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Famous Rat Pathology (Phenotypes) Discussion Plan General References 2017 Brayton RAT PATHOLOGY Discussion Plan Famous Rat Pathology 1. Non Infectious, Non Neoplastic (Phenotypes) 2. Non Infectious, Neoplastic 3. Infectious Cory Brayton, D.V.M., D.A.C.L.A.M., D.A.C.V.P. Associate Professor, Molecular and Comparative Pathobiology Director, Phenotyping Core Johns Hopkins University, School of Medicine Baltimore, MD 21205 TEL: 410 502 3050 ‐‐ FAX: 443‐287‐2954 [email protected] http://www.hopkinsmedicine.org/mcp/PHENOCORE/index.html 1 3 General References: RATS RAT Resources online 1. ACLAM Blue books https://www.elsevier.com/books/book‐series/american‐college‐of‐ laboratory‐animal‐medicine 1. DORA Diseases of Research Animals http://dora.missouri.edu/ – The Rat in Biomedical Research. Fox et al 2006 2. RAT Genome Database ‐‐ with strains Phenotypes etc – Laboratory Animal Medicine. Fox et al 2015 http://rgd.mcw.edu/ 2. Barthold S, Griffey S, Percy D. 2016. Pathology of Laboratory Rodents and Rabbits, Wiley‐ Blackwell. 3. Noah’s Arkive (now at CLDavis) http://noahsarkive.cldavis.org/ 3. Treuting P and Dintzis S, Eds. 2012. Comparative Anatomy and Histology: A Mouse and Human Atlas. Elsevier (Academic Press): London. pp. 361‐381. 4. NTP NON neoplastic lesion atlas http://ntp.niehs.nih.gov/nnl/ new edition in press 2017 –with RATS 5. Pathbase: European mutant mouse pathology database Primary Journals http://www.pathbase.net/ 1. Comparative medicine / JAALAS (Search Comp Med, JAALAS) 2. Journal of Comparative Pathology (search J Comp Pathol) 6. RENI Tissue trimming guide + INHAND terminology and diagnostic criteria http://www.goreni.org/ 3. [Laboratory animals (Sage); Lab An (NY) (Nature.com)] 4. Toxicologic Pathology (search toxicol pathol) 7. VSPO JPC https://www.askjpc.org/vspo/ 5. Veterinary Pathology (search vet pathol) 4 5 Famous Rat Phenotypes Rat Lesions (phenotypes) NOT Neoplastic Neoplastic 1. Non Infectious, Non Neoplastic Nephropathy (D) Pituitary tumors (D) (mineralization, Parathyroid a. Nephropathy (adenomas>> carcinomas) hyperplasia) b. Arteritis ‘Cardiomyopathy’ (D) Mammary tumors (D) (Degeneration, fibrosis, inflammation) (fibroadenoma etc) c. ‘Cardiomyopathy’ Arteritis – polyarteritis Pheochromocytomas . etc Hematopoietic (I) Axonal degeneration Histiocytic sarcomas 2. Non Infectious, Neoplastic Fibromas, sarcomas Adrenal cortical, a. Skin Tumors (most commonly seen) Infectious/parasitic Thyroid follicular or C cell; Zymbal Gland, Urinary bladder (I) b. Hematopoietic (most? Famous) BOLD – possible‐likely COD CCOD c. Pituitary etc (most? Common killer) Not bold ‐ Incidental finding/phenotype to expect D Role of Diet . etc I Role of Infectious agents? E.g. MYCOPLASMA, 7 Trichosomoides crassicauda 7 8 3. Infectious [email protected] 2017 Page 1 of 35 2017 Brayton RAT PATHOLOGY 1.a. Rat Nephropathy 1.a. Rat Nephropathy Most common significant lesion or COD Glomeruli in many studies, especially – LargeMesangium . Cellularity – Older studies/diets . Synechiae – Ad lib feeding – Small Gross : . Sclerotic Tubules – Bumpy/pitted kidneys – Dilated, protein – LARGER then smaller – Degen, regen AKA – Mineral +/‐ Interstitium – CPN Chronic progressive nephropathy – Inflammation – CRD Chronic Renal Disease – Fibrosis RodentPath 10 9 – ORN Old rat nephropathy 10 1.a. Rat Nephropathy Soft tissue mineralization Glomeruli – LargeMesangium Severe nephropathy. Enlarged parathyroid. Cellularity . Synechiae – Small . Sclerotic Tubules – Dilated, protein – Degen, regen – Mineral +/‐ Interstitium – Inflammation RodentPath 11 – Fibrosis 11 12 Soft tissue mineralization Soft tissue mineralization Severe nephropathy? Enlarged parathyroids? Severe nephropathy? Enlarged parathyroids? Stomach Muscle HEART, arteries LUNG septa 13 14 [email protected] 2017 Page 2 of 35 2017 Brayton RAT PATHOLOGY 1.b. Arteritis, periarteritis 1.b. Rat PAN (aka polyarteritis nodosa (PAN)) Gross: Nodular thickening – Thick, nodular, multicolored arteries, mesenteric arcade, Arteritis, periarteritis, pancreas, spermatic cord etc chronic, Histology: – Inflammation neutrophilic lymphohistiocytic, lymphohistiocytic, transmural – periarterial transmural – Mural‐periarterial thickening by inflammation, proliferative –with proliferation (fibroplasia;) hemorrhage‐fibrinoid, – Fibroplasia mineralization – /+Thrombi – laminated, recanalized etc – Fibrinoid – VEINS ARE SPARED – Thrombi – Mineral etc RodentPath 18 17 18 1.b. Rat periarteritis / polyarteritis Rat PAN Earliest in mesentery, Earliest? In pancreas, spermatic – Pancreas cord – Mesentery Most obvious in – Spermatic cord mesentery Nodular thickening Best gross in +/‐ hemorrhage, – Mesentery mineral Veins More common in – Spared SD, SHR, hypertensive rats RodentPath 19 19 20 Rat PAN Rat PAN Thrombi Disrupted elastic lamina – Fibrinoid deposition Proliferation Disrupted elastic – Subintimal lamina – Medial Proliferation – Adventitial – Subintimal Inflammation – Medial – Adventitial Rat crystals are Inflammation blood (Hb) origin 21 22 [email protected] 2017 Page 3 of 35 2017 Brayton RAT PATHOLOGY 1.c. Rat ‘Cardiomyopathy’ ‘Cardiomyopathy’ Myofiber = ‘heart muscle abnormality’ degeneration loss Replacement IN pets & people fibrosis – Impaired function diagnosed by ECG, US Mild chronic – Big – dilated ? Hypertrophic? Small fibrotic inflammation – HOCM COCM RCM Cf human MI +/‐ mineral – usually with ORN RodentPath 23 23 24 ‘Cardiomyopathy’ ‘Cardiomyopathy’ IN TOX ‐ refers to spontaneous changes – Typically multifocal – Inflammation (Rats > mice) – Myofiber degeneration /necrosis/ loss) 1. Inflammation (Rats > mice) 2. Myofiber degeneration /necrosis/ loss) – Fibroplasia +/‐ collagen 3. Fibroplasia +/- collagen vs toxic myocardial degeneration – Usually extensive‐global, compound related Jokinen & al 2012 25 26 Jokinen & al 2012. TP. Etc: Alveolar 1. Etc NON neoplastic histiocytosis Lungs – Alveolar histiocytosis – White spots = foam cell foci – Renne & Al intra‐alveolar Crystals macrophages Alimentary ‐ Ulcers – gastric/duodenal containing foamy – Stressors, dehydration, water / diet restriction cytoplasm Often subpleural in aged animals Increased with hi fat diet – Fldodh Magnuson Magnuson 1974 27 28 [email protected] 2017 Page 4 of 35 2017 Brayton RAT PATHOLOGY Rat ‐ WYD? 1. Etc Non Neoplastic A. Alveolar histiocytosis WYD? B. Acidophilic macrophage A. Blood derived Pneumonia hemoglobin C. Pneumocystosis crystals D. Induced alveolar B. Charcot leyden proteinosis Crystals C. Oxalate crystals D. YM1 crystals Copyright © by Society of Toxicologic Pathology 29 Roger Renne et al. Toxicol Pathol 2009;37:5S-73S 31 1. Etc Non Neoplastic Etc: Rat crystals Eosinophilic crystals, Rat lung; WYD? – Rectangular and linear; – Extracellular, alveoli and capillaries. A. Blood derived – No associated inflammation, nor hemoglobin resemblance to eosinophilic crystalline pneumonia crystals Inset: Okajima stain for B. Charcot leyden hemoglobin. – Considered an artifact of freezing, Crystals intracardiac puncture, and barbiturate C. Oxalate euthanasia. – found only in euthanized rats and not in crystals rats found dead or killed in snap‐traps. D. YM1 crystals – likely crystalized hemoglobin 32 33 Rothenburger et al. Vet Pathol 2015; Copyright © by American College of Veterinary Pathologists Rats ‐ WYD? Rats ‐ WYD? Which is Normal? Gravid Intrauterine hemorrhage, fetal death mummification Cause/s? Vaginal septa 6. Normal vagina, rat. E coli 7. Vagina, rat, vaginal septum with necro-hemorrhagic fluid accumulation. 8. Vagina, rat, thin vaginal septum. 9. Vagina, rat, thick vaginal septum. 10. Vagina, rat, mucus plug accumulation in the proximal part of the vagina. S. Lezmi et al. Vet Pathol 2010;48:964-969 S. Lezmi et al. Vet Pathol 2010;48:964-969 Copyright © by American College of Veterinary Pathologists Copyright © by American College of Veterinary Pathologists 34 35 [email protected] 2017 Page 5 of 35 2017 Brayton RAT PATHOLOGY RAT ‐ WYD RAT Acute – Vacuolation, pyknosis, hemorrhage Chronic – Lipid laden macrophages 36 De Jonghe et al. Toxicol Pathol 2015;43:1141-1148 Copyright © by Society of Toxicologic Pathology 37 De Jonghe et al. Toxicol Pathol 2015;43:1141-1148 Copyright © by Society of Toxicologic Pathology Miscellaneous Rat lesions (phenotypes) Spinal cord Degenerative Myelopathy – Symmetrical demyelination, axon swelling & loss, 1. Non Infectious, Non Neoplastic Gitter cells, gliosis; ventral & lateral tracts T4 –L4 2. Non Infectious, Neoplastic – Sciatic and tibial nerve degeneration; polyradiculoneuropathy a. Skin / Mammary – most obvious b. Hematopoietic – most famous Eye Retinal degeneration (drop out) albino rats c. Pituitary – most common? Eye corneal dystrophy (+/‐ mineralization) – More Tumors: endocrine, reproductive; urinary Hepatodiaphragmatic nodules (mini hernias) tract, etc. Pancreas exocrine atrophy 3. Infectious Pancreas islet pigment, fibrosis (not amyloid) 38 Adrenal cortex cystic degeneration 39 2.a. ‘Skin’ Tumors 2.a. Skin Tumors Mammary Fibroadenoma (F >> M) Most common tumor identified clinically Mammary fibroadenoma Gross: small‐big, soft‐firm ‐‐ Often resectable More common in Female Histo ‐ Mesenchymal –often predominates – 40‐70% incidence in – Glands –can be hard to find SD! – Associated with hi Fibromas ‐ Sarcomas (M > F?) prolactin, Gross: small‐big, soft‐firm – But not necessarily Histo – Mesenchymal pituitary tumors – Fibrosarcoma – collagen Trichrome – Myxoid – myxomatous – bluish Alcian blue RodentPath 41 – PNST‐like (peripheral nerve sheath tumor ) 40 41 c 1990 [email protected] 2017
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