Boorman's Pathology of the Rat: Reference and Atlas PDF
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Boorman’s Pathology of the Rat Boorman’s Pathology of the Rat Reference and Atlas Second Edition Editor Andrew W. Suttie Covance Laboratories, Inc., Chantilly, VA, USA Associate Editors Joel R. Leininger JRL Consulting, LLC, Chapel Hill, NC, USA WIL Research Laboratories, Hillsborough, NC, USA National Institute of Environmental Health Sciences, Durham, NC, USA Alys E. Bradley Charles River Laboratories, Edinburgh Ltd, Tranent, East Lothian, UK Charles River, Tranent, Edinburgh, UK AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1800,SanDiego,CA92101-4495,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom Copyrightr2018,1990ElsevierInc.Allrightsreserved. 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BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress ISBN:978-0-12-391448-4 ForInformationonallAcademicPresspublications visitourwebsiteathttps://www.elsevier.com/books-and-journals Publisher:MicaHaley AcquisitionEditor:MicaHaley EditorialProjectManager:MaryPreap ProductionProjectManager:JuliaHaynes&PriyaKumaraguruparan CoverDesigner:GregHarris TypesetbyMPSLimited,Chennai,India List of Contributors Roger Alison, Roger Alison Ltd., Pathology Consultancy Pierluigi Fant, Charles River Research Europe-Lyon, Services,CaerfyrddinFach,Cilcennin,Lampeter,UK Saint-Germain-Nuelles,France Julia F.M. Baker, Charles River Laboratories, Inc., StaceyL.Fossey, AbbVie,Inc.,Worcester,MA,USA Frederick,MD,USA John R. Foster, ToxPath Sciences Ltd, Congleton, LiseBertrand, BayerCropScience,Lyon,France Cheshire,UnitedKingdom Pamela E. Blackshear, Covance Laboratories, Inc., DenzilFrost, CovanceInc.,Chantilly,VA,USA Greenfield,IN,USA Silvia Guionaud, Pathology, Translational Sciences, Brad Blankenship, Charles River Laboratories, Inc, MedImmuneCambridge,UK Reno,Nevada,USA D.GregHall, EliLillyandCompany,Indianapolis,USA Gary Boorman, Covance Laboratories, Inc., Chantilly, Gordon C. Hard, Private Consultant, Tairua, New VA,USA Zealand SuzanneBotts, Raleigh,NC,USA Adam Hargreaves, PathCelerate Ltd., The BioHub at Michael Boyle, Amgen, One Amgen Center Drive, AlderleyPark,Macclesfield,Cheshire,UK ThousandOaks,CA,USA Ronald A. Herbert, National Institute of Environmental Alys Bradley, Charles River Laboratories, Edinburgh HealthSciences,ResearchTrianglePark,NC,USA Ltd,Tranent,EastLothian,UK Kyathanahalli S. Janardhan, Integrated Laboratory Danielle L. Brown, Charles River Laboratories, Inc., SystemsInc.,ResearchTrianglePark,NC,USA Durham,NC,USA Michael P. Jokinen, Charles River Laboratories - Mark F. Cesta, National Institute of Environmental PathologyAssociates,Durham,NC,USA HealthSciences,ResearchTrianglePark,NC,USA Ken Latimer, Covance Laboratories, Inc., Madison, WI, Vivian Chen, Charles River Laboratories – Pathology USA Associates,Durham,NC,USA Joel R. Leininger, JRL Consulting, LLC, Chapel Hill, PhaedraCole, Zoetis,Kalamazoo,MI,USA NC,USA Michelle C. Cora, National Institute of Environmental Re´gisMasson, CovanceInc.,Porcheville,France HealthSciences,Durham,NC,USA Jenny McKay, IDEXX Laboratories Ltd. Grange House, Darlene Dixon, National Institute of Environmental WestYorkshire,UK HealthSciencesResearchTrianglePark,NC,USA Mark G. Mense, Covance Laboratories, Chantilly, VA, Dale G. Dunn, Covance Laboratories, Inc., Chantilly, USA VA,USA Rodney A. Miller, Experimental Pathology Laboratories, Johnnie J. Eighmy, Covance Laboratories, Inc., Inc.,ResearchTrianglePark,NC,USA Madison,WI,USA Shunji Nakatsuji, Drug Safety Research Labs, Astellas Susan A. Elmore, National Institute of Environmental PharmInc.,Osaka,Japan HealthSciences,ResearchTrianglePark,NC,USA Arun R. Pandiri, National Institute of Environmental Michael R. Elwell, Covance Laboratories, Inc., HealthSciences,ResearchTrianglePark,NC,USA Chantilly,USA Nicola Parry, Midwest Veterinary Pathology LLC, ScotL.Eustis, LasVegas,NM,USA Lafayette,IN,USA xv xvi ListofContributors Deepa B. Rao, Center for Drug Evaluation and Research KathleenA.Szabo, CharlesRiver,Durham,NC,USA (CDER), US Food and Drug Administration, Silver Gregory S. Travlos, National Institute of Environmental Spring,MD,USA HealthSciences,Durham,NC,USA Marlon C. Rebelatto, Translational Sciences, TakekiUehara, Shionogi&Co.,Ltd.,Osaka,Japan MedImmune,Gaithersburg,MD,USA John L. Vahle, Lilly Research Laboratories, Lilly Amera K. Remick, Charles River Laboratories, Inc., CorporateCenter,Indianapolis,IN,USA Durham,NC,USA Justin D. Vidal, MPI Research, Mattawan, MI, USA; Thomas J. Rosol, DepartmentofVeterinaryBiosciences, VetPathServices,Inc.(VPS),Mason,OH,USA OhioStateUniversity,Columbus,OH,USA Katharine M. Whitney, AbbVie Inc; North Chicago, IL, Aude Roulois, GSK R&D—SA Pathology, USA Hertfordshire,UK Jyoji Yamate, Veterinary Pathology, Graduate School of Melissa Schutten, Genentech Inc., South San Francisco, Life and Environmental Sciences, Osaka Prefecture CA,UnitedStates University,Osaka,Japan JohnCurtisSeely, ExperimentalPathologyLaboratories, Katsuhiko Yoshitomi, Sandoz Pharmaceuticals Ltd, Inc.,ResearchTrianglePark,NC,USA Tsukuba-shi,Japan Alok K. Sharma, Covance Laboratories, Inc., Madison, Katsuhiko Yoshizawa, Department of Food Sciences WI,USA and Nutrition, Mukogawa Women’s University, Steven D. Sorden, Covance Laboratories, Inc., Madison, Nishinomiya,Hyogo,Japan WI,USA Bevin Zimmerman, Charles River Laboratories, Inc., CatherineSutcliffe, CovanceInc.,Harrogate,UK Ashland,OH,USA Andrew W. Suttie, Covance Inc., Chantilly, VA, UnitedStates Preface Tounderstandthestructuralchangesthatunderliethosetis- tissues or the methodology used to investigate them— sue alterations that occur with age or by the agency of any these have changed rapidly in recent years—may affect injuriousagent,whetherthisbeamicroorganism,axenobi- the interpretation of results. For many years the use of otic, a food or a chemical, it is necessary to understand a special stains, immunohistochemistry, and electron number of processes. First, normal structure and variation microscopy represented the backbone of tissue investiga- must be properly understood—this will, of necessity, tion, now we are able to scan tissues to detect lesions include an understanding of the development, maturation rather than rely on “random” sampling (however well and the changes accompanying senescence in the organ standardized) we can look at gene expression or suppres- under consideration; a number of developmental variations sion using reliable and comparatively simple techniques or age-related changes have been assumed to bepathologi- and document the mode of action of agents administered cal processes in the past. The observer must also have in experiments in ways which greatly facilitate our under- knowledgeofthechangesseeninfundamentalpathological standing of what has happened to the normal structure in processes,suchasinflammation,andbeawareofthealtera- thedevelopmentofthediseaseprocess. tions in function that accompany the progression through Rat studies are the core ofinvestigations carried outin thatnumberofgeneticandepigeneticchangesthatoccuron the regulation of drugs, agrochemicals and the myriad thepathtothedevelopmentofaneoplasm,forexample. compounds used in various aspects of our complex soci- In this volume a standard work has been brought up- ety. Interpretation of the histological results of rat studies to-date in a manner which strongly supports these objec- is often the critical point in determining exposure levels tives. In each chapter the development of the system con- that might be harmful to man or other animals. This vol- sidered is detailed, changes, variations not suggestive of ume will be invaluable in ensuring that those interpreta- disease are brought to the reader’s attention, and patho- tions are rational and informed; the many beautiful logical processes reviewed in a systematic way. Attention illustrations will help any histopathologist charged with is drawn to the way in which choices about sampling thoseresponsibilities. ProfessorSirColinBerry,MD,PhD,DSc,FRCP,FRCPath ProfessorEmeritusofPathology,QueenMary,London,UK xvii Acknowledgements to Contributors of the First Edition We would like to acknowledge and extend our profound Chapter 18: Specialized Sebaceous Glands—Diana thanks to the editors and contributors of the first edition Copeland-HainesandScotL.Eustis of this book, Pathology of the Fischer Rat, whose work Chapter19:MammaryGland—GaryA.Boorman,Jeffrey laid the foundation for this new edition. Their names are Th.Wilson,MatthewJ.vanZwieten,andScotL.Eustis listedbelowundertheirchaptersfromthefirstedition. Chapter 20: Nose, Larynx, and Trachea—Gary Chapter 1: Introduction—Gary A. Boorman, Scot L. A.Boorman,KevinT.Morgan,andLindaC.Uriah Eustis,Michael R.Elwell,andJoelR.Leininger Chapter 21: Lung—Gary A. Boorman and Scot Chapter 2: The History of the Fischer 344 Rat— L.Eustis GhantaN.RaoandGaryA.Boorman Chapter 22: Spleen, Lymph Nodes, and Thymus— Chapter 3: Oral Cavity, Esophagus, and Stomach—H. Steven A. Stefanski, Michael R. Elwell, and Paul RogerBrownandJerryF.Hardisty C.Stromberg Chapter 4: Salivary Glands—Suzanne Chapter 23: Bone Marrow—William F. Mackenzie B.NeuenschwanderandMichaelR.Elwell andScotL.Eustis Chapter 5: Small and Large Intestine—Michael Chapter 24: Testis and Epididymis—Gary R.ElwellandErnestE.McConnell A.Boorman,RobertE.Chapin,andKunitoshiMitsumori Chapter 6: Peritoneum, Retroperitoneum, Mesentery, Chapter 25: Male Accessory Sex Glands, Penis, and andAbdominalCavity—WilliamC.Hall Scrotum—Gary A. Boorman, Michael R. Elwell, and Chapter 7: Liver—Scot L. Eustis, Gary A. Boorman, KunitoshiMitsumori TakanoriHarada,andJamesA.Popp Chapter 26: Ovary—Roger H. Alison, Kevin T. Chapter 8: Exocrine Pancreas—Scot L. Eustis, Gary Morgan,andCharlesA.Montgomery,Jr. A.Boorman,andYuzoHayashi Chapter 27: Oviduct, Uterus, and Vagina—Joel R. Chapter 9: Urinary Bladder, Ureter, and Urethra— LeiningerandMichaelP.Jokinen Michael P.Jokinen Chapter 28: Heart—William F. MacKenzie and Roger Chapter 10: Kidney—Charles A. Montgomery, Jr., H.Alison andJohnCurtisSeely Chapter 29: Blood and Lymphatic Vessels—Kunitoshi Chapter 11: Brain—Henk A. Solleveld and Gary A. Mitsumori Boorman Chapter 30: Pituitary Gland—William F. MacKenzie Chapter 12: Spinal Cord and Peripheral Nerves— andGaryA.Boorman KunitoshiMitsumoriandGaryA.Boorman Chapter 31: Adrenal Gland—Melvin H. Hamlin, II, Chapter 13: Skeletal Muscle—Margarita andDeborahA.Banas M.McDonaldandBradleyF.Hamilton Chapter 32: Thyroid Gland—Jerry F. Hardisty and Chapter 14: Bones, Joints, and Synovia—Joel R. GaryA.Boorman LeiningerandM.GaryRiley Chapter 33: Parathyroid Gland—John Curtis Seely Chapter 15: Ear and Pinna—Katsuhiko Yoshitomi and andPaulK.Hildebrandt H.RogerBrown Chapter 34: Endocrine Pancreas—M. Gary I. Riley, Chapter 16: Eye and Associated Glands—Katsuhiko GaryA.Boorman,andYuzoHayashi YoshitomiandGaryA.Boorman Chapter 35: Tumor Incidences in Fisher 344 Rats: Chapter 17: Skin and Subcutis—Michael R. Elwell, NTP Historical Data—Joseph K. Haseman, Jane Arnold, Michael A.Stedham,andRobertM.Kovatch andScotL.Eustis xix Chapter 1 Introduction AndrewW.Suttie CovanceInc.,Chantilly,VA,UnitedStates Boorman’s Pathology of the Rat, edited by Andrew Suttie toxicity studies. Boorman’s Pathology of the Rat deals with associate editors Joel Leininger and Alys Bradley, is entirely with the rat, currently the predominant species the second edition of the classic pathology reference, utilized in toxicity studies. The book is divided into organ Pathology of the Fischer Rat, Reference and Atlas. The specific chapters and presents a summary of embryologi- first edition was edited by Gary Boorman, Scott Eustis, caldevelopment,normalmicroscopicanatomy,andphysi- Michael Elwell, Charles Montgomery, and William ology, in addition to variations on normal anatomy, MacKenzie. common aging and background lesions, hyperplastic ThetitleofthesecondeditionisdedicatedtoDr.Gary lesions, neoplasia, and toxicologic changes. The book is Boorman who was one of the editors of the first edition an invaluable addition to the libraries of toxicologic and a coauthor on many chapters. This title honors the pathologists early in their careers as they become familiar service, leadership, scholarship, mentoring, and teaching with the normal anatomic variation and background in that Gary has shown in his long and distinguished career short-termtoxicitystudies,andalsoagingchanges,hyper- in toxicologic pathology, especially rodent pathology. plasia, and neoplasia in carcinogenicity studies. Over theyears,manypathologistsreferred tothe first edi- Experienced pathologists will also find the book useful tion as Boorman’s Rat Book and hence inclusion of particularly in identifying lesions they have not encoun- Gary’s name in the title of the second edition identifies tered previously, and also in refreshing themselves with the second edition as successor to the Pathology of the thebasicsofratpathology. FischerRat. Chapters are predominantly in the same format as the Although the title of first edition referred specifically first edition. Some chapters have been extensively rewrit- to the Fischer Rat, it has been an invaluable resource to ten, while others have used the narrative format from the pathologists and scientists working with all rat strains. A first edition with minimal revision. The inclusion of color major difference between rat strains is in the incidence of photomicrographs required new examples of lesions, the various lesions, rather than their histopathological except when the original slide used in the first edition appearance, hence the relevance of the book to all rat wasavailable. strains. The second edition contains material predomi- The first edition contained control tumor incidence nantly from the Sprague Dawley, Wistar, and Fischer rat tables for F344 rats from NTP carcinogenicity studies. strains, therefore the book title is not specific to one Incidencetablesarenotincludedinthesecondeditionsince strain. data is more readily available from the NTP website, web- Numerous excellent books on toxicologic pathology sites of rat suppliers, and from contract research organiza- are available, with many more planned. Some books con- tions’ historical control databases, and also from centrateoninducedlesionswhileotherscontainspontane- publications.Furthermore,backgrounddatasearchescanbe ous background lesions and neoplasms. In most cases, refined by rat strain suppler identity, dose route, and study these books include lesions from all species used in durationandthisinformationisupdatedfrequently. Boorman’sPathologyoftheRat.DOI:http://dx.doi.org/10.1016/B978-0-12-391448-4.00001-0 Copyright©2018ElsevierInc.Allrightsreserved. 1 Chapter 2 Introduction to First Edition GaryA.Boorman1,MichaelR.Elwell1,ScotL.Eustis2andJoelR.Leininger3 1CovanceLaboratories,Inc.,Chantilly,USA,2LasVegas,NM,USA,3JRLConsulting,LLC,ChapelHill,NC,USA The pathology evaluation of toxicity studies involves not attentionisgiventoconsistencyintheapplicationofdiag- onlytherecognitionofobvioustreatment-relatedlesions,but nosticcriteriaandtheuseofterminology. also the identification of spontaneous lesions that may be Traditionally, pathologists are taught that a diagnosis increased in severity and/or frequency in treated animals. includes a topography (organ/site), a morphologic diagno- Itisnotuncommontofindlesionsthatareadirecteffectof sis, a duration qualifier (if appropriate), a distribution the test substance (such as renal tubular cell necrosis), as qualifier (focal or diffuse), and a severity grade (for non- wellassecondarychangesresultingfromtoxicity.Thelatter neoplastic lesions). Although descriptive diagnoses are may be a reflection of primary toxicity in another tissue necessary for accurate recording of the pathological find- (hemosiderin in the spleen secondary to erythrocyte ings, the use of synonymous terms or the excessive use of destruction) or a physiologic response (myeloid hyperplasia qualifiers can hinder the interpretation of the data. For associated with skin ulcerations in the skin paint study). example, if a pathologist uses the terms acute inflamma- In some instances, toxicity is manifested not as a unique tion, purulent inflammation, and suppurative inflamma- lesion,butasanincreaseintheseverityand/orincidenceof tion (of a particular organ in an individual study), other alesionorphysiologiceffectthatisacommonspontaneous scientistsevaluatingmay beleftwonderingifthepatholo- alteration(nephropathyorsplenichematopoiesis). gist deliberately distinguished between these lesions Short-termstudiesareoftenconductedtoestablishdoses (i.e., the lesions are different) or simply used different for chronic toxicity and carcinogenicity studies. When it is terms to describe the same type of lesion. If several simi- necessary to identify a “no observable effect” level, the lar diagnostic terms are used, it is imperative that a good differences between control and treatment groups can be rationaleisclearlypresentedinthepathologynarrative. extremely subtle. For this reason, it is often helpful to Similar problems result from inconsistent or excessive examinetissuesfromhigh-dosegroupsfollowedbycontrols. use of qualifiers as necessary to distinguish a lesion from When minimal effects are suspected, alternate comparison others having differing pathogenesis and/or biological sig- ofthetargetorganfromtreatmentandcontrolratsisuseful, nificance. For example, it is unnecessary to record sponta- but it may be more important to reexamine the target neous lesions such as cardiomyopathy or nephropathy in organs without knowledge of the dose groups (“blinded rats as focal, multifocal or diffuse is simply a reflection of evaluation”). Reexamination of selected tissues after a the severity of organ involvement. Thus, the extent of periodawayfromthestudyisalsohelpfulinconfirmingthe organ involvement can be considered when assigning a presenceorabsenceofsubtleeffectsintargetorgans. severity grade to the lesion. A distribution qualifier should Thehistopathologyevaluationsoftoxicity/carcinogenicity be used only to describe or identify an inherent feature of studiesrequireanapproachthatmayseematvariancewith the lesion that distinguishes its pathogenesis. For example, the training and background of most pathologists. The necrosisthathasacentrilobulardistributionintheliverhas mainobjectiveisnotsimplydeterminationofmorphologi- a pathogenesis different from necrosis that is focal and cal changes in a single animal, but rather comparison occursrandomlythroughouttheliver;therefore,centrilobu- of incidences and/or severity of lesions in populations of lar is an appropriate and necessary qualifier. In this con- animals that vary only in their exposure to a test com- text,focalandmultifocalareoften usedsynonymously;for pound.Atraditionalcase-by-casediagnosticapproachmay nearlyall spontaneous and induced lesions seeninrats, the causedifficultiesininterpretationofthedataunlesscareful multifocaloccurrence(ofafocallesion)isonlyareflection Boorman’sPathologyoftheRat.DOI:http://dx.doi.org/10.1016/B978-0-12-391448-4.00002-2 Copyright©2018ElsevierInc.Allrightsreserved. 3 4 Boorman’sPathologyoftheRat of the extent of organ involvement. Accurate and Long-term toxicity and carcinogenicity studies are interpretable presentation of the pathology data is facili- unique in terms of expense, time, and lack of repetition. tated by developing a dictionary of terms for each study In contrast to most other scientific endeavors, in which and maintaining both consistency and simplicity of termi- important experiments are usually repeated, societal regu- nologyfortopographyandmorphology. latory decisions may be based on one or a few toxicity/ Terminologyusedbypathologistsfortheclassification carcinogenicity studies. Thus, it is important that pathol- of neoplasms also plays a crucial role in the interpretation ogy data be based on sound judgment and that they be and statistical analysis of data from carcinogenicity stud- subjectedtopeerreviewpriortopresentation tothescien- ies. Evaluations of the potential carcinogenic effects of tific, regulatory, and lay community. A panel of patholo- chemicalsarebasedprimarilyonsite-specificcomparisons gists experienced with rodent tissues, and from varying oftumorsofthesameorsimilarmorphologyorhistogene- backgrounds, can provide a broad view of the potential sis rather than overall comparisons. Thus, it is extremely biological behavior of lesions induced by a chemical important that synonymous terms for topography or mor- whose toxic and carcinogenic potentials are poorly phology are not introduced into the data by the patholo- understood. gist. Excessive subclassification of neoplasms may also confusetheinterpretationofthedataandleadtoerroneous BIBLIOGRAPHY conclusions and impaired hazard evaluation. The subclas- sification of neoplasms in human medicine has particular Baker,H.J.,Lindsey,J.R.,Weisboth,S.H.(Eds.),1979.TheLaboratory applicability because of prognostic significance for the Rat,vol.1.AcademicPress,NewYork,NY. patient, but this is not a consideration in toxicologic Baker,H.J.,Lindsey,J.R.,Weisboth,S.H.(Eds.),1980.TheLaboratory pathology. The goal of the toxicologic pathologist is to Rat,vol.2.AcademicPress,NewYork,NY. record pathology datainaformatthatlendsitself toaccu- Coleman, G.L., Barthold, S.W., Osbaldiston, G.W., Foster, S.J., Jonas, ratebiologicalandstatisticalinterpretation. A.M., 1977. Pathological changes during aging in barrier-reared There is considerable morphological and biochemical Fischer344malerats.J.Gerontol.32,258(cid:1)278. evidence that neoplasms in humans and animals progress Cotchin,E.,Roe,F.J.C.(Eds.),1967.PathologyofLaboratoryRatsand Mice.Blackwell,Oxford. through a series of stages and ultimately become Goodman, D.G., Ward, J.M., Squire, R.A., Chu, K.C., Linhart, M.S., completely autonomous, invade surrounding tissue, and 1979. Neoplastic and nonneoplastic lesions in aging F344 rats. metastasize widely. From a mechanistic point of view, Toxicol.Appl.Pharmacol.48,237(cid:1)248. thisprogressionseemstobeamultistepprocessinwhich Gopinath, C., Prentice, D.E., Lewis, D.J., 1987. Atlas if Experimental the population of cells changes and diversifies with ToxicologicalPathology.MTPPress,Lancaster,England. eventual dominance of subpopulations with properties of Greaves,P.,Faccini,J.M.,1984.RatHistopathology.Elsevier,Amsterdam. enhanced growth, survival, autonomy, and malignant Greene,E.C.,1963.AnatomyoftheRat.Hafner,NewYork,NY. potential. From a morphological point of view, carcino- Haseman, J.K., Tharrington, E.C., Huff, J.E., McConnell, E.E., 1986. genesis proceeds through transitory or progressive stages Comparisonofsite-specificandoveralltumorincidenceanalysesfor of growth including hyperplasia and/or dysplasia, benign 81 recent National Toxicology Program carcinogenicity studies. neoplasia, and finally, overt malignant neoplasia. This Regul.Toxicol.Pharmacol.6,155(cid:1)170. Hebel, R., Stromberg, M.W., 1986. Anatomy and Embryology of the progression, often, but not always, appears as a morpho- LaboratoryRat.BioMedVerlag,Worthsee,FRG. logical continuum, and the terms used to represent each Jacobs,B.B.,Huseby,R.A.,1967.NeoplasmsoccurringinagedFischer of the main stages of the carcinogenic process imply a rats,withspecialreferencetotesticular,uterine,andthyroidtumors. certain biological behavior. The degree of certainty or J.Natl.CancerInst.(U.S.).39,303(cid:1)309. confidence in the assumed biological behavior increases Jones, T.C., Mohr, U., Hunt, R.D. (Eds.), 1983. Endocrine System: as the lesions proceed from hyperplasia, or other preneo- Monograph on Pathology of Laboratory Animals. Springer-Verlag, plastic changes such as dysplasia, to overt malignant NewYork,NY. neoplasia. Jones, T.C., Mohr, U., Hunt, R.D. (Eds.), 1985a. Respiratory System: The degree to which pathologists tacitly accept this Monograph on Pathology of Laboratory Animals. Springer-Verlag, concept of a biological and morphological continuum is NewYork,NY. evident in several different ways. The simple fact that Jones, T.C., Mohr, U., Hunt, R.D. (Eds.), 1985b. Digestive System: Monograph on Pathology of Laboratory Animals. Springer-Verlag, pathologistsusehistologiccriteriasuchasdegreeofcellu- NewYork,NY. lar differentiation, cellular pleomorphism, cellular atypia, Jones, T.C., Mohr, U., Hunt, R.D. (Eds.), 1986. Urinary System: and other cellular characteristics in the absence of inva- Monograph on Pathology of Laboratory Animals. Springer-Verlag, sion or metastasis to make a diagnosis is a reflection of NewYork,NY. this continuum. The fact that grading systems and even Jones, T.C., Mohr, U., Hunt, R.D. (Eds.), 1987. Genital System: staging systems are in common usage in medical pathol- Monograph on Pathology of Laboratory Animals. Springer-Verlag, ogyisalsoareflectionofthebiologicalcontinuum. NewYork,NY.
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