. D. Ovary 1. Atrophy a. Present in virtually all rats at terminal sacrifice on chronic study. b. Consists of reduction in number of follicles and corpora lutea with a variable amount of intracellular pigment in stromal cells. 2. Hyperplasia, interstitial gland (stromal) a. Frequently in combination with atrophy will see hyperplasia of the interstitial glands. 3. Cysts a. Parovarian cysts consist of dilatation of the ovarian bursa. May be difficult to detect on microscopic examination. b. Intraovarian cysts. Exact genesis unknown. Are present in the ovarian parenchyma, therefore are microscopically distinct from parovarian cysts. 4. Papilloma of ovarian rete a. Uncommon, but not rare. b. Seen in the hilar region of the ovary. c. Typical papilloma contained with a dilated tubular structure. 5. Teratoma a. Uncommon, but not rare. b. All three germ layers present. Epithelium and neural tissue are usually most prominent. The mesodermal element may be muscle, fat or other elements 6. Granulosa/theca cell tumors a. Occur in low incidence. b. Microscopically similar to other species. 7. Cystadenomas/adenocarcinomas a. Uncommon. 8. Dysgerminoma a. Not reported in the rat. E. Uterus 1. Wall of uterus and cervix commonly has eosinophil infiltration 2. Mild dilatation is common in young rats 3. Cystic endometrial hyperplasia a. Not as common in rat as in mouse. b. In the rat is primarily cyst formation. The rat has less epithelial proliferation than the mouse. 4. Endometrial fibrosis a. May be normal for old rats. 5. Endometrial stromal polyp a. Very common in old rats. b. Consists of a polypoid mass of endometrial stroma and capillaries covered by epithelium. c. May be infarcted by torsion or other disruption of the stalk. 6. Endometrial stromal sarcoma a. The malignant counterpart of endometrial stroma polyp. b. Some degree of invasiveness is an important criterion in diagnosis. 7. Cystic dilatation of vaginal fornix a. Gross observation of mass near body of uterus or in cervix. b. Lined by stratified squamous epithelium and filled with keratinaceous debris. May contain a neutrophilic infiltration, to the degree that they resemble abscess. F. Mammary gland 1. Sexual dimorphism a. Mammary glands of males and females are microscopically similar at birth. b. By 19 weeks, males and females are markedly different: (1) Females have widely scattered tubuloacinar units. (2) Males have more prominent glandular tissue, but not organized into ductular units. 2. Senescent atrophy a. Decrease in glandular elements with intraluminal concretions and accumulations of pigment-laden cells. 3. Duct dilatation a. Moderately common in aged females. b. Cystic mammary ducts often called galactoceles. 4. Lobular hyperplasia a. Enlarged lobules with relatively normal appearing alveoli. b. Cystic alveoli and dilated ducts may be present. c. Lack a prominent collagenous stroma, which early fibroadenomas have. 4. Fibroadenoma a. Very common neoplasms in aged females, with a lower incidence in aged males. b. May be multiple, and may be nearly as large as the rat. c. Rats have mammary tissue on nearly the entire body, with the exception of the head, tail and distal extremities. Any subcutaneous neoplasm on the trunk of a rat may be a mammary neoplasm. d. Consist of epithelial elements surrounded by proliferating fibrous connective tissue. e. Some neoplasms consist almost entirely of fibrous connective tissue. f. Ovariectomy significantly decreases the incidence of mammary fibroadenomas in female rats. VII. Lymphoreticular and Hematopoietic Systems A. Spleen 1. Increased hemosiderin a. Rat spleen normally has a moderate amount of hemosiderin. More in females than males. b. May be markedly increased in some animals, due to diverse causes. c. Difficult to establish criteria for distinguishing between normal and excessive hemosiderin. 2. Increased extramedullary hematopoiesis a. Rat spleen normally has a small amount of EMH. b. Chronic disease process, eg. neoplasms, commonly are associated with an increase in the level of splenic EMH. c. Difficult to establish criteria for distinguishing between normal and excessive EMH. 3. Mesothelial cyst a. Not uncommon. b. Usually disrupted in processing, with only fibrous tags remaining on surface of spleen. B. Lymph nodes 1. Cystic degeneration a. Consists of cystic dilatation of sinusoids. b. Often so prominent as to be noted at necropsy. 2. Plasmacytosis a. Commonly seen in mandibular lymph nodes. b. May be so prominent as to be noted grossly. c. Medullary region consists of sheets of mature plasma cells. d. Etiology and significance unknown. Seem to be more prominent in association with oral cavity lesions. 3. Senescent atrophy a. Nearly ubiquitous in chronic studies. b. Consist of reduction in lymphoid follicles with a moderate amount of intracellular pigment in medullary area. 4. Mast cells a. Rats have numerous mast cells in many organs. b. Are very obvious when in lymph nodes. 5. Mesenteric lymph node hemangioma a. Uncommon, but not rare in mesenteric lymph nodes. b. Rare in other lymph nodes. C. Thymus 1. Epithelial remnants a. Epithelial tubules or nests in medullary region of thymus of old rats. b. Occasionally see neoplasms of these epithelial elements. 2. Thymic cysts a. May be lined by squamoid cells or tall columnar cells with cilia. 3. Ectopic thymus in thyroid a. Relatively common within or adjacent to the thyroid. 4. Atrophy/involution a. Thymus often difficult to identify at necropsy in aged animals. 5. Thymoma a. Consist of a mixture of "epithelial" and lymphoid elements, similar to other species. b. May have epithelial tubules. c. Often have a moderate population of eosinophils. D. Systemic 1. Large Granular Lymphocyte (LGL) Lymphoma/Leukemia a. Formerly called mononuclear cell leukemia. b. Very common neoplasm in F344 rat. Rare, but occurs in Sprague-Dawley. Reported in Wistar and Wistar-Furth. c. Splenic architecture is effaced by sheets of individualized neoplastic cells. d. Cell morphology is not specific on H&E sections. e. Can involve virtually any organ in the body. f. Early leukemic infiltrates are in the spleen and liver. Are more easily detected in the liver. g. 30-50% of early deaths in 2-year F344 study are due to this disease. h. Death apparently due to hemolytic anemia. Also thrombocytopenic. i. Bone marrow involvement results in reduced bone formation. j. Large granule lymphocytes are NK (natural killer) cells. Constitute 1-5% of normal rat peripheral leukocyte count. k. Large granule lymphocytic leukemia has been reported in man and a cat. 2. Granulocytic leukemia (myelogenous leukemia) a. Uncommon, incidence < 5%. b. Distinct myelogenous differentiation of neoplastic cells. Granulocytic differentiation more common than erythroid or basophilic. c. May be induced by ionizing radiation or some chemical agents. 3. Lymphoma (lymphosarcoma) a. May be classified as follicular center cell, immunoblastic, plasma cell, or lymphoblastic, but usually not typed in routine carcinogenicity studies. Most are B cell origin. b. Slight higher incidence than LGL or granulocytic leukemia, approximately .5-.9% in our laboratory. VIII. Sense Organs A. Eyes and Harderian glands 1. Cataracts and retinal degeneration a. Common in older rats. b. Retinal degeneration may be due to excessive light in animal rooms. c. Careful cage rotation schedule is necessary to prevent excessive incidence in one group. d. Microscopically similar to other species. e. Retinal degeneration often is secondary to cataract, but can occur independently. 2. Phthisis bulbi a. Rupture of the eye due to trauma from cage wire or retrobulbar bleeding. 3. Scleral osseous metaplasia a. Common, more in F344 than in SD. b. Linear or ovoid foci of mineralization or ossification in the middle layers of the sclera, most commonly in the middle or posterior thirds of the eyeball. 4. Keratitis a. Common in rats kept in wire cages and in gang-caged rats. 5. Corneal dystrophy/mineralization a. Common in F344. 6. Porphyrin accumulation in Harderian gland a. Cause of "red tears". b. Nonspecific change, indicating a sick rat. 7. Exorbital lacrimal gland a. Cellular pleomorphism is normal. b. Often get differentiation of Harderian gland type acini. IX. Central Nervous System A. Brain 1. Vacuoles and mucocytes a. Vacuoles commonly seen in otherwise normal brains. b. Mucocytes are vacuoles that contain amorphous gray material. c. Etiology and significance unknown. Probably both are artifacts. d. Mucocytes are reported to be more common in brains that are immersed in alcohol. 2. Lipofuscin pigmentation of neurons a. Microscopically similar to other species. 3. Compression of the brain stem a. Results from expansion of pituitary adenoma. 4. Astrocytoma a. Astrocytomas are fairly common in brain, and rarely occur in spinal cord. 5. Granular cell tumor a. Usually in the superficial cortex, near the meninges. b. Distinctly bounded, as opposed to gliomas. c. Distinctly granular cytoplasm in polygonal neoplastic cells. Granularity is enhanced by PAS stain. B. Spinal cord 1. Degenerative myelopathy a. Posterior paresis or ataxia. b. Lesions in the spinal cord and nerve roots, principally the ventral and lateral white tracts from T4 - L4 region and the ventral spinal roots from mid-thoracic area posteriorly. c. May occasionally see degenerative changes in the sciatic nerve. d. Characterized by demyelination, distended axon sheaths, swollen or absent axons, lipid filled macrophages, and reactive glial cells. 2. Chordoma a. Neoplasm derived from primitive notochord elements. b. Characterized by large vacuolated "physaliphorous" cells. X. Musculoskeletal System A. Skeletal muscle 1. Atrophy of skeletal muscle a. Relatively common, often secondary to degenerative myelopathy. b. Reduction in cross-sectional area of myofibers, with apparent or real increase in endomysial connective tissue. B. Bone 1. Fibrous osteodystrophy a. Common in association with spontaneous nephropathy. 2. Degeneration of sternebral cartilage a. Degenerative cleft formation in intersternebral cartilage is commonly seen. b. Similar changes are reported in vertebra, but these bones are not as commonly sectioned in chronic studies. XI. Integumentary System A. Skin 1. Tarsal granulomas a. Common in rats that are kept in wire cages, and especially in heavier animals. So, more common in males. b. May be very large. 2. Keratoacanthoma a. Common. b. Must be differentiated from squamous papillomas and epidermal inclusion cysts. 3. Amelanotic melanoma a. Probably more common than incidence summaries show. b. Solid sheets of spindled and interlacing cells, usually diagnosed as a neurofibroma/sarcoma or fibroma/sarcoma. c. Electron microscopy shows characteristic premelanosomes. 4. Epidermal inclusion cyst a. Very common, particularly on tail. b. Consist of a cystic space filled with keratinaceous debris and lined by maturing stratified squamous epithelial cells. c. Some may have a neck-like connection to the surface. 5. Chronic inflammation, tail a. Focal to multifocal crusty lesions. b. Chronic inflammation with acanthosis and hyperkeratosis. c. Some lesions may be epidermal inclusion cysts or keratoacanthomas. 6. Auricular chondritis a. Distortion and mineralization of the auricular cartilage. b. Possibly associated with trauma. c. Reported to be a heritable collagen disease in some strains. B. Zymbal's gland 1. Large gland that lies around the external ear canal 2. Very susceptible to carcinogenic influence 3. Carcinomas may be very large. May have both sebaceous and squamous elements, or either element alone 4. Rarely invade into the brain, presumably along cranial nerve tracts DISEASES AND NEOPLASMS OF THE AGING RAT JAMES B. NOLD and GEORGE A. 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INTEGUMENTARY SYSTEM Chiu, T, and KP Lee: Auricular chondropathy in aging rats. Vet. Pathol. 21: 500-504, 1984. Greaves, P, and JM Faccini: Fibrous histiocytic neoplasms spontaneously arising in rats. Br. J. Cancer 43: 402-411, 1981. Greaves, P, J-M Martin, and M-T Masson: Spontaneous rat malignant tumors of fibrohistiocytic origin: an ultrastructural study. Vet. Pathol. 19: 497-505, 1982. Reznik, G and JM Ward: Morphology of hyperplastic and neoplastic lesions in the clitoral and preputial gland of the F344 rat. Vet. Pathol. 18:228- 238, 1981. Squire, RA, et al: Histiocytic sarcoma with a granuloma-like component occurring in a large colony of Sprague-Dawley rats. Am. J. Pathol. 105: 21-30. 1981. Ward, JM, et al: Malignant fibrous histiocytoma. An unusual neoplasm of soft tissue origin in the rat that is different from the human counterpart. Arch. Pathol. Lab. Med. 105: 313-316, 1981. Yoshitomi K and Boorman GA: Palpebral amelanotic melanomas in F344 rats. Vet. Pathol. 30:280-286, 1993. Yoshitomi, K, et al.: Pathology and incidence of amelanotic melanomas of the skin in F-344/N rats. Toxicol. Pathol., 23(1):16-25, 1995. Zwicker, GM et al: Spontaneous skin neoplasms in aged Sprague-Dawley rats. Toxicol. Pathol. 20: 327-340, 1992. CONNECTIVE TISSUE Coleman, GL: Four intrathoracic hibernomas in rats. Vet. Pathol. 17: 634-637, 1980. Kerry, PJ, et al.: Identification of a spontaneous pleomorphic rhabdomyosarcoma in the thoracic and abdominal cavities of a female Wistar rat. Vet. Pathol. 32:76-78, 1995. Stefanski, SA, MR Elwell and K Yoshitomi: Malignant hibernoma in a Fischer 344 rat. Lab. An. Sci. 37: 347- 349, 1987. HISTORICAL CONTROL DATA Chandra, M, and Frith, C H: Spontaneous neoplasms in B6C3F1 mice. Toxicol. Lett. (Amst), 60:91-98, 1992. Dixon D, et al.: Incidence of nonneoplastic lesions in historical control male and female Fischerr-344 rats from 90-day toxicity studies. Toxicol. Pathol. 23(3):338-348, 1995. Haseman, J K: Value of historical controls in the interpretation of rodent tumor data. Drug Information Journal, 26:191-200, 1992. Haseman, J K, et al.: Use of dual control groups to estimate false positive rates in laboratory animal carcinogenicity studies. Fundamental and Applied Toxicology, 7:573-584, 1986. Haseman, J K, et al.: Use of historical control data in carcinogenicity studies in rodents. Toxicol. Pathol., 12:126-135, 1984. Haseman JK, et al.: Neoplasms observed in untreated and corn oil gavage control groups of F344/N rats and (C57BL/6N x C3H/HEN)F, (B6C3F1) mice. J. Natl. Cancer Instit. 75: 975-984, 1985. Haseman, J K: Issues in carcinogenicity testing: Dose selection. Fundam. Appl. Toxicol. 5:66-78, 1985. Haseman, J K: Use of statistical decision rules for evaluating laboratory animal carcinogenicity studies. Fundam. Appl. Toxicol., 14:637-648, 1990. Iwata, H, et al.: Historical control data of organ weight and gross findings in F344/DuCrj rats and B6C3F1 mice. Jikken Dobutsu (Japan) 42:383-396, 1993. Lang, Patricia L: Spontaneous Neoplastic Lesions and Selected Non-neoplastic Lesions in the Crl:CD BR Rat. Charles River Laboratories, 1992. Lang, Patricia L: CD-1 Mouse Liver Tumors in 24 Month Studies, from Charles River Historical Database, 1993 (personal communication), unpublished. Lin K K, and Ali, W A: Statistical review and evaluation of animal tumorigenicity studies, Chpt. 2, In: Statistics in the Pharmaceutical Industry, 2nd Ed., C. R. Buncher and J-Y Tsay, eds., 1994. Lijinsky, W, et al.: Lack of effect of carcinogen treatment on development of tumors arising spontaneously in Fischer 344 rats. Journal of Toxicology and Environmental Health, 39:527-538, 1993. McConnell, E E, et al.: Guidelines for combining neoplasms for evaluation of rodent carcinogenesis studies. JNCI, 76:283-289, 1986. McMartin, D N, et al.: Neoplasms and related proliferative lesions in control Sprague-Dawley rats from carcinogenicity studies. Historical data and diagnostic considerations. Toxicol. Pathol., 20:212-225, 1992. Morawietz, G, et al.: RITA registry of industrial toxicology animal - data progress of the working group. Exp. Toxicol. Pathol., 44:301-309, 1992. NTP Data. Tumor Incidence in Control Animals by Route and Vehicle of Administration - F344/N Rats. Toxicology Data Management System. National Institute of Environmental Health Sciences, POB 12233, Research Triangle Park, NC 27709, July 6, 1993. NTP Data. Tumor Incidence in Control Animals by Route and Vehicle of Administration - B6C3F1 Mice. Toxicology Data Management System. National Institute of Environmental Health Sciences, POB 12233, Research Triangle Park, NC 27709, April 27, 1993. Prentice, R L, et al.: On the use of historical control data to estimate dose response trends in quantal bioassay. Biometrics, 48:459-478, 1992. Vater, S T, et al.: Biological considerations for combining carcinogenicity data for quantitative risk assessment. Regulatory Toxicology and Pharmacology, 18:403-418, 1993. Walsh, K M, and Poteracki, J: Spontaneous neoplasms in control Wistar rats. Fundamental and Applied Toxicology, 22:65-72, 1994. Woutersen, R A: Incidence of tumors in CPB:WU Wistar random rats. Data of control animals from long-term studies. TNO-report V 92.087. POB 360, 3700 AJ Zeist, Utrechtseweg 48, 3704 HE Zeist, The Netherlands. February 1992. Yamamoto, T, et al. Mortality body weight food and water consumptions and clinical signs in SLC B6C3F-1 C57BL-6XC3H mice utilized in chronic toxicity and carcinogenicity studies. Exp. Anim. (Tokyo), 42:397-404, 1993. Clinical Pathology Historical Control Data Galen, R S: The normal range: a concept in transition. Arch Pathol Lab Med, 101:561-565, 1977. Watare, N, et al.: Age-associated historical data of the hematology and blood biochemistry in F344 rats and B6C3F1 mice. J. Toxicool. Sci., 15:223 (abstract), 1990. 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