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Pretty histology Acidophilic Macrophage Crystalline ‘Pneumonia’ 47 Acidophilic Macrophage or Acidophilic Crystalline ‘Pneumonia’ Spectrum of clinical Phenotypes No clinical disease TO Respiratory distress, death Spectrum of Anatomic Pathology Phenotypes Scattered Acidophilic Macrophages or Crystals TO Pulmonary consolidation by acidophilic macrophages & crystals Associations with Pneumocystis etc. agents? – In immunocompromised / immunoweird mice especially? On B6 or 129 background ? Brayton - NON infectious - P 6 YM1, YM2 chitinases in Hyalinosis & Acidophilic Macrophage Pneumonia Haines et al. 2001. Toxicol Pathol. 29(6):653‐61. Pathology of aging B6;129 mice. – Hyalinosis with extracellular crystals multiple sites (respiratory, gall bladder, stomach) Ward et al. 2001. Hyalinosis and Ym1/Ym2 gene expression in the stomach and respiratory tract of 129S4/SvJae and wild‐type and CYP1A2‐null B6, 129 mice. AJP – Hyalinosis (eosinophilic cytoplasmic change) in glandular stomach, respiratory tract, bile duct, and gall bladder of B6,129 CYP1A2‐null & wild‐type mice – Also in both sexes of background 129S4/SvJae strain (WT) – Ym1 in normal and abnormal NOSE olfactory + respiratory, lung, marrow, stomach – Ym2 in hyaline Stomach lesions Nio et al. 2004. Histochem Cell Biol.121(6):473‐82. Cellular expression of murine Ym1 and Ym2, chitinase family proteins, as revealed by in situ hybridization and immunohistochemistry. – chitinase family proteins, widely distributed, bind GAG’s such as heparin/heparan sulfate. – Ym1 is a macrophage protein produced in parasitic infections… • Lung ‐‐ Ym1‐expressing cells are alveolar macrophages, Ym1 localized in RER. • Spleen ‐‐Ym1‐expressing cells in the red pulp identified as immature neutrophils. • Marrow ‐‐ immature neutrophils immunoreactive lose immunoreactivity with maturation. • Marrow ‐‐ needle‐shaped crystals in macrophages showed intense Ym1 immunoreactivity. 48 – Ym2 expression restricted to gastric squamous 49 epithelium in junctional region Hyalinosis in other tissues Pretty histo – nose, stomach, gall bladder Crystals in marrow spleen – macrophages, PMN Thoolen, B., R. R. Maronpot, et al. (2010). "Proliferative and Nonproliferative Lesions of the Rat and Mouse Hepatobiliary System. Tox Path. 2010;38:5S INHAND Nomenclature Fig 25. Rat liver. Pigment in hypertrophic hepatocytes consistent with bile. Cholestasis. Fig 26. Mouse liver. Hyalinosis of hyperplastic bile ducts with crystal formation and peribiliary inflammatory cell infiltrate. Fig 27. Mouse liver. Hyalinosis of hyperplastic bile ducts with crystal formation and peribiliary inflammatory cell infiltrate. Higher magnification of Figure 26. Fig 28. Mouse liver. Hyalinosis of hyperplastic bile ducts with crystal formation. Fig 29. Mouse liver. Numerous intracytoplasmic hyaline bodies in an hepatocellular adenoma. Fig 30. Mouse liver. Intranuclear inclusion 51 body, cytoplasmic invagination. 50 Copyright © by Society of Toxicologic Pathology X 4.4 <strong>Sick</strong> Old Mouse Phenotypes 1. Amyloidosis – multisystem – Rule out glomerulonephritis 2. Arteritis – multisystem 3. Hyalinosis & Acidophilic macrophage pneumonia 4. Neoplasia – discussed Next CONCLUSIONS EXPECT THE EXPECTED –consider the UNexpected PATHOLOGY to diagnose Don’t let the expected conditions mess up your research 52 X Mouse Cancer Quiz 1. Thymic Lymphoma 2. B cell Lymphoma 3. Plasma cell tumors (myeloma) (Harderian, myoepithelioma, Rhabdomyosarcoma etc ) 4. Lung tumors 5. Mammary tumors 6. Mammary Hyperplasia, EMT with pituitary tumors 7. Liver tumors 8. Cancer resistant a) A b) AKR, NODscid, C58 c) BALB/c d) C3H e) C57BL/6 f) FVB/N g) SJL/J WHAT SHOULD YOU EXPECT IN YOUR MICE ? 53 cbrayton@jhmi.edu 2013 X 54 5. 5 Mouse Tumors Tumor Sex Strain predisposition Hematopoietic Lymphoma, HS Lung F>M AKR, SJL/J, NODscid (C57BL, etc) A (FVB, 129, etc) Mammary F>>M C3H (BALB etc) Liver M>>F C3H, CBA, (B6C3 …) Pituitary F > M What strains are famous for what tumor? • Good or Bad for your model ? Is your favorite strain tumor resistant? Rodent Cancer Classification MMHCC – http://emice.nci.nih.gov/ – mouse models of human cancer consortium • Consensus papers hematopoietic liver mammary prostate intestine …. • GEM oriented INHAND http://www.toxpath.org/nomen/ – International Harmonization of Nomenclature and Diagnostic Criteria in Toxicologic Pathology • Rat is complete, mouse is coming • Tox oriented e.g. FDA GLP studies 55
56 Lymphomas Hematopoietic Tumors Mouse V Human – Thymic L (younger) – Follicular B cell Histiocytic sarcoma Leukemias – ALL in children – AML in adult Lymphomas Retroviruses as genetic – Diffuse large B cell engineers FCC lymphomas Common features • Point mutations • Activated Oncogenes • Inactivated Tumor suppressors Mouse Hematopoietic Tumors Spontaneous Distribution T‐cell lymphoma B‐cell lymphoma Histiocytic sarcoma Myeloid leukemia Systemic (generalized) Common Rare Rare Rare Thymus Primarily Rare Rare Rare Spleen Rare Common–follicular or marginal zone Occasionally –red pulp origin Common Peyer's patches Rare Common Occasional Rare Mesenteric Lnodes Rare Common Occasional Rare Liver Rare Rare Common Rare Uterus Rare Rare Common Rare Peritoneum Rare Rare Common Rare Skin Rare Rare Occasional Rare Bone marrow Rare Rare Rare Occasional IHC CD3 CD45r (B220) Pax5 CD68, F480 57 X From Table 1 - Ward 2006 Lymphomas and leukemias in mice. Mouse Hematopoietic Tumors Spontaneous #1 Thymic lymphoma (T lymphoplastic Lymphoma) • B cell tumors are rare in thymus Early onset often < 1y • Thymus 1st disseminates • Short studies … in AKR, C58, scid, NODscid Kras activation Endogenous retroviruses 58 Brayton - NON infectious - P 7 Mouse Hematopoietic Tumors Spontaneous #1 Clinical Signs: Gross Lesions: Histology Mouse Hematopoietic Tumors Spontaneous #1 Overall ‘blue – Starry sky ? Blue cells + tingible body macrophages’ Mouse Hematopoietic Tumors Spontaneous #2 Follicular B cell lymphoma – Not exactly FCC ‐ Most common tumor or lymphoma in some strains GALT, nodes, spleen etc Later onset often > 1y Expect it in control mice > 1yr Endogenous retroviruses 59 59 60 60 61 Mouse Hematopoietic Tumors Spontaneous #2 Clinical Findings: Gross Lesions: Mouse Hematopoietic Tumors Spontaneous #2 Lymph node • Blue tumor • Monotonous population of similar cells with not much cytoplasm – Lymphoma. Mouse Hematopoietic Tumors Spontaneous #3 Histiocytic Sarcoma Most common tumor in some strains Liver Uterus spleen nodes etc Later onset often > 1y Expect it in control mice > 1yr Not such a blue tumor … Not so round cells either … 62 cbrayton@jhmi.edu 62 2013 • Leukemia ? 63 64 Clker.com
Page 1 and 2: Sick (& not so sick) Mice NON Infec
Page 3 and 4: X 1. Sexual Dimorphisms Size Grow
Page 5: X 38 1. Skin Disease 3. 3 Common Cl
Page 9 and 10: X Mouse Mammary Tumors Spontaneous
Page 11: Teratoma in B6, 129 chimera Swollen

Sick - Johns Hopkins Medicine

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