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Toxicologic Pathology 2019, Vol. 47(6) 665-783 ª The Author(s) 2019 Nonproliferative and Proliferative Article reuse guidelines: sagepub.com/journals-permissions Lesions of the Rat and Mouse DOI: 10.1177/0192623319867053 journals.sagepub.com/home/tpx Hematolymphoid System 1 2,c Cynthia L. Willard-Mack, (Chair) , Susan A. Elmore , 3 4,e,g 5,f William C. Hall , Johannes Harleman , C. Frieke Kuper , 6,a 7,d,g 8,g Patricia Losco , Jerold E. Rehg , Christine Ru¨ hl-Fehlert , 9,d,g 10,b 11 Jerrold M. Ward , Daniel Weinstock , Alys Bradley , 12 13 14 Satoru Hosokawa , Gail Pearse , Beth W. Mahler , 2 15 Ronald A. Herbert , and Charlotte M. Keenan Abstract The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below. Keywords INHAND, nomenclature, diagnostic criteria, lymphoid, bone marrow, thymus, spleen, lymph node, MALT a General hematolymphoid subgroup lead 7 Saint Jude Children’s Research Hospital, Memphis, TN, USA b Bone marrow subgroup lead 8 Bayer AG, Wuppertal, Germany c Thymus subgroup lead 9 Global VetPathology, Montgomery Village, MD, USA d Spleen subgroup leads 10 Janssen, Spring House, PA, USA e Lymph node subgroup lead 11 Charles River Laboratories, Tranent, Scotland, United Kingdom f Associated lymphoid organs subgroup lead 12 Eisai Co, Ltd, Drug Safety Research Laboratories, Ibaraki, Japan g Neoplasm subgroup leads 13 GlaxoSmithKline, Ware, United Kingdom 14 Experimental Pathology Laboratories, Research Triangle Park, NC, USA 1 Covance, Somerset, NJ, USA 15 CM Keenan ToxPath Consulting, Doylestown, PA, USA 2 National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA Corresponding Author: 3 Hall Consulting, Inc, Mt Airy, MD, USA Cynthia L. Willard-Mack, Covance, PO Box 2360 Mettlers Road, East Millstone, 4 Independent Consultant, Darmstadt, Germany NJ New Jersey 08875-2360, USA. 5 Independent Consultant, Utrecht, the Netherlands Email: [email protected] 6 Independent Consultant, West Chester, PA, USA 666 Toxicologic Pathology 47(6) Introduction Loss of corticomedullary distinction Best Practices and Diagnostic Challenges Necrosis, lymphocyte General Hematolymphoid Tingible body macrophage, increased Amyloid Proliferative Changes (Non-Neoplastic) Aplasia/hypoplasia Cellularity, increased, epithelial cell Apoptosis, increased, lymphocyte Cellularity, increased, lymphocyte Cellularity, increased, mast cell Epithelium-free areas, increased Extramedullary hematopoiesis (EMH) Thymic corpuscles, increased Infiltrate Spleen Inflammation Organization Metaplasia, osseous Function Mineralization Development Necrosis Histology Phospholipidosis Sampling and Diagnostic Considerations Pigment, macrophage Nonproliferative Changes Tingible body macrophage, increased Aplasia/hypoplasia—see General hematolymphoid Vacuolation, macrophage White Pulp Bone Marrow Apoptosis, increased, lymphocyte Organization Cellularity, decreased, white pulp Function Necrosis, lymphocyte—see General Hematolymphoid Development Tingible body macrophage, increased—see General Histology Hematolymphoid Sampling and Diagnostic Considerations Red Pulp Nonproliferative Changes Angiectasis Angiectasis Cellularity, decreased, red pulp Cellularity, decreased, adipocyte Congestion Cellularity, decreased, bone marrow Contraction Dyshematopoiesis Ectopic tissue, spleen Fibrosis Erythrophagocytosis Hypersegmentation, granulocyte Fibrosis Inflammation—see General Hematolymphoid Pigment, macrophage—see General Hematolymphoid Necrosis—see General Hematolymphoid Vacuolation, macrophage—see General Hematolymphoid Serous atrophy of fat Proliferative Changes (Non-Neoplastic) Proliferative Changes (Non-Neoplastic) White Pulp Cellularity, increased, adipocyte Aggregates, macrophage, increased Cellularity, increased, bone marrow Cellularity, increased, plasma cell, white pulp Cellularity, increased, macrophage Cellularity, increased, white pulp Cellularity, increased, mast cell Red Pulp Thymus Cellularity, increased, adipocyte Organization Cellularity, increased, macrophage Function Cellularity, increased, mast cell Development Cellularity, increased, mesothelial Histology Cellularity, increased, plasma cell, red pulp Sampling and Diagnostic Considerations Cellularity, increased, stromal cell Nonproliferative Changes Extramedullary hematopoiesis, increased Apoptosis, increased, lymphocyte Hyperplasia, nodular Cellularity, decreased, lymphocyte Lymph Node Corticomedullary ratio, decreased Organization Corticomedullary ratio, increased Function Cyst, epithelial Development Ectopic tissue, parathyroid Histology Ectopic tissue, (specify tissue) Sampling and Diagnostic Considerations Ectopic tissue, thymus Nonproliferative Changes Hypoplasia Cortex, Paracortex, and Medullary Cords Inflammation—see General Hematolymphoid Aplasia/hypoplasia—see General Hematolymphoid Involution, age-related Apoptosis, increased, lymphocyte Willard-Mack et al. 667 Cellularity, decreased, lymphocyte Proliferative Changes (Non-Neoplastic) Necrosis—see General Hematolymphoid Aggregates, macrophage Pigment, macrophage—see General Hematolymphoid Cellularity, increased, lymphocyte Tingible body macrophage, increased—see General Cellularity, increased, macrophage Hematolymphoid Hyperplasia, follicle-associated epithelium Inflammation—see General Hematolymphoid Hyperplasia, goblet cell, follicle-associated epithelium Sinuses and Lymphatics Hypertrophy/hyperplasia, high endothelial venules (HEV) Dilatation, sinus Metaplasia, squamous, follicle-associated epithelium Erythrocytes, intrasinusoidal Other Lymphoid Tissues Lymphangiectasis Tertiary Lymphoid Structures (TLSs) Pigment, macrophage—see General Hematolymphoid Organization Vacuolation, macrophage—see General Hematolymphoid Function Proliferative Changes (Non-Neoplastic) Development Cortex, Paracortex, and Medullary Cords Histology Aggregates, macrophage, increased Sampling and diagnostic considerations Cellularity, increased, interdigitating dendritic cell Proliferative Changes (Non-Neoplastic) Cellularity, increased, lymphocyte Tertiary lymphoid structures (TLSs) Cellularity, increased, plasma cell Serosa-Associated Lymphoid Clusters (SALCS) Cellularity, increased, stromal cell Organization Hyperplasia, angiomatous Function Hypertrophy/hyperplasia, high endothelial venules (HEVs) Development Sinuses and Lymphatics Histology Cellularity, increased, macrophage, intrasinusoidal Sampling and diagnostic considerations Cellularity, increased, mast cell Proliferative Changes (Non-Neoplastic) Fibrosis SALCs, increased Mucosa-Associated Lymphoid Tissue (MALT) Hematolymphoid Neoplasms Organization Hematopoietic Neoplasms Definition and Function of MALT Leukemia, erythroid Development Leukemia, megakaryocytic Histology Leukemia, myeloid Sampling and Diagnostic Issues Leukemia, NOS Nonproliferative Changes Lymphoid Neoplasms Aplasia/hypoplasia—see General Hematolymphoid Lymphoma Apoptosis, increased, lymphocyte—see General Hematolymphoid Histiocytic Neoplasm Cellularity, decreased, lymphocyte Histiocytic sarcoma Degeneration, follicle-associated epithelium Mast Cell Neoplasms Hyaline material Leukemia, mast cell Inflammation—see General Hematolymphoid Tumor, mast cell, benign Lymphangiectasis—see General Hematolymphoid Tumor, mast cell, malignant Mineralization—see General Hematolymphoid Thymus Neoplasms Necrosis—see General Hematolymphoid Thymoma, benign Pigment, macrophage—see General Hematolymphoid Thymoma, malignant Tingible body macrophage, increased—see General Hematolymphoid 668 Toxicologic Pathology 47(6) Introduction and function.1 Cell trafficking occurs in primary, secondary, and tertiary lymphoid organs. Reticular fibers act as conduits The INHAND Project (International Harmonization of Nomen- that conduct soluble mediators to specific locations in the sec- clature and Diagnostic Criteria for Lesions in Rats and Mice) is ondary lymphoid organs (eg, high endothelial venules [HEVs] a joint initiative of the Societies of Toxicologic Pathology from in the lymph node) in order to enhance recruitment and migra- Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North tion of specific lymphocytes into the lymphoid organ for fur- America (STP) to develop an internationally accepted nomen- ther development, function, and interaction with other cell clature for proliferative and non-proliferative changes
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