2018 Rat Gross Path - flashcards | Quizlet

Wistar: original outbred albino lab rat; common in Europe; relatively small; long lived

Sprague‐Dawley (SD): derived from Wistar; early sexual maturity; large F344: commonly used by NIH; small; long lived

Two common rat strains and their general phenotypes?

Salivary gland

Diffuse necrotizing sialoadenitis with edema

(normal in a)

Sialodacryoadenitis virus (SDAV)

(Rat coronavirus)

Highly contagious. Transmitted by aerosol, contact, fomites. High morbidity, low mortality.

Gross: chromodacryorrhea; swollen salivary glands with edema and necrosis; enlarged cervical lymph node; rhinitis; interstitial pneumonia; eye lesions due to Harderian gland damage (keratoconjunctivitis, corneal ulcer, megaloglobus, exophthalmos, hypopyon, hyphema)

Histo

- Sialoadenitis (parotid and submaxillary salivary glands) and dacryoadenitis (Harderian and other lacrimal glands) with ductal edema, necrosis and/or squamous metaplasia

- Interstitial pneumonia with necrotizing bronchitis and bronchiolitis; hyperplastic BALT

- Necrotizing laryngitis, tracheitis, and rhinitis +/- epithelial hyperplasia

- Ocular changes secondary to lacrimal gland damage (keratitis sicca, impaired drainage, hyphema, megaloglobus)

DDx: cytomegalovirus, papovaviral sialoadenitis (athymic nude rats), hypovitaminosis A (squamous metaplasia of salivary gland ducts)

Eye

Megaloglobus with hyphema

Sialodacryoadenitis virus (SDAV)

(Rat coronavirus)

Scrotum

Multifocal scrotal hemorrhage

Kilham's rat virus or Rat virus

One of several rat parvoviruses. Common in lab, wild, and pet rats. Common contaminant in biological products.

Transmission: oronasal, transplacental, milk, feces, urine, fomites Pathogenesis

- Infects rapidly growing cells: vascular endothelium, lymphoreticular and hematopoietic tissues, developing cerebellum and liver

- Endotheliotropic: causes thrombosis and infarction

Gross

- Congestion and hemorrhage (scrotal and testicular site is classic) - Hemorrhagic encephalopathy with malacia

- Cerebellar hypoplasia (neonates if in utero infection)

- Decreased fertility, fetal resorption, small litters, runts possible

Histo

- Endothelial cell and megakaryocyte damage -> hemorrhage, thrombosis, necrosis

- IN inclusions

Brain (fixed)

Multifocal cerebral and cerebellar hemorrhage and malacia

Kilham's rat virus or Rat virus

Lung

Multifocal to coalescing necrosuppurative pneumonia +/- pleuritis

Pseudotuberculosis

Corynebacterium kutscheri

Transmission: direct contact, oronasal. Persistent asymptomatic carriers common (latent infections may advance with age and immunosuppressive conditions - stress, other infections, irradiation, experimental manipulation). Low morbidity, high mortality in affected. Lesions in any tissue, but in rat, lung is major site. Septic emboli trapped in organs or tissues with large capillary network (lung, liver, kidney) and/or responsible for filtering blood (synovia, glomeruli).

Gross: systemic suppurative inflammation w/ necrosis

- Lung: abscesses +/- hemorrhage and pleuritis (fibrinous or fibrous)

- Abscesses in liver, kidney, preputial glands, skin

- Suppurative arthritis, otitis media, pododermatitis

- Hepatic necrosis, pyelonephritis, fistulous tracts in skin

Histo: bacteria prominent in lesions

- Lung: interstitial abscesses (hematogenous spread), caseous necrosis, suppurative exudate in airways

- Liver: caseous necrosis

- Kidney: embolic glomerulitis, abscesses, +/- pyelonephritis

DDx: opportunistic bacteria, Mycoplasma, fungal pneumonia

Lung (fixed)

Multifocal to coalescing necrosuppurative pneumonia +/- pleuritis

Pseudotuberculosis

Corynebacterium kutscheri

Kidney

Multifocal suppurative embolic nephritis

Pseudotuberculosis

Corynebacterium kutscheri

Heart, liver

Multifocal necrotizing myocarditis and hepatitis

Tyzzer's Disease

Clostridium piliforme

Transmission: ingestion of infective spores from feces/contaminated food or bedding/environment (up to 1 yr).

Gross: focus on intestine, liver, heart

- Multifocal necrosis in liver, heart

- Megaloileitis: greatly dilated, hyperemic ileum

- Terminal ileum, LI: hyperemia, edema, hemorrhage, and/or necrosis

- Mesenteric ln: enlarged, hyperemic and edematous

Histo

- Necrotizing hepatitis, enterotyphlocolitis and myocarditis +/- hemorrhage, dystrophic calcification, fibrosis

- GIT: can have edema, blunted and fused villi, crypt epithelial hyperplasia, ulceration

- Vegetative form of bacteria (pickup sticks) may be visible at edge of lesions with H&E or Warthin-Starry silver stain

DDx for necrotizing hepatitis: Clostridium piliforme, Salmonella spp., other gram negatives

DDx for megaloileitis: IP chloral hydrate anesthesia

Intestine

Necrohemorrhagic ileitis with adynamic ileus (megaloileitis)

Tyzzers

Lung

Multifocal to coalescing suppurative bronchopneumonia with bronchiectasis

Mycoplasma pulmonis

Endemic in wild, pet rodents. Infected animals NOT suitable for research. Disease outcome depends on strain, age, concurrent infections, nutritional status, environmental factors.

Transmission: contact, aerosol, intrauterine

Target tissues: respiratory tract, middle ear, endometrium, synovium

Lesions

- "Cobblestone" lung (older adults) - suppurative bronchopneumonia +/- abscesses, atelectasis, bronchiolitis with bronchiolectasis, lymphoid hyperplasia, type II pneumocyte hyperplasia

- Female repro lesions (partially resorbed fetuses, suppurative salpingitis, oophoritis and/or endometritis)

- Chronic suppurative rhinitis, otitis media, laryngitis, tracheitis

- Chronic suppurative arthritis (rare component of disease in the rat) DDx (respiratory lesions): CAR bacillus, Corynebacterium kutscheri ***Vet Pathol 2009;46:952-959 - "Lymphomas" in rat (Europe)

Ear (fixed)

Bilateral suppurative otitis media

Mycoplasma pulmonis

Mesenteric arteries

Multifocal to coalescing necrotizing and proliferative mesenteric arteritis with aneurysmal dilatation

Polyarteritis nodosa

Incidence high in SD and Spontaneously Hypertensive Rats (SHR), esp in aged males and those with late-stage chronic nephropathy.

Causes: spontaneous, immune-mediated, drug-induced

Site: medium-sized arteries/arterioles in any tissue except lung (common in mesentery, heart base, testes, epididymides, spermatic cord and connective tissue of spleen, pancreas). VEINS ARE SPARED.

Gross: thickened tortuous arteries/nodular arterial thickening (hemoabdomen if rupture)

Histo: transmural lymphohistiocytic periarteritis, proliferation, fibrinoid degeneration/necrosis of intima and media. Chronically there is intimal hyperplasia, medial and periarterial fibrosis, mineral, +/- thrombosis. Other species affected

- Mice (necrotizing polyarteritis) - typically present with head tilt/ vestibular syndrome

- NHPs (polyarteritis nodosa)

- Dogs (Beagle pain syndrome) - typically present with neck pain

Pituitary gland

Pituitary adenoma +/- compression of overlying brain

Common in SD (~80% females, 60% males); slightly less in Wistar. Predisposing factors: age, genetics, diet, breeding history.

Most arise from pars distalis, but pars intermedia tumors possible also. Most often chromophobe adenomas and prolactin producing.

Gross: hemorrhagic, expansile, may compress ventral brain

Histo: usually sharp demarcation from brain, cells are larger than normal with abundant pale cytoplasm, few mitoses

IHC: usually prolactin +

DDx pituitary hyperplasia: very common in aged rats

DDx carcinoma: more infiltrative, but rarely metastasize

Thyroid gland

Unilateral thyroid adenoma

Spontaneous or induced

The most common thyroid tumors are C-cell neoplasms, followed by follicular cell tumors. No sex predilection. Can be induced with simvastatin.

Adrenal gland

Pheochromocytoma

Common neoplasm in certain strains (male F344).

Esophagus

Megaesophagus (normal to compare)

Transgenic (Pvrl3- Cre) rat

Vet Pathol 2014;51(6):1187-1200. Report of 90% prevalence in transgene- positive animals.

Gross: megaesophagus containing compacted food and saliva.

Histo: muscle degeneration, inflammation, and reduced number of myenteric ganglia.

Small intestine

Adynamic ileus

IP chloral hydrate anesthesia

May not be apparent until up to 5wks after administration. DDx: megaloileitis with Tyzzer's disease

Large intestine

Intraluminal pinworms

Pinworms

Syphacia obvelata, Syphacia muris, Aspiculuris tetraptera

Found in cecum and colon. Direct life cycles. Often subclinical but young animals with heavy infestations can have diarrhea, poor weight gain, impaction, rectal prolapse, intussusception.

Abdomen

Peritoneal mesothelioma

Mesothelioma

Common neoplasm in rat (esp males, F344). All considered malignant. Primary site is often the tunica vaginalis of the testes

Gross: pale tan nodules/plaques on tunica vaginalis or abdominal surfaces; spread throughout the peritoneum is common; ascites

Histo: complex papillary fronds of stroma covered by mesothelial cells; often have epithelioid and mesenchymal components

IHC+: cytokeratin and vimentin

DDx (neoplastic): peritoneal sarcomatosis associated with telemetry implants (Toxicol Pathol 2012;40:113-121), ovarian yolk sac carcinoma (Vet Pathol 2014;51(3):659-662), metastatic ovarian adenocarcinoma or biliary carcinoma, mesenteric liposarcoma

DDx (non-neoplastic): reactive/hyperplastic mesothelium, abdominal fat necrosis, chronic peritonitis from intraperitoneal injections, Cysticercus fasciolaris

Liver, spleen, abdomen

Hepatic and splenic lymphoma;

Icterus

Large granular leukemia (LGL)

aka large granular lymphocytic leukemia, or LGL lymphoma

Classic disease of F344 (~33% males, 20% females), Wistar, Wistar-Furth. NOT retroviral associated. Blastic lymphocytes in all organs. Starts in splenic marginal zone with spread to liver, lung, lymph nodes.

C/S: pale (icteric) rat with watery blood

Clin path: blood leukocytes can exceed 400,000/ml3, mononuclear cells with azurophilic granules; thrombocytopenia, anemia

Gross: hepatosplenomegaly +/- lymphadenopathy, icterus

Histo: intravascular leukocytosis/leukemia; neoplastic cells are small, pleomorphic with a small amount of reddish cytoplasm

DDx on gross: lymphoma, histiocytic sarcoma

Toxicol Pathol 2015;43:852-864.

Mesenteric lymph node

Lymphoma

Other than LGL, lymphoid tumors are uncommon in rats. Usually result in enlarged lymph nodes and/or hepatosplenomegaly.

Haired skin

Ulcerative dermatitis

Staphylococcus aureus

Common commensal of skin and mucous membranes. Can be associated with ulcerative skin lesions, especially in NK-deficient beige rats. More often in males. Trauma by persistent scratching is important in disease.

Ear

Proliferative dermatitis

Ear Mange

Notoedres muris

Proliferative dermatitis. Can result in disfigurement of ears. J Wildl Dis 2014;50(1):104-8.

Haired skin (flank)

Yellow crusting

Sucking mite

Ornithonyssus bacoti

Report of lesions in wild black rat (J Comp Path 2017;157:163-173). Histo: lymphoplasmacytic and eosinophilic dermatitis; mites attached

Feet

Ulcerative pododermatitis

Predisposing factors: aged, male, wire cages, ad lib diet.

Gross: ulceration and scabbing of the hock.

Histo: epidermal ulceration, chronic inflammation, granulation tissue; +/‐ hyperostosis of underlying bone. Vet Pathol 2016;53(2):233-243.

Haired skin

Fibroma (with central ulceration)

Age-associated lesion (Vet Pathol 2016;53(2):233-243).

Zymbal's gland

Adenocarcinoma

Zymbal's gland tumor

Zymbal's gland is an external auditory sebaceous gland at ear base. Tumors can grow very large very quickly, locally invade and may invade into brain. Mets to lungs very rarely.

Gross: resemble abscesses, can express caseous material

Histo: proliferative sebaceous and squamous elements

Haired skin

Keratoacanthoma

Common in rats. Derive from squamous epithelium of hair follicle infundibulum. Uncommonly progress to SCC.

Gross: nodular mass, communicates with surface via pore

Histo: well-demarcated mass with large central keratin-filled cavity surrounded by hyperplastic squamous epithelium; central pore

DDx: squamous cell carcinoma, squamous papilloma, squamous cyst

J Toxicol Pathol 2013; 26(3):27S-57S.

Mammary gland

Mammary fibroadenoma

Most common mammary neoplasm (SD > F344, Wistar). Fibroadenoma >>> carcinoma. Can occur in males also (uncommon).

Predisposing factors: age, genetic, dietary (delayed with caloric restriction), environmental, prolactin level. NO retroviruses implicated. Can occur anywhere except head, tail and distal extremities.

Gross: large, lobulated, firm, usually non‐ulcerated, SQ mass

Histo: well circumscribed, firm, lobular mass with variable amounts of mature collagen and ductular/glandular elements

Mammary gland

Mammary fibroadenoma

Liver

Multiple hepatic cysticerci

Cysticercus fasciolaris

Rare in lab, occasional in pets, common in wild rats (J Comp Path 2017; 157:163-173). Larval stage of cat tapeworm (Taenia taeniaformis). Transmission: ingestion of eggs in cat feces. Gross: cysts in liver.

Histo: granulomatous inflammation, fibroplasia

Associated lesions: pulmonary arteriolar hypertrophy (Vet Pathol 2010;47: 292-297); fibrosarcoma around the cyst

Liver

Histiocytic sarcoma

Most often in SD rats >1yr old.

DDx: lymphoma, fibrosarcoma, metastatic carcinoma, granulomas, abscesses (C.kutscheri, S.pneumoniae, K.pneumonia and P.aeruginosa)

Common bile duct (arrow)

Ectasia and cholangitis (normal in A)

Experimental manipulation

Toxicol Pathol 2015;43:651-661. Recall that rat lacks a gall bladder.

Brain (fixed)

Meningeal granular cell tumor

Granular cell tumor

Most common primary CNS tumor. Can also be in female repro tract. Gross: single or multiple nodules, expansile, compressive, non-invasive Histo: PAS+/diastase resistant granules in neoplastic round cells

IHC+: vimentin, ubiquitin, Iba-1

IHC-: GFAP, synaptophysin

EM: Neoplastic cells containing phagolysosomes

Other species: uterus of mouse; lung/bronchi of horse; tongue and meninges of dog; brain/meninges of ferret

Brain/ pineal gland (fixed)

Malignant pinealoma

Very rare spontaneous lesion in rats and other species. Report of 8 cases (Toxicol Pathol 2015;43:838-843).

Gross: red-brown mass in area between cerebral hemispheres and cerebellum (infiltrating both).

Histo: cellular atypia, high mitotic index, giant cells, necrosis, rosettes and pseudorosettes. IHC+ for synaptophysin, NSE.

Testis

Interstitial cell tumor (Leydig cell tumor)

Very common neoplasm in aged rats, especially F344. Almost all considered benign (malignant if invade structures adjacent to testis or met). Can be bilateral or multiple within one testis.

Associated clin path finding: hypercalcemia in F344

Gross: circumscribed, yellow or white masses, often hemorrhagic

Testis

Bilateral mesothelioma of tunica vaginalis; Unilateral interstitial cell tumor with contralateral testicular atrophy

Interstitial cell tumor and mesothelioma

Look for mesothelioma and interstitial cell tumor concurrently, especially in F344.

Prostate gland

Normal

Prostate gland

Diffuse suppurative prostatitis

E.coli

Induced model of bacterial prostatitis.

Lung (fixed)

Diffuse interstitial pneumonia

Sendai virus (Parainfluenza virus-1)

Rare in lab rodents (mice, rats) now. Transmission: aerosol, direct contact. Additive effect with M. pulmonis. Can be zoonotic.

Histo: inclusions in airway cells and syncytia are very suggestive; rhinitis, bronchiolitis, alveolitis with epithelial proliferation, lymphoid cuffing, interstitial fibrosis

DDx: Rat coronavirus, Parainfluenza Virus 3, Pneumonia Virus of Mice

Thorax

Diffuse fibrinous pleuropneumonia

Streptococcus pneumoniae

Can be asymptomatic carriers but concurrent infections or environmental changes may precipitate disease.

Transmission: contact, aerosol, human carriers (ZOONOTIC).

Lesions

- Fibrinosuppurative polyserositis (always consider Strep with fibrin) - Suppurative to fibrinosuppurative bronchopneumonia

- Fibrinosuppurative meningitis, rhinitis, otitis media

- Embolic suppurative lesions (liver, spleen, kidney)

Lung

Diffuse granulomatous interstitial pneumonia

Pneumocystis carinii, Pneumocystis wakefieldiae

Transmitted by contact, dirty bedding, fomites. Disease in immunocompetent and immunodeficient animals.

Lesions depend on immune status:

- Immunodeficient: lungs fail to collapse; raised subpleural foci; intra- alveolar, foamy eosinophilic material with intralesional trophozoites, cysts

- Immunocompetent: lymphohistiocytic interstitial pneumonia and perivasculitis (formerly "rat respiratory virus"; Vet Pathol 2009;46:992- 999; Comp Med 2011;61:45-59; Vet Pathol 2012;49:440-452).

Lung

Granulomatous to eosinophilic pneumonia

Eosinophilic Granulomatous Pneumonia of Brown Norway Rats

Very high prevalence in Brown Norway rats of all ages, from multiple locations, and of any health status, including gnotobiotic.

Cause unknown, may be related to a hypersensitivity reaction.

Gross: multiple pale tan/gray foci throughout parenchyma

Histo: granulomatous pneumonia with epithelioid cells and/or multi- nucleated giant cells; edema; perivascular and peribronchiolar eosinophils Special stains are negative, as are cultures and serology.

Lung

Alveolar histiocytosis

Common in old rats (esp F344 and SD) and reported in wild rats (J Comp Path 2017;157:163-173). Cause unknown but increased with high fat diet. Histiocytes contain FFA, cholesterol, phospholipids. NOT thought to be infectious.

Gross: 1‐3mm pale tan/yellow foci on pleural surface

Histo: subpleural clusters of foamy macrophages in alveoli

DDx: clusters of foamy macs seen in inhalation or gavage studies

Ear

Granulomatous auricular chondritis

Auricular chondropathy

Can be spontaneous or associated with metal ear tags or trauma. Presumed immune‐mediated reaction (to Type II collagen?).

Gross: nodular thickening and distortion of pinna (often bilateral)

Histo: granulomatous inflammation with destruction of cartilage, nodular cartilage hyperplasia, osseous metaplasia

Ear

Granulomatous auricular chondritis

Auricular chondropathy

Eye

Chromodacryorrhea

Common response to stress and illness. Due to porphyrin pigments from Harderian gland.

Eye

Cataracts

Inherited (ICR or inherited cataract rat is a model) or associated with aging, radiation, excessive light exposure (albino r

Kidney

Chronic fibrosing interstitial nephritis

Chronic progressive nephropathy (CPN)

aka Chronic Renal Disease, Old rat nephropathy

Most important disease of rat kidney. Common cause of early death on carcinogenicity studies and can be difficult to distinguish from drug‐ related effects in toxicity studies. Prevalence very high, especially in males (earlier onset, more severe). Lesions may begin by 3-6 months of age in some strains (F344, SD, hypertensive strains).

Predisposing factors: male, age (>1yr), diet (ad lib, high protein), immune factors, high prolactin, microbial status

C/S: progressive renal malfunction/failure

Gross: initially enlarged then shrunken, pale, irregular‐shape, surface pitting, +/‐ small cysts

Histo

- Glomeruli: thickening of tufts by eosinophilic material, synechiae, basement membrane thickening, glomerulosclerosis

- Tubules: protein casts, dilated with flattened epithelium, degeneration/regeneration, mineralization

- Interstitium: fibrosis, lymphoplasmacytic aggregates

Secondary hyperparathyroidism may occur, with mineralization (lung, stomach, blood vessels, pleura), fibrous osteodystrophy

Kidney

Nephrocalcinosis

Deposition of calcium phosphate in renal tissue. High prevalence. Predisposing factors: female, strain (BDIX and F344 >> SD, Wistar), diet (high levels of Ca, phosphorus, low Ca:phosphorus ratios or Mg)

Gross: large deposits may appear as pale areas, may crunch when cut Histo: deposition most frequently at corticomedullary junction, in tubular epithelial cells and tubular lumina

Kidney

Hydronephrosis

SD, Brown Norway, Zucker and Gunn strains especially. Often incidental. Often right kidney in males (due to passage of internal spermatic vessels across ureter?).

Kidney

Unilateral nephroblastoma

Model for Wilm's tumor in humans. Rare except in subline of SD (genetically predisposed, 14% incidence) but can be chemically-induced (ENU, MNU). Histo has 3 components (blastema, stroma, immature epithelium forming tubules). J Toxicol Pathol 2014;27:91-95.

Urinary bladder

Hemorrhagic cystitis

Cystolithiasis

Ammonium magnesium phosphate (struvite), carbonate and oxalate are common. When in urinary bladder, can be associated with hemorrhagic cystitis, hematuria, urinary obstruction.

Comp Med 2015;65(6):486-491.

Urinary bladder

Hemorrhagic and proliferative cystitis with uroliths

Cystolithiasis

Ammonium magnesium phosphate (struvite), carbonate and oxalate are common. When in urinary bladder, can be associated with hemorrhagic cystitis, hematuria, urinary obstruction.

Urinary bladder

Transitional cell carcinoma

Can be spontaneous or experimentally induced.