Alveolar Histiocytosis. Non-infectious conditions of Rats. Alveolar Histiocytosis

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1 Non-infectious conditions of Rats Charles B Clifford, DVM, PhD, DACVP Charles River Alveolar Histiocytosis Synonym: Alveolar lipidosis Prevalence: Very high in aged rats, moderate in younger animals may be >50% in F-344 rats, also common in SD. Grossly: visible as white to pale tan foci, usually about 1 mm in diameter, visible on the pleural surface foci may extend slightly above the pleural surface in uninflated lung may be numerous Alveolar Histiocytosis cause is unknown, not considered to be infectious should not be mistaken for any of the infectious pneumonias of rats, e.g., P. carinii animals are seronegative any lymphoid infiltrate is slight and localized perivascular lymphoid cuffing not a prominent feature hemosiderin is not a feature; would suggest previous hemorrhage

2 Eosinophilic Granulomatous Pneumonia of Brown Norway Rats Prevalence: Very high in Brown-Norway rats Observed in BN rats of all ages, from Asia, North America and Europe, and in rats of any health status, including gnotobiotic Cause is unknown, may be related to a hypersensitivity reaction special stains are negative, as are cultures and serology Chronic Progressive Nephropathy Synonyms: Chronic Progressive Nephrosis, Chronic Progressive Glomerulonephropathy, Progressive Renal Disease, and Old Rat Nephropathy Prevalence: Very high, especially in males May be minimal lesions by 3-6 months of age in some strains (F- 344, SD) Most important age-related disease of rat kidneys Among most common causes of death in rats in lifetime studies

3 Chronic Progressive Nephropathy Microscopically: glomerular changes are characterized by thickened basement membranes, thickening of the capillary tufts, adhesions to the parietal layer of Bowman s membrane, and segmental glomerulosclerosis. with progression, numerous tubules in both the cortex and medulla are often dilated and filled with eosinophilic proteinaceous casts can have mild multifocal nonsuppurative interstitial inflammation Secondary hyperparathyroidism may occur, resulting in widespread mineralization Chronic Progressive Nephropathy Etiopathogenesis poorly understood, probably multifactorial First, genetic predisposition Sprague-Dawley and F344 rats have high incidence Wistar and Long-Evans stocks have lower incidence Esp. high in hypertensive rats Second, sex Males have earlier onset, higher incidence at any given age, and greater severity of lesions than do females

4 Chronic Progressive Nephropathy Etiopathogenesis - continued Third, Diet - mechanism hypothesized to be: overfeeding >> prolonged increases in renal blood flow and GFR >> glomerular hypertrophy >> macromolecule filtration deficits, mesangial damage, glomerulosclerosis, and protein leakage Protein levels in diet may also play a secondary role Chronic Progressive Nephropathy Diet control to reduce CPN Regardless of actual mechanism, 25-30% caloric reduction: decreases incidence and severity of CPN in female rats decreases severity of CPN in male rats increases survival in both sexes Nephrocalcinosis Prevalence: High, especially in females Defined as the deposition of calcium phosphate in renal tissue Additional terms are sometimes employed to reflect location in cortex, medulla, etc. Nephrocalcinosis In addition to gender, the incidence varies with age and strain may occur in F-344 rats by 7 weeks incidence in F-344 rats may reach 50%, compared to 0 7% Sprague-Dawley and Wistars An especially high incidence and severity is observed in BDIX rats Nephrocalcinosis The incidence and severity of nephrocalcinosis may be increased by dietary manipulation high levels of calcium high phosphorus low calcium:phosphorus ratios low magnesium Unknown if dietary levels of these minerals cause spontaneous background incidence Nephrocalcinosis Grossly: Larger mineral depositis may appear as pale areas, and may be crepitous when cut Microscopically: Mineral deposition is observed most frequently at the corticomedullary junction, in cells of the pars recta and thin loops of Henle, as well as in the lumen of these tubules

5 Hydronephrosis Prevalence: Very high in Brown Norway, Gunn and Zucker Low to moderate in many other strains Generally higher in males than females Higher in right kidney than left Hydronephrosis Grossly: Appearance may vary from normal to greatly enlarged and translucent Associated with urothelial hyperplasia and hemorrhage resulting in hematuria in the Brown Norway and the Lewis x Brown Norway rat

6 Cardiomyopathy Synonyms: Murine Progressive Cardiomyopathy, Chronic progressive cardiomyopathy, myocardial degeneration and fibrosis Prevalence: A major cause of death in aged male rats of many strains, when fed ad libitum, including Sprague-Dawley and F-344. May be observed (minimal severity) as early as three months of age. Reported incidence varies greatly Probably different thresholds by different pathologists Cardiomyopathy Grossly, heart may be enlarged, occasionally with pale streaks increased heart weight correlates well with histologic severity Microscopically, myocardial necrosis interstitial infiltration of mononuclear cells later, fibrosis may be more prominent large reactive nuclei are also observed in myofibers most commonly affected sites are apex, papillary muscles, left ventricular free wall and interventricular septum Cardiomyopathy The incidence and severity of cardiomyopathy can also be dramatically reduced at any age by moderate dietary restriction, i.e., reduction of 25-30% of total caloric intake relative to ad libitum overfed rats

7 Arteritis Synonyms: Panarteritis nodosa, Periarteritis, Polyarteritis Prevalence: Moderate. Very high in Spontaneously Hypertensive Rats (SHR), higher in males Grossly - thickened tortuous arteries, especially in mesenteric arcade Also suspensory connective tissue of spleen, pancreas and testis. Can occur in almost any tissue, but not reported in lung Microscopically Fibrinoid necrosis of intima and media, Mural leukocytic infiltration. Chronically - intimal hyperplasia, medial fibrosis and periarterial fibrosis and dense infiltrations of leukocytes. Arterial stenosis or thrombosis may occur. Hypertension Can lead to arteriosclerosis Common in aging rats of many strains Very common in Spontaneous Hypertensive Rat (SHR) Susceptible strains, e.g., SHR-SP, can also develop malignant hypertension Onion-skin appearance to affected vessels in heart, kidney.

8 Ringtail Prevalence: Sporadic and infrequent Affects rats and mice Primarily a disease of sucklings and weanlings Cause: Never experimentally reproduced (nothing in literature) Historically reported to be associated with low humidity Ringtail Grossly: tails swollen, with annular constrictions distal portions more severely affected may have distal necrosis Must distinguish from bite wounds, other trauma, infarcts, etc.

9 Ringtail Microscopically: Acanthosis, hyperkeratosis Subepidermal congestion Epidermis often intact (compared to ulcers with serocellular crusting in bite wounds) Age-related changes in the skin Prevalence: Very high Often observed but rarely reported Alopecia: especially on the dorsum very common in Brown Norway rats Age-related changes in the skin Old albino rats appear more yellow with age, due to accumulation of sebum The rings of scales covering tail increase with age to 190 at 1 year, and become more prominent and more yellow with time Yellowish material on the tail and at the base of the ear also may become black with time, probably from oxidation and/or bacterial action Age-related changes in the skin Male rats accumulate brown pigmented foci on the skin, termed scales, occasionally reported as freckles scales can be detached, and overlay skin of normal color found on the dorsum, and some on the tail and perineum scale formation is abrogated by gonadectomy nature of scale pigment is unclear, but may be oxidized lipid or amino acids

10 Auricular Chrondropathy Prevalence: Low to moderate Synonyms: Auricular chondritis, cauliflower ear Grossly: Nodular thickening and distortion of pinna May sometimes be associated with inflammation, triggered by eartags Also observed in rats without eartags Malocclusion Prevalence: Low to moderate Malocclusion of incisors most often observed in older rats, and may be associated with gingivitis It can be caused by lack of wear on incisors (powdered diet) Sporadically observed in younger rats, in which it may either be congenital or due to trauma

11 Osteoarthritis Synonym: Degenerative joint disease Prevalence: Moderate Cause unknown, but age-related, likely related to weight May also be induced experimental model - Collagen, adjuvant, etc. Osteoarthritis may have a higher incidence in animals housed in wire-bottom caging (rarely used now) Tarsal joints are affected most, and may appear grossly thickened Histologically, there is erosion of articular cartilage and degeneration of the matrix Tinctorial change, fibrillation, proliferation, necrosis, bone lysis, synovial hyperplasia, etc.

12 Endocrine Neoplasms Neoplasia Endocrine neoplasms are the most common spontaneous tumors of aged Sprague-Dawley, Wistar-Han, and F344 rats (except interstitial cell tumors and LGL leukemia in male F344) Pituitary Thyroid Adrenal Medulla Pituitary Neoplasms Tumors of the pars distalis are the most common tumors of the pituitary. Other tumors are infrequent Most are adenomas Most are chromophobe adenomas By immunohistochemistry, most secrete prolactin Pituitary Neoplasms Grossly, the pituitary is enlarged and often hemorrhagic Microscopically: adenomas are expansile and sharply delimited cells are larger than normal, with abundant pale cytoplasm (chromophobes) and have enlarged vesicular nuclei histologic pattern may vary mitoses are occasionally observed (low rate)

13 Pituitary Neoplasms Carcinomas are more infiltrative, but rarely metastasize. Criteria for carcinoma = metastasis or aggressive invasion (STP, 1990) Multicenter control group data for Sprague-Dawley (CD) rats show much variation in use of the term carcinoma some large studies have no carcinomas in control rats in others, most of the pituitary tumors are considered malignant total number of pituitary tumors (adenomas plus carcinomas) is fairly consistent at ~ 70-80% in females and 50-70% in males. Thyroid Neoplasms The most common thyroid tumors are C-cell neoplasms (>5%), followed by follicular cell tumors No sex predilection C-cell adenomas defined as compressive masses of C- cells, with diameter > 5 average follicular diameters Smaller C-cell proliferations are termed hyperplasia Thyroid Neoplasms C-cell adenomas: cells closely resemble normal, may be oblong if compressed Carcinomas: pleomorphic cells usually a high mitotic rate usually vascularized and may have areas of mineralization, necrosis and hemorrhage Key criteria for carcinomas = invasion, necrosis, metastasis

14 Pheochromocytomas Incidence in 2 year studies (benign + malignant) F-344 rats: ~ 26% in males, 6% in females CD rats: ~ 13% in males, 3% in females Wistar-Han rats: ~ 3% in males, 2% in females Pheochromocytomas Benign pheochromocytomas, synonymous with pheochromocytomas: defined as a discrete mass of cells arranged in islets or trabeculae may be confined to the medulla or may compress the cortex some atypia may be present, with cells smaller than normal, and with more basophilic cytoplasm mitotic rate is variable Malignant pheochromocytomas: defined as pheochromocytomas which invade the capsule or metastasize

15 Mammary Neoplasms Incidence: CD rats: > 50% of control female CD rats will usually have mammary tumors at the conclusion of a two-year study F344 and Wistar Han rats: up to 30% Incidence in male rats usually < 1% In females, most are fibroadenomas, with carcinomas being 2nd most common Age of onset delayed by caloric restriction Mammary Neoplasms Fibroadenomas: firm, circumscribed, lobulated, subcutaneous masses may be located anywhere along mammary chain may become massive and ulcerated if rats are not euthanized ulceration can cause anemia composed of varying ratios of fibrous tissue and ductal epithelium fibrous tissue appears mature ductal epithelium may vary from a single layer of cuboidal cells with no atypia to focal epithelial proliferation, pleomorphism, moderate atypia and increased mitotic rate. Cysts lined by attenuated epithelium may also be present.

16 Mammary Neoplasms Adenomas: discrete, circumscribed masses composed almost entirely of glandular epithelial structures with scant stroma if alveoli are formed, they may be empty or distended with secretions the epithelium is usually uniform, cuboidal to columnar cytoplasmic vacuolation may be present there is usually little or no atypia mitotic rate may be slightly elevated may have tubular, secretory, papillary or cystic papillary patterns Mammary Neoplasms Adenocarcinomas: distinction of adenoma vs. adenocarcinomas is controversial, as rat mammary tumors seldom metastasize or even invade locally tumors with marked atypia, a high nucleus to cytoplasm ratio, variable growth patterns, high mitotic rates or abnormal mitoses are considered malignant the rare tumors that invade or metastasize are unequivocally considered malignant adenocarcinomas may have multiple patterns; more common patterns are papillary, tubular, cribriform and comedo

17 Lymphoreticular Neoplasms Prevalence: CD and Wistar Han, both sexes: ~ 2-3% F344 rats: ~ 33% for males and 20% for females, virtually all of which are mononuclear cell leukemia Rat lymphoid neoplasms are NOT thought to be retroviral-associated Lymphoreticular Neoplasms Large Granular Lymphocyte leukemia: also called large granular lymphocytic leukemia, or LGL lymphoma or leukemia also reported in other rat strains, including Wistar and Wistar-Furth arise in marginal zone of spleen, soon spread to the liver, lung, lymph nodes previously thought to arise from NK cells, then thought to have a more heterogeneous lymphocyte origin, now seem to be considered NK cells Lymphoreticular Neoplasms Large Granular Lymphocyte leukemia: Grossly, usually marked splenomegaly and hepatomegaly, with variable lymphadenopathy Microscopically : cells are small, non-cohesive, pleomorphic relatively small amount of cytoplasm which stains reddish nuclei are irregular, round to reniform, and may be eccentric, with sparse chromatin and small nucleoli mitotic rate is low Neoplastic cells can diffusely involve the spleen, hepatic sinusoids, and pulmonary interstitium

18 Skin Neoplasms In CD, Wistar Han and F344 strains, male rats have approximately 10% incidence of skin neoplasms, compared to 5% in females. The most common tumors are fibromas and squamous cell neoplasms, especially the keratoacanthoma Fibromas: Skin Neoplasms benign tumors consisting of dense interwoven bands of collagen, with only a few fibroblasts, and little or no cellular pleomorphism or mitotic activity some care required, to insure that fibromas are distinguished from mammary fibroadenomas Fibrosarcomas are much less frequent in rat skin, and are easily distinguished by their much greater cellularity, often with much pleomorphism, a high mitotic rate, and local invasion Squamous cell neoplasms: papillomas: Skin Neoplasms resemble those in other species exophytic, with a well-differentiated stratified squamous epithelium covering a fibrovascular core Non-viral in origin

19 Skin Neoplasms Squamous cell neoplasms: keratoacanthomas (cutaneous horn is considered a variant): probably also arise from a squamous cell these are invaginations, sometimes multilocular, which communicate with the surface via a pore lined by thick stratified squamous epithelium and filled with keratinaceous epithelium may progress to squamous cell carcinoma

20 Skin Neoplasms Squamous cell neoplasms: Squamous cell carcinomas: invasive tumors which usually extend into the subcutis usually composed of multiple nests of pleomorphic cells may have markedly enlarged nuclei and prominent nucleoli may metastasize. Sebaceous adenoma of preputial gland Prevalence: Testicular Neoplasms common in aging rats of many strains ~ 88% in F344 rats ~ 3% in CD and Wistar Han rats most testicular tumors in the CD and Wistar Han and virtually all in the F344 rat are interstitial cell tumors Testicular Neoplasms Interstitial cell tumors: grossly: appear as circumscribed, yellow or white testicular masses, often hemorrhagic can be bilateral can be multiple within one testis

21 Testicular Neoplasms Interstitial cell tumors: Microscopically: interstitial cell masses < 3 seminiferous tubule diameters are considered focal hyperplasia can be seen at a high incidence in F344 rats < 1 year old adenomas are > 3 tubule diameters, compress adjacent tubules. cells show pleomorphism or an increased nucleus:cytoplasm cells enmeshed in endocrine-type sinusoidal network may have necrosis, hemorrhage, and pseudocysts Interstitial cell tumors: Microscopically: Testicular Neoplasms Almost all interstitial cell tumors are considered benign Malignant designation should be reserved for tumors that invade structures adjacent to the testis or metastasize

22 Mesotheliomas Often tabulated with testicular neoplasms, as they often arise on the tunica vaginalis. More properly, should be categorized as tumors of body cavities Prevalence: primarily in males < 1% in male CD rats ~ 3% in male Wistar Han and F344 rats Mesotheliomas All mesotheliomas are considered malignant Grossly visible as white or beige plaques on the tunica vaginalis or throughout the abdomen (spontaneous thoracic mesotheliomas are very rare) Mesotheliomas Microscopically: Neoplastic foci consist of complex papillary structures Prominent, well vascularized stroma covered by one or more layers of cuboidal cells Spread throughout the peritoneum is common Mesotheliomas must be distinguished from mesothelial hyperplasia, which is common Hyperplasia, usually not visible grossly, has focal thickening, occasionally papillary projections, but no stratification or fibrovascular stalk

23 More background tumor incidence data are available at: Thanks for your attention!