Mouse Pathology Glossary Non-Neoplastic (1-15); Neoplastic (16-29); References (30-36)

Table5revisedandupdatedfrom(Brayton2006).Nonneoplasticchanges;briefdefinitionsordescriptionsofsomeconditions(phenotypes)thatmaybe encounteredinmice.Thisisnotacompletelistandglossaryofallnonneoplasticconditionsthatmayoccurspontaneouslyorbeinducedinmice.The informationisderivedprimarilyfromresourcesusedinthechapter.Itisprovidedtofacilitateunderstandingofterminologyinthechapter,andisnotan officiallysanctionedglossary,dictionaryorontology.Terminologyanddefinitionswillcontinuetochangeasconditionsarecharacterizedfurtherandasnew conditionsareinduced. SYSTEM Organ,condition; synonyms (historicalterms) MULTISYSTEM i.e.generalizedconditionthatinvolvesmultiplesystemssimultaneously,orconditionthatmayoccurinvarioussystemsorat varioussites Amyloidosis Amyloid deposition in mice can occur in many tissues including liver spleen, kidney, lung, heart, parotid, gland, adrenal gland, ReactiveAA thyroid, esophagus, skin, stomach small and large intestines. With H&E, amyloid is homogeneous eosinophilic amorphous SenileAApoAII extracellularmaterial.Itstainspositivelywithcrystalviolet,CongoredandthioflavineTstains. InCongoredstainedsectionexposedtopolarizedlight,amyloidshoulddemonstrategreenbirefringence. Intestinalamyloiddepositionisinlaminapropriaandsubmucosa,withileumusuallyaffectedearliestmostseverely. Renalamyloidoccursprimarilyinglomerularmesangium,butmaybeinterstitialespeciallyaroundcollectingtubulesinpapilla. Splenicamyloidoccursprimarilyinmarginalzonesaroundfollicles. Lymphnodeinvolvementisprimarilyofmesentericnodeswithamyloiddepositsatperipheryinsubcapsularsinuses. HepaticamyloidoccursfirstaroundportalveinsandtheninperisinusoidalspacesofDisse. Cardiacamyloidspreadsfromaroundcapillaries. Pulmonaryamyloiddepositionisinsepta. Adrenalamyloiddepositsareprimarilyintheinnercortexsurroundingthemedulla. Parotidglandinterstitialamyloiddepositionmayseparateacini Thyroidandparathyroidglandscanhaveinterstitialamyloiddeposition. (Frithetal.1991;Higuchietal.1991;HogenEschetal.1996) Nasalamyloidprobablyisnotamyloid(usually).(Hainesetal.2001;Doietal.2007) Amyloidosis,reactiveAA AAamyloidhasapredilectionforspleen,liver,gutandkidney,andoftenisassociatedwithchronicinflammatoryconditions.(Frith etal.1991;Higuchietal.1991;HogenEschetal.1996) Amyloidosis,senile Massesofamyloidinlung,heartandileumsuggestAApoAII.Senileamyloidexclusivelyislikelytobefoundingonads,papillary AApoAII dermis,epineurium,andlung.(Frithetal.1991;Higuchietal.1991;HogenEschetal.1996) Amyloidosis,systemic Maitaetal.1998definedthetermfortheirstudyasamyloidosisinvolving3ormoredifferentorgansortissues.Thyroid,adrenal,

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Arteritis;polyarteritis; systemicarteritis; (periarteritis) kidneysmall,intestine,ovarywerepredilectionsitesinthisstudy. Inflammationofarteries.Seeabove(MULTISYSTEM)Smallmediummusculararteries,usuallyinmultiplesites,havemedial thickeningwithvariabledepositionofeosinophilicmaterial,andhavemildmarkedperivascularfibrosisandpredominantly lymphocytic,mononuclearinfiltration.Theremaybeearlyfibrinoidnecrosisorthrombi.Commonsitesincludeheart,thymus, tongue,uterus,testes,mesentery,kidneyandurinarybladder.(Frithetal.1988;Faccinietal.1990;Plendletal.1996;Elwelletal. 1999)Maitaetal.1988definedsystemicarteritisasarteritisinvolving3ormoredifferentorgansortissues.Thymusovary,uterus, kidney,heart,werepredilectionsitesinthisstudy,andthrombosisfrequentlywasassociatedwiththelesions. Markeddilatationofvascularchannels(veins,sinusoidsorlymphatics).Thelesioncanoccurinanyorganbutmostcommonly involvesthespleen,ovary,liverorlymphnodes.Itmaybedifficulttodistinguishfromhemangiomawithangiectaticareas,butthe liningendothelialcellsshouldbenormalinsizeandmorphology.(Frithetal.1988;Plendletal.1996;Elwelletal.1999;Haradaetal. 1999) Similartohamartoma,includingthemasslesionrequirement,butunlikehamartoma,includesheterotopictissueofanadultor embryonicnature(topographicalanddevelopmentalanomaly)Pathbase2004Theyaresoft,raisedmassesonthedorsal midline,primarilyabovethesuturesoftheskull.Theymaybenoticedbecauseofabnormallylonghair,changeindirectionofthe hairs,orchangeinhaircolorcompared.Microscopically,themassesconsistofnormaladiposetissueinthereticulardermisand subcutisthatsometimesextendsthroughthecranialsutures,enteringthebrain,orexpandingintotheventricles.Largemasses maycontainnormalappearingthyroid,intestine,respiratoryepitheliumlinedcysts,squamousepithelialcysts,boneandmarrow, cartilage,glands,andangiomatousanomalies.Overlyingepidermisisintact..Thisconditionresembles"lipomatous"hamartomas, acongenitaldefectinhumanbeings.(Adkisonetal.1991) Epithelialcytoplasmiceosinophilicchange.Itmaybeespeciallycommoninin129relatedmiceincludingB6;129mice,butsimilar changeshavebeenrecognizedinB6andotherstrains.Thematerial,whichmaybeintracytoplasmicorextracellularashyaline acidophilicmaterialorasneedleshaped,rectangularorsquarecrystals,hasbeenidentifiedasachitinase.Affectedtissuescan includelung,inwhichtheconditionisknownasacidophilicmacrophageoracidophiliccrystallinepneumonia,nasalmucosa, trachea,lung,stomach,gallbladder,bileducts.(Wardetal.2000;Wardetal.2001)Seeadditionaldetailsindiscussionaboveor listedbyorganbelow. Mildinflammatorycellinfiltrates,especiallylymphocyticfoci,mayoccurinvarioustissuesinagingmice,intheabsenceof discernibleincitingagents.Frequentlytheseareinterstitial,perivascularorperiductaldependingonthetissue.Affectedtissues mayinclude:Harderianglands,salivaryglands,nasalcavity,trachea,lung,gallbladder,hepaticportalareas,glandularstomach, thyroid,kidney,urinarybladder,prostategland.(Radovskyetal.1999;Wardetal.2000;Hainesetal.2001) Melaninpigmentcanbefoundinvarioustissues,otherthanskin,hairfolliclesandretinalpigmentedepithelium.Becauseitis consideredtobeanormalfinding,itisnotreportedinsomestudies.Commonlyaffectedtissuesinclude;spleen,heartvalves, meninges,choroidplexus,parathyroid.(Wardetal.2000;Hainesetal.2001) EspeciallyinDBArelatedmice,dystrophiccalcificationormineralizationislikelytooccurinvarioustissuesespeciallyintheheart butalsoinaorta,testes,tongue,skeletalmuscle,cornea,kidney,stomach,smallintestine,ovarywithincidenceandseverity increasingwithageandwithoutapparentsexdifferences(innongonadaltissues).(Ringsetal.1972;Maedaetal.1986;Yamate etal.1987;Yamateetal.1990)InBALB/candC3Hrelatedmicemineralizationismostcommonintheheartandcornea.(Van

Angiectasis

Choristoma,lipomatous hamartoma

Hyalinosis

Inflammation; lymphocytic infiltrates Melanosis

Mineralization

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Winkleetal.1986) (Frithetal.1983;Everittetal.1988;Vargasetal.1996)Extracardiacsofttissuemineralizationalsomayoccur inC3Hmice.(Highmanetal.1951)Inmostotherstrains,softtissuemineralizationisunusual.(Elwelletal.1999) Dilatationoftheesophagus.Dilatationusuallyisofthethoracicesophagus,visibleatnecropsy,withapparentimpactionby ingestedmaterial.Theconditionmaybeacontributorycauseofdeathinsomecases.(Wardetal.2000;Hainesetal.2001)In somestrains(ICRC)megaesophagushasbeenassociatedwiththepresenceofsmoothmuscleinsteadof(normal)skeletalmuscle inthedistalesophagus.(Randeliaetal.1988;Randeliaetal.1990) Seeabove(MULTISYSTEM)

ALIMENTARY Esophagus,dilatation; megaesophagus

Gallbladder; inflammation Gallbladder;hyalinosis

Seeabove(MULTISYSTEM)Gallbladderswithhyalinosismaybegrosslyenlargedwiththickenedopaquewalls.Extracellularcrystals (identifiedaschitinase),whenpresent,tendtobelargeandrectangulartosquare.Affectedbileductshadassociatedmucoid metaplasiaandfibrosis.Theacidophilichyalineorcrystallinematerialhasbeenidentifiedasachitinase.(Wardetal.2000;Wardet al.2001) Intestine,amyloidosis Seeabove(MULTISYSTEM)Amyloiddepositionisinthelaminapropriaofthesmallintestine,especiallyintheileum.(Frithetal. 1991;Higuchietal.1991;HogenEschetal.1996) Liver,amyloidosis Seeabove(MULTISYSTEM)Amyloiddepositionisinsinusoidsbeneaththesinusoidalliningcells,isdistinctlyhomogeneousand eosinophilic.(Frithetal.1991;Higuchietal.1991;HogenEschetal.1996) Liver,angiectasis; See above (MULTISYSTEM) Hepatic angiectasis involves dilatation of the vascular sinusoids and may be either focal or diffuse. telangiectasis,peliosis Angiectasismaybedifficulttodistinguishfromhemangioma.Inangiectasis,thevascularspacesaredilatedandprominentandtheir hepatis liningendothelialcellsarenormalinappearance,numberandsize.(Frithetal.1988;Haradaetal.1999) Liver,centrilobular Enlargement of centrilobular hepatocytes, with increased amount and variable staining characteristics of cytoplasm, with gradual hypertrophy decreaseincellsizeclosertoportalareas.Itisespeciallylikelyinstudiesoftoxicantsthatinduceproliferationofperoxisomesorof smoothendoplasmicreticulum.(Haradaetal.1999) Liver,centrilobular Centrilobularhepatocellularnecrosiscanoccurwithischemiaorchronicpassivecongestion,andisseeninFVBmicebelievedtohave necrosishepatocyte diedaftersevereorprolongedseizures.(Goelzetal.1998) Liver,extramedullary EMHoccursnormallyinfetalandneonatalmouseliver.Intheadultmouseitmaybesecondarytoinfectiousdiseaseorneoplasia. hematopoiesis(EMH) Smallfociornestsofimmaturegranulocytes,nucleatederythrocytesormegakaryocytesarescatteredinsinusoids.Granulopoietic focimaybeprimarilyperiportal.MegakaryocytesandnucleatederythrocyteshelptodistinguishEMHfrominflammationand leukemiaorlymphoma.(Frithetal.1988;Haradaetal.1999) Liver,fociofcellular Alteredstainingqualitiesandtexturalappearanceofthecytoplasmandsizeofhepatocytes,comparedtoadjacentnormal alteration;altered hepatocytes.Thereisnoobviousdisruptionoftheliverarchitecture,norcompressionofadjacentnormalparenchyma.Theymay hepatocellularfoci beclassifiedaseosinophilic,basophilic,clearcell,ormixed.Theyaremuchmorecommonincarcinogentreatedthanincontrol mice,andaremorecommoninmalethaninfemalemice. ClearcellfociconsistofcellswithpaleorsometimeslacycytoplasmthatstainwithPASstainpriortobutnotafterdiastase digestion,suggestingthepresenceofglycogen.Theirnucleitendtobecentralratherthanflattenedagainstthecellmembraneas

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inlipidvacuolatedcells. Eosinophilicfociconsistofcellsthattendtobelargerthanadjacentnormalhepatocyteswitheosinophiliaduetoincreased cytoplasmicmitochondriaand/orsmoothendoplasmicreticulum. Basophilicfociconsistofcellsthattendtobesmallerthanadjacentnormalhepatocyteswithbasophiliaduetorelatively increasedcytoplasmicfreeribosomesandroughendoplasmicreticulum. Mixedcellfocicontainvaryingproportionsof2ormoreofanyofthecelltypes.(Frithetal.1979;Haradaetal.1996;Haradaetal. 1999) Seeabove(MULTISYSTEM:)Fociofacuteandorchronicinflammatorycells(primarilylymphocytes)distributedrandomlyand sporadically.Mildchronicinflammationcharacterizedbyrandomandorportalorperivascularprimarilylymphocyticinfiltrates. Someofthesecasesmaybeattributabletohelicobacterorotherinfections.(Haradaetal.1996;Haradaetal.1999;Wardetal. 2000) Focalnecrosismaybeanincidentalfindingofunknownetiology,ormayberelatedtoinfections(MHV,Clostridiumpiliforme, helicobacters),toxicants.Itmayinvolvesinglecells,singleormultiplelobules,anditmayvaryindistribution.Coagulationnecrosis withhypereosinophiliccytoplasmandpyknoticorabsentnucleiisthetypicalmorphologicfeature,andcanbecommoninsome studies.(Haradaetal.1996;Haradaetal.1999;Wardetal.2000) Distinctiveroundeosinophilicintranuclearinclusionsinhepatocytesmaynearlyfillthenucleus.Theirincidenceincreaseswithage andtheyareconsideredtobeinvaginationsofthecytoplasmintothenucleus. Intracytoplasmicinclusionsarelesscommonandmayoccurnearneoplasms,andmay consistofcondensedsecretoryproteinsin dilatedcisternaeofroughendoplasmicreticulum.(Frithetal.1979;Haradaetal.1996;Haradaetal.1999) Hepatocellularvacuolizationduetofattychangeisespeciallycommoninoldobesecontrolsandismorecommoninmalethanin female mice. It also may occur in response to a toxicant. Initially there is usually a centrilobular distribution. The empty clear vacuoles peripherally compress nuclei, and represent lipid that was removed during tissue processing. The lipid nature can be confirmedbystainingfrozensectionswithOilRedOorSudanBlackB.FrithandWard,1988;Haradaetal.1996) Hepatocellularanisocytosisandanisokaryosis,withenlargedcellsandnucleiincreasewithage,andinresponsetovariousagents. Theremaybebinucleateormultinucleatehepatocytes.Theincreaseinnucleussizeornumberisassociatedwithpolyploidy.(Frithet al. 1988; Lu et al. 1993; Styles 1993) Premature polyploidy occurs in some mutant mice with defective DNA repair mechanisms. (Chipchaseetal.2003) Focal or lobular change resulting in complete absence of acini, or only few small acini with pale exocrine cells due to reduced zymogengranules,andnormalisletsofLangerhansuspendedinfattystroma.Itsoccurrenceonlyinagedmicesuggeststhatitisa trueatrophyandnotahypoplasia.(Frithetal.1988;Faccinietal.1990;Boormanetal.1991) Seeabove(MULTISYSTEM)Mildchroniclymphocyticinterstitialinfiltratesintheexocrinepancreas. Seeabove(MULTISYSTEM)Salivaryglandsmaydevelopamyloidosis.Theparotidglandsareserousglandsthatextendfromthe baseoftheearsventrallyandposteriorly.Withsevereamyloidosisacinimaybewidelyseparatedbyamorphousacidophilic

Liver;inflammation

Liver,necrosis hepatocytes

Liver,hepatocellular inclusions

Liver,hepatocellular vacuolization, steatosis,(fatty change,fatty metamorphosis) Liver,hepatocyte karyomegaly, cytomegaly; polyploidy Pancreas,exocrine atrophy Pancreas,inflammation, chronic Salivarygland, amyloidosis

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Salivarygland,ductal hyperplasia material,withhistochemical(staining)propertiesofamyloid.(Westetal.1965;Sashimaetal.1990) Ductal hyperplasia usually is associated with lobular acinar atrophy and is more common in the submaxillary and parotid salivary glandsthaninthesublingualgland.Thelesiontypicallyinvolvesasinglelobuleinwhichsomeaciniareatrophiedandreplacedby hyperplasticducts,andtheremaybeassociatedinflammatoryinfiltrates.(Frithetal.1988;Bottsetal.1999;Seely1999;Wardetal. 2000) See above (MULTISYSTEM) This typically is chronic lymphocytic or lymphoplasmacytic interstitial, perivascular or periductular inflammation,andmaybemorecommoninmalethaninfemalemice.(Frithetal.1988;Faccinietal.1990;Bottsetal.1999) Increasedthicknessofsquamousmucosaduetohyperplasiaofstratifiedsquamousepithelium,usuallywithhyperkeratosis,and likelytooccurafteradministrationofirritants.(Frithetal.1988;Leiningeretal.1999) Increasedthicknessofglandularmucosaduetohyperplasiawithincreasedpitandglandlength.Pitsbecomeelongatedandmore basophilic.Theremaybemucosalfoldingbutglandarchitectureisretained.Epithelialcellsmaybeenlarged,hypertrophied. Severecasesmayhaveherniationofglandsintomuscularismucosae,butbasementmembraneisnotpenetrated.(Bettonetal. 2001) Gastricplaquehasbeenusedtorefertofociofglandularhyperplasiaassociatedwithgastrichyalinosisin129S4/SvJaeandrelated mice.Theyaremostcommoninthecardiacglandularstomachatornearthelimitingridge.Grosslydiscernibleareasofplaque likethickening,sometimeswithhemorrhageareperiesophageal.Histologicallyglandsareelongated,hyperplastic,andmaybe focallydisorganizedwithlossofnormaldifferentiationpatterns.Theplaquescontainfociofhyalinizedepithelialcellsthat seemedtoarisefromchiefcellsinthemidregionoftheglands.Someepithelialcellscontainonlyafewintracytoplasmic droplets,orcellsmaybedistendedwithnucleidisplacedperipherallybybrightlyeosinophilicmaterial.Glandularluminamay containabundantextracellularrectangulareosinophiliccrystals,asopposedtoneedleshapedorsquarecrystals.Theyare metachromaticwithDominicistainasarethehyalinegranuleswithinepithelialcells.Theeosinophilichyalineandcrystalline materialhasbeenidentifiedasachitinase.(Hainesetal.2001;Wardetal.2001) Eosinophiliccytoplasmicdegenerativechange,termedhyalinosis,ismostcommoninthecardiacglandularstomachatornearthe limitingridge,andfrequentlyisassociatedwithplaquelikethickening.Seeabove.Haines,Chattopadhyayetal.2001;Ward,Yoon etal.2001) Inflammationinthedentalalveolus(toothsocket)oraroundthetooth.Inmicethediseaseismostseverinthemaxillaryarch.It canbeginasgingivitisinitiatedbyhairimpaction,plaqueorcalculus,andcanprogresstosevereinflammatorychangeswith resorptionoftoothandalveolarbone.(Losco1995;Longetal.1999) Abnormaldevelopmentormalformationsofinjuredandordisplacedodontogenictissues;maybeusedtorefertothespectrum ofnonneoplasticincisormalformationsinvolvingthetoothandperiodontalstructures.Histologicallytherecanbemildcystic changesinthedevelopingportionsoftheincisorsorthetoothmaybereplacedandsocketfilledandexpandedirregularmasses ofdentinlikematerialwithfragmentsoftoothandbone..(Losco1995;Longetal.1999;Wardetal.2000) Malocclusioninmiceultimatelymanifestsaslongmaxillaryincisorsthatgrowoutfromandcurlbackintothemaxilla,andlong mandibularincisorsthattendtogrowupwardsfromthemandible.Micewiththisconditioncannoteathardpelletedchow.

Salivary,gland inflammation Stomach,forestomach; squamousepithelial hyperplasia Stomach,fundicmucosal hyperplasia,gastric hyperplasia; adenomatous hyperplasia Stomach,glandular hyperplasia,plaque

Stomach,gastric hyalinosis Teeth,alveolitis, periodontitis, periodontaldisease Teeth,dentaldysplasia

Teeth,malocclusion

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CARDIOVASCULAR Heart,cardiomyopathy Traumaandgeneticshavebeenimplicatedinthis condition.(Losco1995;Longetal.1999;JaxNotes2003) Fociofmyocardialnecrosisormyocytedegeneration(myocytolysis)withminimaltomildmononuclearinfiltrationby,withor withoutfibrosis,whichmaybemorecommonintheleftventricle.(Plendletal.1996;Priceetal.1996)Someauthorsinclude mineralizationinthisdefinition,e.g.inBALB/cmice.Someauthorsmayusemyocardialnecrosis,inflammation,fibrosis.(Frithet al.1988;Faccinietal.1990) Arteritis/polyarteritisinvolvingcoronaryarteries.Seeabove,MULTISYSTEM. Seeabove,MULTISYSTEM. Seeabove,MULTISYSTEM.InBALB/candrelatedmicemineralizationisepicardial,ontherightventricularfreewall.(Frithetal. 1983)Mineralization,maybeassociatedwithdegenerativechangesespeciallyinfemaleC3Hmice,andinvolvesmyocardium. (Frithetal.1983;Everittetal.1988;Vargasetal.1996)InDBAmicemineralizationismyocardialandepicardialandtheremaybe mineralizationofothersofttissues,e.g.tongue,testes,aorta.(Yamateetal.1987;Brunnertetal.1999)Mineralizedfociare basophilicwithhematoxylinandeosin(H&E),blackwithvonKossa,andredwithAlizarinRedstaining.(Frithetal.1988;Maitaetal. 1988) Thrombiareusuallyintheleftatrium,whichmaybeenlargedandred.Thedegreeoforganizationdependsontheageofthe thrombus.Somethrombimaycontainfociofcartilaginousmetaplasia.Withlargethrombitheremaybesecondarychronic passivecongestion.Thrombosismaybeassociatedwithuremiaandkidneydisease,includingamyloidosis,maynotbeassociated witharteritis,andmaybemorecommoninmales.(Frithetal.1983;Frithetal.1988;Maitaetal.1988;Faccinietal.1990;Elwell etal.1999)Insomecasesbothatriamaybeinvolvedortheremaybeventricularthrombi.(Hagiwaraetal.1996) Markeddilatationofsmallvessels.Seeabove(MULTISYSTEM). Inflammationofarteries.Seeabove(MULTISYSTEM) Alsocalledpolyarteritis;systemicarteritis;periarteritis Smallnodulesofadrenalcorticalcellssurroundedbyaconnectivetissuecapsulearesometimesassociatedwiththeadrenalcapsule, andmaycontaincellofzonaglomerulosaand/orzonafasciculata.(Yarrington1996;Nyskaetal.1999) Especiallyinmalemice,smalladrenalsmaybedifficulttofind.Histologicallythecapsularsurfaceisirregular,corticalthicknessis reducedand/orvariable,andtheremaybe1ormorefociofcorticalcellhypertrophyorhyperplasia.(Halletal.1992)(Yarrington 1996;Nyskaetal.1999) Hyperplasiaofadrenalsubcapsularcellsthatmayrepresentadrenalsubcapsularreservecells.TheymaybespindledtypeAcellsor polygonallipidladentypeBcellsthatmorecloselyresemblenormalcorticalcells.Agedmice,especiallyfemalesinsomestrains, commonlyhavesubcapsularaccumulationsorproliferationsofbasophilicspindle(TypeA)cells,withsparsecytoplasmandindistinct cytoplasmic borders, which may be associated with mast cell infiltration. The lesion may be focal or diffuse, involving the entire subcapsularcortex.Hyperplasticfocimayslightlybulgethecapsulebutexhibitnominimalcompression,andshouldnotbelarger thantheregularwidthofthecortexinayoungmouse,butthedistinctionbetweenhyperplasiaandadenomamaybearbitraryand

Heart,coronaryarteritis Heart,melanosisvalves Heart,mineralization (dystrophiccardiac calcinosis,epicardial mineralization)

Heart,thrombi

Vessels,angiectasis Vessels,arteritis; ENDOCRINE Adrenalcortex, accessorycortical nodule Adrenalcortex,atrophy

Adrenalcortex, hyperplasia subcapsularcell

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difficult. (Frithetal.1988;Faccinietal.1990;Yarrington1996;Kimetal.1997;Nyskaetal.1999) Adrenalcortex, Enlargementofadrenalcorticalcellsduetoincreasedcytoplasmwithzonafasciculataprincipallyaffected.(Yarrington1996;Nyska hypertrophy etal.1999;NTP2000) Adrenalgland, See above (MULTISYSTEM) The inner most cortex is the first predilection site for amyloid deposition, and deposits can progress amyloidosis peripherallytoinvolvezonafasciculate,butusuallysparezonaglomerulosa.(HogenEschetal.1996;Yarrington1996;Nyskaetal. 1999) Adrenalgland,pigment Agedmicemaydevelopdepositionofceroid(lipogenic)pigmentinitiallyincorticalcellsandmacrophagesnearthecorticomedullary ceroid;(Lipogenic junctionthatcanprogresstosurroundthemedulla.Smallamountsofthecytoplasmicpigmentaregranulartoamorphousyellow pigmentation;Lipoid brown.Affectedcellsbecomeenlargedanddistendedwithbrownmaterial.Theirnucleimaybecomepyknoticandtheremaybe multinucleatedcells.Ceroiddepositsintheovaryaremainlyininterstitialcells.Ceroidpigmentsareyellowbrownlipidderived pigment;Brown pigmentsthatautofluoresce,arePASpositive,acidfast,stainbluewiththeSchmollreaction,arepositivewithSudanblack,and degeneration) arenegativeforiron.(Yarrington1996;Nyskaetal.1999) Pancreaticislet IncreasedsizeofisletsofLangerhantohyperplasia(increasednumber)ofcells,whichmorphologicallyaresimilartothoseinsmaller hyperplasia normalislets.Hyperplasiamaybedifficulttodistinguishfromthenormalsizevariationofisletsandhyperplasiaofbetacellsoccurs normallyduringpregnancy.Hyperplasiausuallyinvolvesmorethanoneislet(multifocal),andmayinvolveallisletsinasection.(Sass etal.1978;Frithetal.1988;Faccinietal.1990;Boormanetal.1999) Parathyroidmelanosis Seeabove(MULTISYSTEM) Pituitarycysts Singleormultiplesmallcystsoccurprimarilyinparsdistalisorparstuberalis.Theymaybelinedbyciliatedepitheliumand sometimescontaineosinophiliccolloidlikesecretion.Somemayrepresentcraniopharyngealduct(Rathkespouch)remnants.Cystic orcystlikedegenerationofparsdistalisoccursoccasionallyinaginguntreatedcontrolmice,butoccursearlierandwithhigher incidencewithincreasingdosesofestrogeniccompounds.Focaldegenerationandlossofcellsinparsdistalisresultsinsmall irregularspacesoftencontainingsomeeosinophilicmaterialandcelldebris.(Frithetal.1988;Mahleretal.1999) PituitaryParsdistalis; Hyperplasticfocihaveindistinctedgesandarenotcompressive,theyaredistinguishedfromadjacenttissuebyslightlydifferent hyperplasia stainingproperties(usuallypaler)withincreasednumberordensityofcells.Theymaybecomposedofchromophobeoracidophil cells.Chromophobecellsmaysecreteprolactin.(Frithetal.1988;Mahleretal.1999;Capenetal.2001) Pituitaryparsintermedia Diffuseornodularthickeningoftheparsintermediaduetohyperplasia.Thecellsarelargeandpalecomparedtoparsdistaliscells, hyperplasia andmaybelargerandmorebasophilicthantypicalparsintermediacells.Tumorsofparsintermediaarerare. (Frithetal.1988;Mahleretal.1999;Wardetal.2000;Capenetal.2001) Thyroidgland,ectopic Ectopicthyroidtissue,typicallyconsistingofafewcolloidcontainingfolliclesmayoccurinthemediastinumorthymus.Small tissue cystsinoraroundthethyroidgland,linedbyciliatedcuboidalcellsorsquamousepithelialcellsareconsideredtoberemnantsof thepharyngobrachialisductoroftheultimobranchialductrespectively.Thymicrests(smallaccumulationsofthymictissue)may occurinornearthethyroidglands. Thyroidgland,cysts Ultimobranchialcysts,linedbyciliated,cuboidalorsquamousepithelialcellsoccasionallyoccurinornearthethyroidgland. (Faccinietal.1990;Hardistyetal.1999)

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Thyroidgland, inflammation Parathyroidgland,cysts Parathyroidgland, ectopictissue GENITAL,FEMALE Ovary,atrophy Seeabove(MULTISYSTEM)Inflammationinthethyroidglandisuncommoninuntreatedmice.Theremaybeoccasionallymphoid infiltratesorarteritis.(Hardistyetal.1999) Parathyroidcystsmaybemultilocular,arelinedbyamonolayerofcuboidaltocolumnar,oftenciliated,epitheliumandusually containeosinophilicproteinaceousmaterial.(Faccinietal.1990;Hardistyetal.1999) Ectopicparathyroidtissuemayoccurinthemediastinumorthymus.Thymicrests(smallaccumulationsofthymictissue)may occurinorneartheparathyroidglands.(Faccinietal.1990;Hardistyetal.1999) Incidenceandseverityofovarianatrophyincreaseswithageinfemalemice,andmaybeinducedwithestrogeniccompounds. Atrophicovariesaresmallerthannormalovarieswithreducednumbersoffolliclesandespeciallyofcorporalutea,andrelatively increasedinterstitialtissue.Clustersoflargeyellowbrown(ceroid)pigmentedinterstitialcellsarecommon. (Frithetal.1988;Maekawaetal.1996;Davisetal.1999) Ovariancystsmaybesingleormultiple,mayvaryinsizeandmostareagerelated.(Davisetal.1999) FollicularandlutealcystsderivefromanovulatoryGraafianfolliclesandarethemostcommonovarianlesioninmiceonsome studies.Theymaybesingleormultipleandmayessentiallyreplacetheovary.Theyarelinedby14layersofcuboidalgranulosa cells.Theyshouldnotbeconfusedwithcysticcorporaluteathatderivefromovulatoryfolliclesandproduceprogesterone.These havemorethan6layersofhypertrophiedlutealcellssurroundingacentralcavitythatmaybebloodfilled. Epithelialinclusioncystsarelinedby1severallayersofcolumnarepithelialcellsthatformpapillarystructuresthatprojectinto centrallumen.Theymaybeprecursorsofcystadenomasorcystadenocarcinomas. Epidermoidcystsarelinedbysquamousepithelialcells,maybefilledwithlaminatedkeratindebris,canbefoundwithteratomas. Paraovariancystsarisefrommesovarium,arelinedbyciliatedcolumnarepithelialcells,andwallcontainssmoothmuscle. Retecystsderivefromdilatedtubulesofreteovarii.Theyarelinedbycolumnarepithelialcellswithapicalnuclei. Bursalcystscanbecommon.Theovarymaybecompressedwithinthecysticallydistendedovarianbursa. Ceroidisthemostcommonpigmentinmouseovaries,andtheremaybeahighincidenceofdepositionofthisagerelated pigmentafter1yearofage.Ceroiddepositsintheovaryaremainlyininterstitialcells.Theyareyellowbrownlipidderived pigmentsthatautofluoresce,arePASpositive,acidfast,stainbluewiththeSchmollreaction,arepositivewithSudanblack,and arenegativeforiron.Hemosiderinladenmacrophagesarelikelyinsitesofearlierfollicularhemorrhage.(Frithetal.1988; Maekawaetal.1996;Davisetal.1999) Thepresenceofendometrialglandsinthemyometriumisseenwithcysticendometrialhyperplasiaandcanbeinducedby administrationofestrogeniccompounds.Glandssometimesextendtotheserosa. (Frithetal.1988;Maekawaetal.1996;Davisetal.1999;Davisetal.2001) Angiectasisintheuterususuallyoccursinthemyometrium,andarteritisalsocanoccurintheuterus.Seeabove,(MULTISYSTEM). Cysticendometrialhyperplasiaisthemostcommonuterinechangeinsomestudiesofagedfemalemiceandtheincidencemay approach100%.Theconditionalsocanbeinducedbyhormonesandagentswithestrogenicproperties.Theuterusmaybe markedlyenlargedbyincreasednumbersofglandspluscysticdilatationofmanyglands.Endometrialglandsarecysticand

Ovarycyst

Ovarypigment

Uterus,adenomyosis

Uterus,angiopathy Uterus,cystic endometrial hyperplasia

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increasedinnumber.Theremaybeadenomyosis(endometrialglandswithinthemyometrium)inseverecases.(Frithetal.1988; Maekawaetal.1996;Davisetal.1999;Davisetal.2001) Uterus,hemosiderosis Hemosiderindepositionisespeciallylikelyinagedmultiparousfemales,likelyrelatedtoinvolutionofplacentalsites. (Frithetal.1983;Maekawaetal.1996) Uterus,hydrometra, Markeddilatationofhornsorbodyoftheuterus.Oneorbothhornsandthecorpusmaybeinvolved.Thelumencontainsserous mucometra proteinaceousormucoidmaterial,andtheuterinewallmaybethinandatrophicduetoprolongeddistention.Thecauseoftenis notdetermined,imperforatevaginaisalikelycause.(Sheldonetal.1980;Frithetal.1988;Sundbergetal.1994) Uterus,mineralization Mineralizationisespeciallylikelyinagedmultiparousfemales,likelyrelatedtoinvolutionofplacentalsites. (Frithetal.1983;Maekawaetal.1996) GENITAL,MALE Epididymis,karyomegaly Karyomegalyfrequentlywithassociatedcytoplasmicvacuolationintheepitheliumofthecaudaepididymiscausingtheenlarged celltobulgeintothelumen,hasbeenacommonfindinginrecentevaluationsif129andrelatedmice. (Wardetal.2000;Hainesetal.2001) Epididymis,sperm Granuloma,orpyogranulomatousinflammationresultingfromruptureofaductwithreleaseofspermandductcontentsto granuloma interstitium.Thelesionmayincludemultinucleatedgiantcellsandcholesterolclefts.Itmaybesecondarytoruptured spermatocele,whichisadilatedductsegmentfilledwithspermatozoa.(Frithetal.1988;Radovskyetal.1999) Preputialgland,cystic Ductalectasiaandglandatrophycanbecommoninpreputialandclitoralglands,whicharecomposedofmodifiedsebaceous ducts,ectasia aciniandsquamousducts.Associatedsuppurativeandchronicinflammationiscommon.(Frithetal.1988;Seelyetal.1999) Preputialgland, Suppurativeandchronicinflammationinpreputialandclitoralglandscanbecommon,withdevelopmentofabscesses.(Frithetal. inflammation 1988;Seelyetal.1999) Prostategland,atypical Proliferationofprostateepithelium,withoutdisturbanceofacinararchitectureorcompressionofadjacenttissue. epithelialhyperplasia (Radovskyetal.1999;Wardetal.2000) Prostategland, Seeabove,MULTISYSTEM.Lymphocyticfociandarteritiscanoccurintheprostate.(Radovskyetal.1999;Hainesetal.2001) inflammation Testes,atrophy, Degenerationinseminiferoustubulesmanifestsinitiallyasscatteredvacuolatedornecroticspermatogeniccellsoftenwith degenerationtubular multinucleatedgiantcellsandreducednumbersofgerminalepithelialcells.Moreadvanceddegenerationmanifestsasseverely depletedgermcells,depletedandflattenedSertolicells,andfewremainingspermatogonia.Lipofuscinorceroidpigmentinthe testesincreaseswithageandmaybeassociatedwithdegenerativechanges.(Radovskyetal.1999) Testes,interstitial Increasednumbers(hyperplasia)ofinterstitial(Leydig)cellsbetweenseminiferoustubules.Thesenoncompressivecollectionsof (Leydig)cell typicalinterstitialcellsmaybefocal,multifocal,ordiffuse,andrangeindiameterfromabout25%ofthediameterofa hyperplasia seminiferoustubuleto3seminiferoustubulesdiameter.Interstitial(Leydig)cellshaveabundanteosinophilic,sometimes vacuolated,cytoplasm,andusuallycentralnucleuswithprominentnucleolus.(Gordonetal.1996;Radovskyetal.1999;Rehmet al.2001;Pathbase2004) Testes,Mineralization FocaldystrophicmineralizationoftheseminiferoustubulesmayoccuroccasionallyinsomestrainsandcommonlyinDBA/2mice.

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Itmayrepresentpreviousareasofinjury.Histologicallythebasophilicconcretionsmaybeamorphousorconcentrically laminated.(Ringsetal.1972;Frithetal.1988;Yamateetal.1990;Radovskyetal.1999) Unilateralovariesandcysticendometrialhyperplasiawithcontralateraltestesandepididymides,ortruehermaphroditeswith unilateralovotestesshouldbeexpectedinEScellchimericmice,butareunusualspontaneousfindingsinmoststocksandstrains. (Whittenetal.1979;Eicheretal.1980;JankowskaSteiferetal.1992;McIntyreetal.2007) Fociofreplacementofmarrowbyfibrousconnectivetissue,notassociatedwithrenalor(Wijnandsetal.1996)parathyroid lesions,canoccurinanybonesbutarecommonlyreportedinsternum,femur,vertebraeespeciallyinagingfemalemice.In advancedlesionsthemarrowcavitymaybealmostreplacedbyfibrousconnectivetissueorbonytrabeculae.(Sassetal.1980; Frithetal.1988;Wijnandsetal.1996;Longetal.1999;Wardetal.2000)Intramedullaryboneproliferationmaybereferredtoas hyperostosis.Seebelow,MUSCULOSKELETAL. Relativeorabsoluteincreaseinnormal(usuallygranulopoietic)myeloidelementsinthebonemarrowusuallyisaresponseto infectionornecrosis,e.g.tumoralnecrosis.Severegranulopoietichyperplasiamaybedifficulttodistinguishfromgranulocytic leukemia.(Frithetal.1985;Koganetal.2002) Lymphoidhyperplasiaofthelymphnodescanbecommoninespeciallyinfemales,insomestudiesofagingmice.Expansiondueto hyperplasiaoccursinBcellareas(follicles, germinalcenters),Tcellthymicdependentareas(paracortex).Marginalsinus isoften filledwithlymphocytesandmedullarycordsexpandedbyplasmacells.Thelymphocytesaremature,usuallytherearefewmitotic figures.Lymphoidhyperplasiaandplasmacytosisvanbeareactiontochronicinflammatorylesionsortumorantigens.(Frithetal. 1985;Frithetal.1988) Accumulationsofmacrophagesorhistiocytesinthesubcapsularandmedullarysinusesoflymphnodes.Theplumpmacrophages mayhaveabundantdistinctlyeosinophiliccytoplasmandmaycontainhemosiderin,otherpigments,erythrocytesandother phagocytosedmaterial.(Frithetal.1985;Frithetal.1988) Accumulationsofplasmacellsinthesubcapsularandmedullarysinusesoflymphnodes. Seeabove,MULTISYSTEM.Earlylesionsoccurinthewhitepulpandspreadtotheredpulp. Seeabove,MULTISYSTEM. Seeabove,MULTISYSTEM.Bothhemosiderinandmelaninpigmentoccurinthespleensofmice.Hemosiderinisgoldenbrownand usuallyincytoplasmofmacrophagesorreticularcells.ItstainspositivelywithironstainssuchasPrussianblue.Melaninalsooccurs inthespleenofmicewithpigmentedskin.Itisslightlydarkerthanhemosiderin,maybeinelongatestrandsratherthanclumps(like hemosiderin),isnotassociatedwithmacrophagesandisironnegative.(Frithetal.1985;Frithetal.1988) Thespleenisanimportanthematopoieticorgan,andtheredpulpexpandsduetoincreased,proliferative,normalhematopoietic elements.Theincreasemaybeprimarilyinerythroidorgranulopoieticelements.Megakaryocytesalsoarecommonintheredpulp andmayincreaseaswell.(Frithetal.1985;Koganetal.2002) Increasederythropoiesisischaracterizedbyfociofimmatureerythrocyticprecursorswithsmalldarklystainingnucleiintheredpulp. Increasederythropoiesismayormaynotbeassociatedwithanincreaseingranulopoiesis.(Frithetal.1985;Frithetal.1988)

Testes,ovotestes& hermaphrodites HEMATOPOIETIC Bonemarrow, fibroosseouschange, (myelofibrosis) Bonemarrow, hyperplasiamyeloid granulocytic Lymphnode, hyperplasia, lymphoid

Lymphnode,infiltration, macrophages;sinus histiocytosis Lymphnode,infiltration, plasmacells Spleen,amyloidosis Spleen,arteritis Spleen,melanosis

Spleen,extramedullary hematopoiesis,EMH (myeloidmetaplasia) Spleen,hyperplasia erythroid

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Spleen,hyperplasia myeloidgranulocytic Increasedgranulopoiesis(e.g.duetoinfectionorabscess)usuallyoccursinbonemarrowaswellasinspleenandtheremaybe granulopoieticelementsinliver,adrenalsandlymphnodesaswell.Normalmaturationincludingmatureneutrophilsshouldbe discernedingranulopoiesis.Aprimary(inciting)causesuchasabscess,ulcerativedermatitisortumoralnecrosisshouldbesoughtin casesofmarkedgranulopoiesis.(Frithetal.1985;Koganetal.2002) Thistermmaybeusedtorefertoapparentincreaseinmonocyte/macrophageorreticuloendothelialcells.(Frithetal.1985; Wijnandsetal.1996) Thethymusreachesmaximalsizeatsexualmaturityandthenundergoesgradualinvolution.Thymussizeandrateofinvolution varieswithmousestrain.(Pelegetal.1984;Hsuetal.2003)Duringinvolutionthymussizedecreasesduetogradualreductionin cortexandlymphocytecontent,andthemedullabecomesmoreprominent,withapparentincreaseinconnectivetissue,andin epithelialelements,whichmayformcysts,cordsortubules.Temporaryandreversibleinvolutionoratrophyoccursduring pregnancy,infection,malnutrition,aftersurgeryorotherstressors,andcanbecausedbytoxicinsults.Earlyatrophymay manifestasastarryskyappearanceduetophagocytosisofnecrotic/apoptoticlymphocytesbyphagocytes.(Wijnandsetal.1996; Wardetal.1999) Epithelialcystsinthethymusmaybecomemoreprominentduringinvolutions.Theymaybelinedbysquamoustocolumnarcells withsomeciliatedcells.SomecystsmaycontaincelldebrisandPASpositiveglycoproteinmaterialandmaybeinvolvedincell disposal. Focalordiffusehyperplasticchangescanoccurinthecortexormedulla,in1orbothlobes.Theremaybefocallymphocytic accumulationsinthecortexormedullary,orfollicleswithgerminalcenter.(Wijnandsetal.1996;Wardetal.1999) Mammaryglandsmaybegrosslyenlargedandhavelobuloalveolarhyperplasiawithdistendedsecretoryalveoliandductsthat thatcontaineosinophiliccolloidlikesecretorymaterial.Theyresembleglandsduringpregnancyordelayedinvolution.The conditionmaybecommoninoldervirginandmultiparousFVB/Nmicewithorwithoutassociatedpituitarylesions,andhasbeen associatedwithmousemammarytumorvirusinfection.InFVB/Nmicetheremaybesquamousnoduleswithinthehyperplastic gland.(Medina1982;Frithetal.1988;Nietoetal.2003;Wakefieldetal.2003) Theconditioncanoccurinmanystrainsofmiceandacariasisshouldberuledout.IthasbeenreportedmostcommonlyinC7BL relatedstrains.Itmaybeginasadorsalpapulardermatitis,progressingtofociofalopeciaandsmallulcers,thenexpansionofthe ulcers,withdeepnecrosis,intensesuppurativeandchronicinflammatoryresponses,andsecondarychangessuchas lymphadenopathy,myeloidhyperplasia,amyloidosis.(Sundberg1996)InoutbredSwissmicetheearsandneckmaybeaffected mostcommonlyandseverelyandhasbeencalledprogressivenecrosingdermatitisofthepinna.(Slattumetal.1998) Histologically,allspecieshavedystrophicanagenstagehairfolliclesassociatedwithaperiandintrafollicularinflammatorycell infiltrate.(McElweeetal.1998;McElweeetal.1999) Noninflammatory,progressivelossordestructionofarticularcartilage,withthickeningofunderlyingbone,andsometimes subchondralcystsandosteophytesinvariousstrains.Kneeandelbowjointsmaybemostseverelyaffected,andvertebrae especiallythoracicvertebraemaybeaffectedalso.(Longetal.1999)

Spleen,hyperplasia reticular Thymus,atrophycortex orlymphoid depletionor involution

Thymus,cysts

Thymus,hyperplasia, lymphoid INTEGUMENT Mammaryhyperplasia, functionalwithout atypia

Skinulcer,inflammation, ulcerativedermatitis

Alopeciaareata MUSCULOSKELETAL Skeletal,degenerative jointdisease; osteoarthritis

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Bonehyperostosis endosteal NERVOUS Brain,hypocallosity Brain,lipofuscin Brain,melanosis meninges Brain,mineralization thalamus Endostealboneproliferation.Estrogensmayinducethisconditioninmice.Inadvancedstagesofspontaneousfibroosseous lesions,themedullarycavitiesmaybenearlyfilledbybone(seebonemarrow,above).(Highmanetal.1981;Wardetal.1999) Smallorabsentcorpuscallosumconnectingcerebralhemispheresoccursespeciallyin129andBALB/cstrains.(Wahlsten1982; Livyetal.1991;Livyetal.1997) Browntingedcytoplasmofneuronalcellbodies,duetolipofuscinaccumulation,increaseswithage,andmaybemostprominent ingranulecellsofthedentategyrus.(Mooreetal.1995;Mooreetal.1995;Radovskyetal.1999) Seeabove,MULTISYSTEM.

Smallfoci(upto100umdiameter)ofbasophilicmineralized,material,occursusuallybilaterallyinthethalamusofoldmice,withan incidenceofabout5%inCD1andB6C3F1mice.(Faccinietal.1990)Theyusuallyareassociatedwithbloodvesselsandconcentric laminationmaybeevidentwithH&E.Theystainnegativeforamyloidandiron,andareweaklypositivewithAlcianblue,primarilyat theperipheryofthedeposits.TheyaredarkbrownorblackwithdistinctlaminationbyVerhoeff'smethod,andhavearedcoreand darkperipherywithAlizarinRed.(Morganetal.1982;Frithetal.1988;Radovskyetal.1999) RESPIRATORY Lung,acidophilic Acidophilicmacrophagepneumonia,alsoreferredtoasacidophiliccrystallinepneumoniaischaracterizedbyabundant Macrophage macrophagesdistendedwitheosinophilic(acidophilic)granularorcrystallinematerialinairways.Intracellularorextracellular pneumonia eosinophilicneedlelikecrystalsinairwaysmayormaynotbeconspicuousandmaystainbluewithPerlsreaction(foriron). (Wardetal.2000;Wardetal.2001) Lung,acidophiliccrystals Intracellularorextracellular,nonbirefringent,acidophiliccrystals,identifiedasachitinase,canbestrikingordominantfeatureof acidophilicmacrophagepneumonia(acidophiliccrystallinepneumonia)insomecases. (Wardetal.2000;Wardetal.2001) Lung,alveolarepithelial Hyperplasia(increasednumbers)ofalveolartypeIIcellsorbronchiolarsecretorycells.Thesetypicallyarepoorlydemarcatedfoci hyperplasia ofhypercellularitywithseptalthickeningduetoincreasednumbersofplumptypeIIcellsorbronchiolartypecellswith bronchoalveolar preservationofalveolarseptalarchitecture.Atypiaandmitosesareunusual.Thesemaybeprecursorsofadenomaorcarcinoma. (Dixonetal.1999;Dungworthetal.2001) hyperplasia(TypeII cellhyperplasia) Lung,inflammation, Seeabove,MULTISYSTEM.Theseusuallyconsistofsmallperivascularlymphocyteaggregates,ormildincreasebronchiole perivascular associatedlymphoidtissue(BALT).Theyshouldbeminimalinuntreatedmicenotexposedtorespiratorypathogens. peribronchiolar (Ernstetal.1996) Nose,amyloidosis, Expansionofnasalseptumbysubmucosaldepositionofamorphousacellulareosinophilicmaterialalsohasbeenreferredtoas nasalamyloidosis septalamyloidosis.ThesubmucosalamorphouseosinophilicmaterialinnasalseptacommonlystainsbetterwithPASor trichromethanwithCongored.Probablyitusuallyisnotamyloid. (Monticelloetal.1990;HogenEschetal.1996;Hainesetal.2001;Doietal.2007) Nose;olfactory Nasalolfactoryepithelialhyalinosisisprimarilyneartheolfactory/respiratorytransitionareas,withfociofhyalinosischaracterizedby

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epitheliumhyalinosis Nose;respiratory epitheliumhyalinosis eosinophilicintracytoplasmicinclusions,identifiedasachitinase,originatingatthebasalaspectsofliningcells.(Wardetal.2000; Wardetal.2001) Nasalrespiratoryepitheliumtendstobemoreaffectedthanolfactoryepithelium,particularlyintheregionsofthenasalglands, Affectedrespiratoryepithelialcellsmaybedistendedwithperipheraldisplacementofnucleibyeosinophilichyalinematerial. Inflammationusuallyisnotassociatedwithepithelialchanges.Extracellularcrystalswerevariablyneedlelike,rectangular,orsquare. Theacidophilichyalinematerialandcrystalshavebeenidentifiedasachitinase.Inflammationusuallyisnotassociatedwith epithelialchanges.(Wardetal.2000;Wardetal.2001) Seeabove,MULTISYSTEM.Theseusuallyconsistofsmallsubmucosallymphocyticaggregates. Trachealepithelialcytoplasmcontainsandmaybedistendedbyamorphousorspicularhyalineeosinophilicmaterialthathasbeen identifiedasaYM1chitinase.(Wardetal.2000;Wardetal.2001) Epithelialcytoplasmcontainsandmaybedistendedbyamorphousorspicularhyalineeosinophilicmaterialthathasbeenidentified asaYM1chitinase.(Wardetal.2000;Wardetal.2001) Inflammationofthemiddleear.Theremaybeintensesuppurativeexudatesinthelumen,withinflammatoryandproliferative changesintheliningepithelium,orthechambermaybefilledwitheosinophilicserousmaterialwithfewinflammatorycellsand littlechangeintheliningepithelium.Somelesionshavefibrosisandlipidlikematerialwithcholesterolcleftsresembling cholesteatomaorcholesterolinicgranuloma.Organismsmaybedifficulttodiscern.(Hainesetal.2001) Inflammationofeyelidandconjunctiva.Thisconditionmaybequitecommoninseveralpigmentedandnonpigmentedmouse strains.Initiallythereissuppurativeconjunctivitisand/orulcerationatthemucocutaneousjunction,progressingtosuppurative inflammationinvolvingmeibomianducts,withconjunctivalulceration.Variousbacterialspeciescanbeisolated,buttheirroleas pathogensoropportunistsisunclear.(Smithetal.1996) Opacificationofthelens,resultinginawhiteorgraylens.(Smithetal.1994;Hubertetal.1999) Changesinlensfibersincludefiberswelling,Vacuolation,liquefactionandformationofMorgagnianglobules.Damagetolens epitheliumcanresultinepithelialflattening,proliferation,layeringandformationofbladdercells.Laterchangesmayinclude mineralization,cholesterol/lipiddeposition,orcompleteliquefactivenecrosis.Withhypermaturecataracts,leakageoflens materialmayprovokeaninflammatoryresponse.(Frameetal.1996)Smith,Rodericketal.1994;Hubert,Gerinetal.1999) Inflammationofthecorneawithvascularizationofthenormallyavascularcornea.Theremaybeulceration,cornealthickening duetoedema,erosionorulcerationoftheanteriorsurface.(Frameetal.1996;Hubertetal.1999) Grosslyevidentwhiteareaonanteriorcorneaduetomineralization.Histologicallythereismineralizationofthebasement membraneandstromawithvaryingdegreesofedema,inflammation,vascularizationofthestroma,anderosionorulceration. [DBA/2(29.1%),C3H(16.2%),CF1(16.2%)BALB/c(10.0%)>CD1(4.3%)andC57BL/6(4.1%)]diet?NH3etcfactors?(Van Winkleetal.1986;Frameetal.1996)

Tracheainflammation Tracheahyalinosis Tracheamucosalgland acidophiliccrystals SPECIALSENSES Ear,otitismedia

Eye,Blepharo conjunctivitis

Eye,cataractgross Eye,cataract microscopic

Eye,keratitis, neovascularization Eye,cornealopacity, Cornealdystrophy, Corneal mineralization,Band keratopathy Eye,retinaldegeneration Homozygosityforrd1mutationinPde6blocus(gene)resultsinbilateralcompletelossofouternuclearlayer(rodandconenuclei) andoftheoutergranularlayer(innerandoutersegmentsofrodandconephotoreceptors),sothattheinnernuclearlayer

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appearstoabuttheretinapigmentedepithelium(RPE).Asthediseaseprogressesthereislossofretinalvasculatureandpigment inRPE(inpigmentedmice),fociofthinningoftheinnernuclearlayer,andlossofganglioncellsandnervefibers.(Smithetal. 1996;Changetal.2002;Serfilippietal.2004;Zeissetal.2004) Agerelatedorlightrelateddegenerativechangesintheretinawithreductionoftheouterlayersduetolossofphotoreceptor cells.Normallytheouternuclearlayeris1012nucleithick.(Smithetal.1996)Somestudiesmayusethetermforrd1associated retinaldegeneration.(Halletal.1992) Seeabove(MULTISYSTEM)Theseusuallyconsistofdiscreteinterstitialmononuclearinfiltrates.(Frithetal.1988;Faccinietal. 1990;Bottsetal.1999) Seeabove(MULTISYSTEM)Thislesioncanresembleglomerulonephritisandshouldbedistinguishedbyspecialstains.Glomeruliare enlargedwithmesangiumexpandedbynodularordiffuseaccumulationsofacellulareosinophilichomogeneousmaterial.Renal papillarynecrosisisusuallyassociatedwithrenalamyloidosisortoxins.(Frithetal.1988;Wolfetal.1996) Membranoproliferativeglomerulonephritischaracterizedbydepositionofeosinophilichyalinematerialinglomerularbasement membraneswithproliferationofmesangialcellsandinflammatorycellinfiltrationseemstobethemostcommonGNinmost chronicstudies.Earlychangesoffocalmesangialthickeningwithincreasednumbersofepithelialcells,progresstoincreased lobularseparationofglomeruli,thickeningofglomerularcapillarywallsandincreasedmesangialmatrix. BasementmembranethickeningwithPASpositivematerial,usuallyattributedtoimmunoglobulin,isexpected. CongoredandtrichromestainsshoulddistinguishGNfromglomerularamyloidandcollagendepositionrespectively. (Faccinietal.1990;Montgomery1998;Son2003;Pathbase2004) Thetermimpliesscarringorfibrosisandrelatedlatechangesintheglomerulartuftinprogressiveglomerulardisease.Itmay includesmall,fibrotictuftsandadhesionstotheglomerularcapsule(synechiae).(Faccinietal.1990)Thetermalsomaybeused toincludeawiderangeofglomerularchanges(includingverylittlesclerosis)withvarioustubularchangesandinterstitial inflammation.(Maitaetal.1988) Distentionoftherenalpelvismaybemildwithlittlechangeinkidneysize,orthedilatedpelvisandkidneymaycauseabdominal distentionwithcompressionatrophyofkidneyremnants.Possiblecausesincludeurinaryobstructionduetocalculi,tumorsor inflammation.Itmaybeunilateralorbilateral.Theremaybehydroureterifobstructionischronicanddistalintheurinarytract. (Frithetal.1988;Seely1999)Itshouldnotbeconfusedwithgeneticallydeterminedpolycystickidneysyndromesthatusually involvebilateralprogressivedevelopmentofmultiplecystsoftubulesand/orcollectingducts,culminatinginrenalfailure,and sometimesassociatedwithextrarenalcystsandotherabnormalities.(Werderetal.1984;Trudeletal.1991;Nakayamaetal. 1994;Rickeretal.2000) Seeinterstitialnephritis. Indiffusechronicinterstitialnephritis,kidneysarereducedinsizewithgranularornodularsurfaces.Inthesubacutestage cellularinfiltrateincludeslymphocytes,plasmacells,andfewerneutrophilsormacrophages.Tubulesaredilatedwithvarying degreesofdegenerationandregeneration.Thechronicstageischaracterizedbyfocalordiffusefibrosis,withlymphocyticor lymphohistiocyticinfiltration;tubulesmaybecysticwithproteinaceouscastsorbeatrophic,theremaybeareasoftubular

Eye,retinalatrophy

Harderiangland,chronic inflammation URINARY Kidney,amyloidosis

Kidney, glomerulonephritis (GN)

Kidney, glomerulosclerosis

Kidney,hydronephrosis

Kidneyinflammation Kidney,interstitial nephritis

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regenerationorhyperplasia.Glomeruliusuallyaresparedifprimaryinsultisinterstitial,ortheconditionmaybesecondaryto glomerulonephritis.(Faccinietal.1990;Montgomery1998)notverycommonincontemporarycolonies. Thetermusuallyincludestubularchanges:tubularregeneration,occasionallywithtubularcasts,thickenedbasementmembrane, crowdingofnucleiandinflammatorycellinfiltration.(Son2003)Someauthorsmayincludeorglomerulonephritisinthisterm. Someauthorsrefertotheconditionaschronicprogressivenephropathy,similartotheconditioninrats.(Wolfetal.1996) Interstitialnephritisandnephropathyhavebeenusedtorefertosimilaroridenticalconditions.(Faccinietal.1990) Hyalinedropletsthatcontainlysozymefromtumorcellscanbefoundinproximaltubulesinsomemicethathavehistiocytic sarcoma.Thebrightlyeosinophiliccytoplasmicdropletscanbestrikinginaffectedkidneys.(Hardetal.1991;LacroixTrikietal. 2003) Fociofmineralizationaregranular,faintlybasophilicandfilltubularlumina,usuallyatthecorticomedullaryjunction,orinthe loopsofHenleinthemedulla.Itmayoccuraspartofthespectrumofchangesinnephropathyorinterstitialnephritis,andnot diagnosedasaseparateentity.(Frithetal.1988;Faccinietal.1990;Seely1999) Maitaetal.1988Son2003.usesthetermdysuriatorefertourinaryobstruction,withurinarybladderseverelydilatedand urethranearisthmuspluggedbygelatinousplugwithsperm,ortheobstructionmaynotbeidentified,andtheremaybe hydroureterorhydronephrosis.Otherauthorsrefertoconditionasobstructiveuropathy(Faccinietal.1990)orMUS(Mouse urologicsyndrome).(Faccinietal.1990;Bendele1998) MUShasoneormoreofthefollowingfeatures:bladderdistension;peripreputialurinestaining,alopecia,andedema; paraphimosis;urethralblockage;ulcerativebalanoposthitis;hydronephrosis;pyelonephritis;rectalprolapse;andperineal ulcerativedermatitis.(Everittetal.1988)InacuteMUSmicearefounddeadwithnopriorclinicalsigns.Inthechronicform, theremaybeventralwetting,dermatitis,paraphimosis,peniletrauma,urinarycalculi,pyelonephritisorhydronephrosis.(Bendele 1998) Seeabove(MULTISYSTEM) Seeabove(MULTISYSTEM)

Kidney,nephropathy

Kidneytubule,hyaline droplets Kidneytubule, mineralization (nephrocalcinosis) Urinaryobstruction, dysuria

Urinaryobstruction, MUS

Urinarybladder,arteritis Urinarybladder, inflammation

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Table6.revisedandupdatedfrom(Brayton2006).Neoplasms,briefdefinitionsordescriptionsofsomeneoplasmsthatmaybeencounteredinmice.Thisis notacompletelistandglossaryofallneoplasmsthatmayoccurspontaneouslyorbeinducedinmice.Theinformationisderivedprimarilyfromresourcesused inthechapter.Itisprovidedtofacilitateunderstandingofterminologyinthechapter,andisnotanofficiallysanctionedglossary,dictionaryorontology. Terminologyanddefinitionswillcontinuetochangeasneoplasmsarecharacterizedfurtherandasnewneoplasmsareinduced. SYSTEM Organ,neoplasm (historicalorobsoleteterms) ALIMENTARY Intestine,polyp Amassoftissuewhichprojectsoutwardorupwardfromthenormalsurfacelevelbeingmacroscopicallyvisibleasa hemispheroidal,spheroidal,orirregularmoundlikestructuregrowingfromarelativelybroadbaseoraslenderstalk.These maybeadenomasbutarenotspecifiedinsomereports.(Maekawaetal.1996;Shackelfordetal.1999;Pathbase2004) Intestine,adenoma Benignneoplasmofenterocytesofintestinalmucosa.Theseareuncommonspontaneousneoplasmsinmice,andaremore likelytooccurinthesmallintestine(especiallyintheduodenum)thaninthelargeintestine.Theyarefrequentlysmalland maynotbedetectedintheunopenedintestine.Typicallytheyarepolypoidandprojectintothelumen.Mucosal architecturemaybedistortedandtheremaybebranchingvilliortubularcryptproliferation.Theremaybecrypt herniationbutwithoutpenetrationofbasementmembrane.Theepitheliumisrelativelywelldifferentiated,butmaybe morebasophilicthanadjacentnormalepithelium.Theremaybeassociatedinflammatorychangesespeciallyifthereis ulceration,andtheneoplasmsmayarisenearaPeyerspatch..(Frithetal.1988;Maekawaetal.1996;Shackelfordetal. 1999;Bettonetal.2001) Intestine,adenocarcinoma Malignantneoplasmofenterocytesofintestinalmucosa.Largetumorsmayberecognizedgrosslywhentheyexpandthe intestine.Theremaybesingleormultiplenodulesorpolypoidmassesthatprojectintothelumenorendophytic,sessile neoplasmsmayresultinathickenedwallwithirregularmucosalsurface,andpresentgrosslyasadiverticulumorbulgeof theserosalsurface.Distinctionbetweenadenomaandadenocarcinomamaybedifficultwhenthereisnometastasisor obviousinvasionthroughthebasementmembraneintotheintestinewall.Invasiveglandsfrequentlyareassociatedwitha markedinflammatoryandscirrhousresponse.Normalarchitectureislostandtheremaybecysticandsolidareas.The neoplasticcellsusuallyarebasophilic,moreanaplasticandpleomorphicthaninadenomas,cuboidaltocolumnarandthere maybegobletorsignetring,orPanethcellcomponents.Thereareincreasedmitoticfiguresandnucleimaybe pleomorphic.(Frithetal.1988;Maekawaetal.1996;Shackelfordetal.1999;Bettonetal.2001) Intestine,cecumcarcinoid Neoplasmofneuroendocrine(enterochromaffin)cellsoftheintestinalmucosa.Gastrointestinalcarcinoidor neuroendocrinetumorsareveryrareneoplasmsinmice.Theymaybeinducedinthestomachbyantisecretoryagentsthat causehypergastrinemia.Malignancyisdeterminedbyinvasionand/ordistantmetastasis.Neuroendocrinetumors typicallyfeatureapacketedpatternofclustersofpolygonalcellssupporteddelicatefibrovascularstroma.Cytologic featuresmaybesimilartootherendocrinecellswithmoderatetoamplegranularcytoplasm,aroundnucleuswith prominentnucleous/i,andthebulkofthecytoplasm,ratherthanthenucleus,mayapposethevasculature.Thecellsmay beargyrophilic,andstainwithchromograninAorneuronspecificenolase.(Maekawaetal.1996;Bettonetal.2001)

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Intestine,fibrous histiocytoma Theseneoplasmsderivefrompluripotentialmesenchymalstemcellsandalsoexhibithistiocytoidfeatures.Inmicethese arerareoutsideofthesubcutis/skin,Histiocyticsarcoma(seebelowHEMATOPOIETIC)shouldbeconsideredespecially whenthereisinvolvementofliverandotherorgans.Schwannoma(nervesheathtumor)andfibromaorfibrosarcomaalso shouldberuledout.(SeebelowINTEGUMENT.)(Ernstetal.2001). Hepatocellularneoplasm,adenomavs.adenocarcinomanotdistinguished.Usuallyothertypesoftumorsintheliver (cholangioma,cholangiocarcinoma,hemangioma,hemangiosarcoma,hepatoblastoma,histiocyticsarcoma,metastatic neoplasm)arenotincludedinthiscategory,unlessdiagnosesweremadebygrossexaminationonly. Benignneoplasmderivedfromhepatocytes.Theseusuallyaredistinctlydemarcatedorcircumscribednodules,110mm diameter,thatlacklobularorganization,compressadjacentparenchymaandmaybulgefromtheliversurface.Theydonot invadeadjacentparenchymaorvesselsanddonotmetastasize.Theyconsistofauniformpopulationofwelldifferentiated cellsthatresemblenormalhepatocytesbutmaybelargerorsmallerthanadjacentnormalhepatocytes,andcanhavemore basophilic,eosinophilic,orvacuolatedcytoplasm.Hepatocellularcarcinomasmayarisewithinadenomas.(Frithetal.1994; Haradaetal.1999;Deschletal.2001) Malignantneoplasmderivedfromhepatocytes.Carcinomasinmiceoftenhavedistincttrabecularoradenoidpatterns. Moderatelywelldifferentiatedhepatocellularcarcinomasarecomposedoflargerhepatocytesthatvaryinsizeandshape intrabecularorsolidpatterns.Thepoorlydifferentiatedtumorsarecomposedofcellswithlesscytoplasmandmore immaturenucleiandsomehaveextremelylargeanaplasticcells. Metastasesaretypicallytothelung,andcarefulexaminationmayrevealpulmonarymetastasesinupto40%ofmale B6C3F1orC3Hmicewithhepatocellularcarcinomathatareallowedtoliveouttheirlifespan.Metastasesusuallyoccur onlywhentumorsarelarge(>10mm).(Frithetal.1994;Haradaetal.1999;Deschletal.2001) Seetable5,Theymaybereportedasneoplasticornonneoplasticfindings,dependingonthestudy. Hemangiomainliver,seehemangiomabelow.Theseneoplasmsmaybedifficulttodistinguishfromangiectasis(table5). Hemangiosarcomainliver,seehemangiosarcomabelow. Theserarespontaneousorinducedlivertumorsmaybeanundifferentiatedvariantofhepatocellularcarcinoma,andfetal orductularoriginshavebeenproposed.Histologicallysimilarneoplasmsoccurinchildren,buthepatoblastomasonlyoccur inagedmice.Theyarealmostalwaysfoundwithinoradjacenttohepatocellularcarcinomasandaredistinctbecauseof theirbasophiliarelativetoadjacentparenchyma.Thetumorsfrequentlyhavedistinctivepatternsincludingrosettes,rows orribbons,organoidornestlikestructureslinedbydistinctbutdelicatevascularchannels.Thechannelsaresurroundedby oneseverallayersofradiallyorconcentricallyarrangedneoplasticcells.(Frithetal.1994;Haradaetal.1999;Deschletal. 2001) Neoplasmofmyoepithelialcellsofglandularstructuresincludingsalivarygland;mammaryglandandpreputial/clitoral glands.Relativelyrareinmice(84%inBALB/cJinSundberg,1991,1992).Typicallypresentaslargesoftfluctuantmassesin ventralneck.Whenopened,theycontainthick,opaque,redbrownfluid(theresultofliquefactivenecrosis.Mestastases arerare.Theymaybemostlikelyinthesubmaxillaryorparotidsalivaryglands.Histologically,theyarebiphasictumors, composedoflargepleomorphiccellsincludingelongatedorspindleshapedmesenchymaltypecells,mixedwithareasof

Livertumor

Liver,adenoma hepatocellular;(Type Anodulehepatoma, hyperplasticnodule, carcinoma) Liver,carcinoma hepatocellular(Type Bnodule,trabecular carcinoma,malignant hepatoma)

Liver,fociofcellular alteration Liver,hemangioma Liver,hemangiosarcoma Liver,hepatoblastoma

Salivarygland, myoepithelioma

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polyhedralepithelioidcells.Areasofdegenerationandnecrosiscanresultinpseudocystsfilledwithmucusandnecroticcell debris.Theneoplasticcellsmaypalisadearoundbloodvessels.Largertumorsmaymetastasizetothelung.(Sundberg1992; Bottsetal.1999;Pathbase2004) Benignneoplasmofstratifiedsquamousepitheliumofthenonglandularstomach(forestomach).Theseareusually exophyticvillousorarborescentoutgrowthsoffibrovascularstromacoveredbyneoplasticstratified.Theremaybe acanthosisandhyperkeratosisbutmaturationisnormalandmitoticfiguresarerare.TheincidenceincontrolB6C3F1mice, Swissmiceandotherstrainsusuallyis<2%.(Maekawaetal.1996;Bettonetal.2001;Pathbase2004) Squamouscellcarcinomaarisingfromstratifiedsquamousepitheliumoftheforestomach.Inthestomachthesemalignant neoplasmstendtobepolypoid,withmarkedcellularpleomorphism,keratinpearlsandmanymitoticfigures.Theyexhibit invasion,andulceration,inflammationandfibrosisofsubmucosaarecommonfeatures.TheincidenceincontrolB6C3F1 mice,Swissmiceandotherstrainsusuallyis<2%. Seebelowhemangioma.(angioma) Seebelowhemangiosarcoma.(angiosarcoma) Benignneoplasmofendothelialcellscanbefoundatanysiteinthebody.Themostcommonsitesarespleenandliver. Subcutis,skeletalmuscle,andfemalereproductivetractareothercommonsites.Cavernoushemangiomasaredilated cavernousspacesthatarelinedbyendothelialcellsandfilledwithredbloodcells.Capillaryhemangiomasare circumscribedaccumulationsofsmallcleftlikespaceslinedbytypicallyplumpendothelialcellsandcontainingredblood cells,orspacesmaybevacantorflattened.Mitoticfiguresarerareinhemangiomas. (Frithetal.1982;Boothetal.1995;Peckhametal.1999;Ernstetal.2001) Malignantneoplasmsofendothelialcells,consistingofdilatedvascularspacesofvaryingsizeswhichmayormaynotbefilled withredbloodcells,noncircumscribedandlocallyinvasive..Cellsmaybeverypleomorphicandvessellikestructuresmay bedifficulttoappreciateinpredominantlysolidneoplasms.Thecellsliningvascularspacesareplumpwithovalbasophilic nuclei,indistinctcellborders,andmayhavebizarremitoticfigures.Thereisoftenpilingupofliningcells.Particularlyinthe spleen,tumorsmaybepredominantlysolid.Necrosis,hemorrhage,andthrombiarefrequent. (Frithetal.1982;Boothetal.1995;Peckhametal.1999;Ernstetal.2001) Neoplasmofmesothelialcellsthatlinepleural&peritonealcavities.RAREspontaneoustumorsinmicebutmaybeinducedby intrapleuraloraerosolexposuretoasbestosorothermineralfibers.Epithelial,mesenchymalormixedpatterns;nodularor diffuseinvolvementofpleuralorperitonealsurfaces.Nodularmesotheliomasarecharacterizedby1toseveralnoduleson pleuralorperitonealsurfaces,andmaybebenignormalignant.Diffusemesotheliomashavemanycontiguousnodulesor thickconfluent,creeping,growthoversurfacesandtendtobemalignantwithdeepinvasion.Epithelialtypeneoplasmsmay bepapillarywithexophyticfrondsofpleomorphiccellssupportedonfibrousstalks,ortubularwithatypicalcellsforming glandularpatterns,orsolidwithmanybizarreatypicalcellswithkaryomegalyorseveralnuclei.Mesenchymaltypeareas consistofinterlacingbundlesofspindlecellswithnuclearpleomorphism.(Dixonetal.1999;Dungworthetal.2001)

Stomach,forestomach, squamouspapilloma

Stomach,forestomach, squamouscellcarcinoma

CARDIOVASCULAR Heart,hemangioma; Heart,hemangiosarcoma; Vessels,hemangioma

Vessels,hemangiosarcoma

Heart,mesothelioma

ENDOCRINE

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Adrenalcortex,subcapsular cellhyperplasia Adrenalcortex,adenoma; (adrenaladenoma; adrenalcortical adenoma) Seetable5. Benignneoplasmofadrenalcorticaltissue.Expansileaccumulationsofneoplasticcellswithlowmitoticactivitythatare welldelineatedfromadjacentnormalcortex,typicallybulgethesurfaceofthegland,compressunderlyingcortexand exceedtheregularwidthofthecortexinayoungmouse.TypeAadenomasarecomposedofspindledcells.TypeB adenomas(solidadenomas)arecomposedofmorepolygonal,smallorlargerlipidladencellsthatresemblenormal adrenalcorticalcells.Inbothtypesneoplasticcellsappeartobepacketedbyfinevascularstroma.Thetumorsfrequently havebothcelltypes,andusuallymaybenamedforthepredominantcelltype.Mastcellsintermingledwiththetumorcells oftenareassociatedwiththeTypeAtumors.Smallaccessoryadrenalcorticalnodules,areespeciallycommoninBALB/c mice.In,oststrains/studiescorticaladenomaarerelativelyuncommon,usually<1%incidenceeveninoldpopulations,but aremorecommonthancarcinomas.(Yarrington1996;Nyskaetal.1999;Capenetal.2001) Neoplasmoftheadrenalmedulla.Thesetumorsaremuchlesscommoninmicethantheyareinrats,andlikehuman pheochromocytomas,spontaneoustumorsinmiceproducecatecholamines.Theneoplasticcellsarerelativelyuniform polyhedralcellsthatresemblenormalmedullarysecretorycellswithcentralnucleiandfinelystippledcytoplasm,andare supportedorpacketedindelicatefibrovascularstroma.Astumorsenlarge,thestromatendstobelessconspicuousand capillariesaredistendedwithblood.CytoplasmofneoplasticcellsmaybemorebasophilicwithH&Ethanthatofnormal medullarycells.Lesionsthatinvolve<50%ofthemedullaanddonotcompressadjacenttissuemaybediagnosedas hyperplasia.Lesionsthatinvadetheadrenalcapsuleorspreadbeyondtheadrenalglandareclassifiedasmalignant pheochromocytoma.(Tischleretal.1996;Nyskaetal.1999;Capenetal.2001) Isletcelladenomasinmicetypicallyinvolveasingleisletinahistologicsection,incontrasttohyperplasiawhichtypically affectsmultipleisletsorallisletsinalobule.Isletadenomasarelargerthanhyperplasticisletsandcompressadjacentnormal pancreas.Adenomasmaybemorevascularthannormalorhyperplasticisletsandcellstendtobewelldifferentiated,with fewmitoticfigures.Usuallythesearefunctionalbetacelltumorsthatproduceinsulinwithoutcausinghypoglycemia. Carcinomasareevenlesscommonandtendtobelargerthanadenomasbutalsocomposedofwelldifferentiatedcells,but demonstrateinvasionordistantmetastasisusuallytotheliver.(Boormanetal.1999;Capenetal.2001) Benignneoplasmofpituitarygland.Adenomasofparsdistalisaremorecommonthanofparsintermedia.Parsdistalis adenomascanbecommoninagedfemalemice.Adenomasaredistinguishedfrompituitaryhyperplasiabybeing welldelineatedandcausingcompressionofadjacentnormalcells,butthedistinctionmaybesubtle.Theyaretypically composedoflargecellswithabundanteosinophiliccytoplasm,andangiectaticorcystlikespacesarecommon. MammotrophorprolactinsecretingadenomasoftheparsdistalismaybeespeciallycommoninfemaleC57BL6/Jmice. Carcinomasoftheparsdistalisarerareandarediagnosedwhenthereisunequivocalinvasionintosurroundingtissuesor distantmetastases.(Schechteretal.1981;Frithetal.1988;Mahleretal.1999;Capenetal.2001) Seetable5. BenignneoplasmderivedfromcalcitoninproducingCcells(parafollicularcells)ofthyroidgland.Thesearemuchless commonthanthyroidfollicularadenomasinmice(comparedtorats).Theyoccurassolidnests(asopposedtopapillaryor

Adrenalmedulla, phaeochromocytoma (adrenalmedullary (chromaffin)celltumor)

Pancreasisle;adenoma insulinoma)

Pituitarygland,adenoma

Pituitarygland,hyperplasia, parsdistalis/intermedia Thyroid,Ccell,adenoma

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follicularstructurestypicaloffollicularadenomas)ofpolygonalpalepolyhedralcellswithindistinctcytoplasmicborders. Theyhavebeen(arbitrarily)distinguishedfromhyperplasticfocibyoccupyinganarealargerthan5averagefollicles. (Hardistyetal.1999;Capenetal.2001) MalignantneoplasmderivedfromthecalcitoninproducingCcells(parafollicularcells)ofthethyroidgland.Thedistinction betweenadenomaandcarcinomaisnotclearlydefined.Theremaybecentralnecrosis.Invasionofextrathyroidaltissue maybetheonlyusefulcriterionformalignancy.(Hardistyetal.1999;Capenetal.2001) Benignneoplasmofthyroidfollicularcells.Thyroidtumorsareuncommoninmice,<1%inmoststudies,andfollicularcell adenomaisthemostcommonlyreportedspontaneoustumor.Usuallyinglewelldelineatedlesionsinotherewisenormal thyroidgland.Themostcommontypeisasmallpapillaryadenoma,inwhichapapillaryprojectionoffollicularepithelium extendsintoacysticlumen.Follicularpatternsconsistingofsmallcolloidcontainingfolliclesmixedwithnormalsizedfollicles, andsolidpatternswithcellsinsheetsanddenselypackednodulesarelesscommon.Follicularepitheliumiscuboidal, cytoplasmstainsslightlymorebasophilicthanadjacentnormalthyroid,andtheremaybecolloidinfolliclelumens.Solid patternadenomasmayresembleCcelltumors(Thomasetal.1996;Hardistyetal.1999;Capenetal.2001) Malignantneoplasmofthyroidfollicularcells.Thesearemuchlesscommonthanfollicularcelladenomas,andmaybe difficulttodistinguishfromthem.Theprimarypatternissolid,buttheymayhavefollicular,papillaryormixedpatterns.They areusuallylargerthanadenomas,withmoreatypia,andevidenceofinvasionordistantmetastases.(Thomasetal.1996; Hardistyetal.1999;Capenetal.2001) Benigntumoroftheovary.Thetypeofadenomaisnotspecifiedinsomereports.Tubulostromaladenomaorcystadenoma arelikely,butwithgrossexamination,thetermmayrefertoanyovarianneoplasm. Malignantneoplasmderivedfromtrophoblasts,andconsideredtobegermcellneoplasms.Trophoblastsaregiantcells withnucleiupto50udiameterthatarefoundinnormalembryonicmembranesandproducechorionicgonadotropins. Chroriocarcinomasarerareneoplasmsinmiceevenincarcinogenstudies,andusuallyoccurintheuterus.Theyare composedofsheetsoflargeanaplasticmultinucleatedsyncytioblasts,andsmallerbasophiliccellsthatresembleplacental cytotophoblastspleomorphic,aswellasmoretypicalgiantuninucleatedtrophoblastsandhighlyanaplastictrophoblastlike cells.Hemorrhageisaprominentfeature.(Davisetal.1999;Davisetal.2001) Benignneoplasmderivedfromthesurfaceepitheliumoftheovary.Itisacommonspontaneousovarianneoplasminsome strainsofmice.Anastomosingpapillaryfronds,linedbynonciliatedcuboidalcolumnarcellsprojectintothecystlumen.The cystliningtypicallyiscuboidalcolumnarepithelium,whichmayincludeciliatedcells.Thecystlumenmaycontaineosinophilic serousfluidorblood.(Frithetal.1988;Maekawaetal.1996;Davisetal.1999;Davisetal.2001) Ovarianneoplasmderivedfromsexcordstromalcells.Granulosacelltumorsareusuallyunilateral,butmaybebilateralor occurinconjunctionwithanotherovariantumor.Theyarecharacterizedbyadiversityofpatternsincludingsolid,tubular, follicular,trabecular.Theneoplasticcellsresemblenormalgranulosacellsandhavescanttomoderateamphophilic vacuolatedcytoplasmdependingontheirdegreeofluteinization.Theytendtohavesmallovalnucleiwithstippledchromatin, andtheremaybefewtomanymitoticfigures.Sometumorshavedistinctiveareasoffusiformthecalikecells.Somelarge tumorshaveareasofnecrosisandhemorrhageandprominentlipofuscinladencells.Mitosesvaryinnumberfromfewto

Thyroid,Ccell,carcinoma

Thyroid,follicularcell, adenoma

Thyroidfollicularcell, carcinoma

GENITAL,FEMALE Ovary,adenoma Ovary,choriocarcinoma

Ovary,cystadenoma

Ovary,granulosacelltumor

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numerous.CallExnerlikerosettesarerarebutmaybefoundinthefolliculartypes.Malignantgranulosacelltumorsexhibit morecellularpleomorphism,highmitoticrates,localinvasion,frequentnecrosisandhemorrhage,andmaymetastasizetothe lungs,kidneys,lymphnodes.(Frithetal.1988;Maekawaetal.1996;Davisetal.1999;Davisetal.2001) Hemangiomaintheovary,seeabove,CARDIOVASCULAR. Hemangiosarcomaintheovary,seeabove,CARDIOVASCULAR. Neoplasmsderivedfromovariansexcordstromalcells. Theyarecomposedofendocrinestromalcellsoftheovaryand includeneoplasmsofgranulosa,thecaandluteacellorigin,Sertolicelltumors,andfibromaorfibrosarcomaofstromalcell origin.Neoplasmsmayincludemorethanonesexcordstromalcelltypeandusuallyarenamedforthepredominantcell type,butsomereportsmayusenamesthatindicatemorethanonecelltype.(Davisetal.1999;Davisetal.2001) Benign ovarian neoplasm derived from sex cord stromal cells. They may be the most common ovarian tumor in some strainse.g.BALB/c.Luteomasaregenerallywellcircumscribedbutnotencapsulated,andmayinvolvetheentireovary.They consistoflargepolygonalcellsthatcloselyresemblethecellsofanormalcorpusluteum.Theyshouldexceedthesizeof3 normalcorporalutea.Theneoplasticcellshaveabundantpalegranulareosinophilic,sometimesvacuolated,cytoplasm,anda singleroundnucleus,usuallywithfewmitoticfigures.Insomeluteomasthecellsmaybebrowntingedduetoceroid,whichis PASpositiveandacidfast.Mastcells,scatteredorinclusters,maybecommoninluteomasofBALB/candC57BL/6butare lesscommoninthoseoftheC3Hstrains.(Frithetal.1988;Maekawaetal.1996;Davisetal.1999;Davisetal.2001) Ovarian neoplasm derived from sex cord stromal cells. Sertoli cell tumor is a rare ovarian neoplasm, and histologically resembles testicular Sertoli cell tumors, with a distinctive tubular pattern of elongated epithelial cells with homogeneous faintlyeosinophiliccytoplasmandbasal,roundnuclei,palisadingonthinstrandsoffibrovascularstroma.Mitoticactivityis usuallylow. Thistermprobablyreferstoamixedsexcordstromaltumor. Benignormalignantgermcellderivedneoplasmcontainingderivativesfromall3germlayers(endoderm,mesoderm, ectoderm).Ovarianteratomasarerarebutusuallyseeninyoungmice,andarefrequentlycysticwithamixtureofepithelial celltypes,includingprominentareasofcornifying,stratifiedsquamousepithelium,ciliatedtallcolumnarepitheliumand intestinalepithelium,sometimesthyroidorpancreas,alongwithwelldifferentiatedcartilage,bone,skeletalorsmooth muscle,andvariableamountsofwelldifferentiatednervoustissueresemblingcerebralcortex.Benigntumorstendtoappear moredifferentiatedwitheasilyrecognizablematuretissues.Malignanttumorstendtobelessdifferentiated,withlargeareas ofnecrosisandhemorrhage,andarehighlymetastatic.(Frithetal.1988;Maekawaetal.1996;Davisetal.1999;Davisetal. 2001)Extragonadalteratomasareusuallyinchimericmice,originatingfromEScells.(Blackshearetal.1999) Ovarianneoplasmderivedfromsexcordstromalcells,withthecacellandSertolicelllikeareas. Benignovarianneoplasmderivedfromsexcordstromalcells.Thenodulesarecomposedofdenselypackeddistinctive fusiformthecacellstypicallyinbundlesorwhorlingpatterns,supportedondelicatefibrovascularstroma.Palerluteinized cellclustersmaybeinterspersedbetweenstrandsoffusiformthecalcells.Theprinciplecelltypeisfusiform,withanoval nucleusandsparsebasophiliccytoplasm.Luteinizationischaracterizedbyincreasedcellsize,faintlyeosinophilic,brownish,

Ovary,hemangioma. Ovary,hemangiosarcoma Ovary,Sexcordstromal tumors

Ovary,luteoma

Ovary,Sertolicelltumor

Ovary,SertoliLeydigcell tumor Ovary,teratoma

Ovary,thecaSertolicell tumor Ovary,thecoma

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foamycytoplasmandaround nucleuswithadelicatechromatinpattern.Largetumorsmayhaveextensivenecrosiswithonly perivascularpersistenceofviabletissue.(Frithetal.1988;Maekawaetal.1996;Davisetal.1999;Davisetal.2001) Benignneoplasmderivedfromthesurfaceepitheliumoftheovary.Itisthemostcommonspontaneousovarianneoplasmin somestrainsofmice.Tubulostromaladenomasareatleast23mmdiamandcompressadjacentovariantissueoreffacethe ovary.Theyarecomposedofcordsortubulesofnonciliatedcuboidalorcolumnarcellsseparatedbylargeroundpolygonal cellsthatresemblestromalinterstitialcellsandhaveeosinophilicfoamyorvacuolatedcytoplasm,sometimeswithgolden brownpigment.Theyhavebeeninterpretedasinvaginationsofmesothelial(orgerminal)epitheliumintotheovarianstroma, sometimesdividingtheovaryintomultiplelobules.Theseinvaginationsusuallypresentasvariablysizedtubularstructures, linedbysimplecolumnar,cuboidaloroccasionallyflattenedepithelium.Tubulostromalhyperplasiadoesnotformdiscrete masses,isnotcompressive,norinvasive,butdifferentiationoftheseconditionsmaybearbitrary.(Frithetal.1988;Maekawa etal.1996;Davisetal.1999;Davisetal.2001) Malignantneoplasmderivedfromthesurfaceepitheliumoftheovary.Comparedtotubulostromaladenoma,these neoplasmsaremuchlesscommon,andfeatureincreasedcellularatypia,increasedmitoticindex,hemorrhagemetastasis,and invasionbeyondtheovarianbursa.(Maekawaetal.1996;Davisetal.1999;Davisetal.2001) Benignneoplasmofuterinemucosalepithelium.Thesemaybeonabroadbaseoronastalk(whentheymaybecalled polyps).Theyformwelldifferentiatedglandularortubularpapillarystructureslinedbycuboidalepithelium.Stromal proliferationshouldnotbeafeature(seestromalpolyp).Maekawa,Maitaetal.1996;Davis,Dixonetal.1999;Davis, Harlemanetal.2001) Malignantneoplasmofuterinemucosalepithelium.Theseareuncommoninmice.Theyarepoorlycircumscribedmasses thatextendintoandoccludetheuterinelumen,invadedeeplyintomyometriumandbeyond,andmaymetastasizeto lungs.Theneoplasticepithelialcellsmaybewelldifferentiatedorverypleomorphic.Necrosisandhemorrhageare common.(Maekawaetal.1996;Davisetal.1999;Davisetal.2001) Hemangiomaintheuterus,seeabove,CARDIOVASCULAR. Hemangiosarcomaintheuterus,seeabove,CARDIOVASCULAR. Benignneoplasmofsmoothmusclecellsofthemyometrium.Theymaybereportedinupto3%ofCD1orB6C3F1mice insomestudiesandaremorecommonthanleiomyosarcomas.Theyaresolitarywellcircumscribedmassesthatmay compressadjacenttissues.Theyarecomposedofdenselycellularsheetsofinterlacingbundlesandwhorlsofspindlecells, witheosinophiliccytoplasmsimilartoadjacentmyometrialsmoothmusclecells.(Maekawaetal.1996;Davisetal.1999) Malignantneoplasmofsmoothmusclecellsofthemyometrium.Theyarepoorlydelineatedmasseswithdisorganizedand invasivegrowthpatterns,andmayhaveareasofnecrosisandhemorrhage.Thespindledcellsmaybemorepleomorphic thaninleiomyoma.(Maekawaetal.1996;Davisetal.1999) Polypoidmassofuterinestromaltissuethatprojectsintotheuterinelumen.Itiscoveredbycuboidalcolumnarepithelium thatiscontinuouswithandsimilartoendometrialliningepithelium.Theremaybeendometrialglandularelementsaswell. Mostendometrialpolypshaveabundantloosestromacomposedofstellateorspindlecellsandnumeroussmallblood vessels,andmayhaveafewlargedilatedorpleomorphicendometrialglands.Whenthepolypiscomposedprimarilyof endometrialglandulartissuewithlittlestroma,itmaybereferredtoasaglandularpolyp.(Maekawaetal.1996;Davisetal.

Ovary,tubulostromal adenomas;Tubular adenoma(tubular mesothelioma)

Ovary,tubulostromal adenocarcinoma Uterus,adenoma endometrial

Uterus,adenocarcinoma endometrial

Uterus,hemangioma Uterus,hemangiosarcoma Uterus,leiomyoma

Uterus,leiomyosarcoma

Uterus,polypstromal

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1999;Davisetal.2001) Uterus,stromalsarcoma Malignantneoplasmofuterinefibrovascularstroma.Uncommon,reportedin<1%ofCD1orB6C3F1miceonchronic studies.Somemayariseinstromaofuterinepolyps.Composedofsheetsofpoorlydifferentiatedspindlecells,maybe pleomorphicandwithgiantcellandmanymitoses.RuleoutHistiocyticsarcoma,involvinguterus.Variableamountsof fibrillarorcollagenousmatrix,andendotheliumlinedvascularspaces.RuleoutHemangiosarcoma.Theremaybenecrosis, hemorrhageandinfiltrationofmyometrium,cervixandadjacentstructures.Metastasisisrare.Differentialdiagnoses includehistiocyticsarcoma,leiomyosarcoma,fibrosarcomaandSchwannoma. (Maekawaetal.1996;Davisetal.1999;Davisetal.2001) GENITAL,MALE Testes,interstitialcelltumor, TumorderivedfromtesticularLeydigcells(interstitialcells).Bothbenignandmalignantspontaneousinterstitialcelltumors Leydigcelltumor arerareinmice,butcanbeinducedwithsyntheticornaturalestrogensincertainstrains,especiallyinBALB/cmice. Unilateral,withnorightorleftpredilection.Tumorsmaybedifficulttodistinguishfrominterstitialhyperplasia. Hyperplasticfocimaybedistinguishedbysize(<3seminiferoustubulesdiameter)andnoncompression,comparedto adenomas(>3seminiferoustubulesdiameter),compresssurroundingtissueandexhibitsomecellularpleomorphism. SpontaneousLeydigcelltumorstendtobewelldifferentiated&ofsolid,diffusetype,composedofroundhomogeneous cellswitheosinophilicgranularcytoplasm.Small,wellcircumscribedtumorsareadenomas,andlargetumorswhichare invasiveormetastasizearereferredtoascarcinomas.Largercarcinomasmaymetastasizetolungs.(Frithetal.1988; Prahaladaetal.1994;Gordonetal.1996;Mahleretal.1997;Radovskyetal.1999;Pathbase2004) Testes,teratoma;Testicular Benignormalignantgermcellderivedtumorsofthetestescontainingtissuesfromall3germcelllayers(endoderm, germcelltumor(TGCT) mesoderm,ectoderm).Testicularteratomasarerarebutusuallyseeninyoungmice,especiallyof129strains.Should containavarietyofepithelialtypes,includingcornifying,stratifiedsquamousepithelium,ciliatedtallcolumnarepithelium andintestinalepithelium,sometimesthyroidorpancreas,alongwithwelldifferentiatedcartilage,bone,skeletalorsmooth muscle,andvariableamountsofwelldifferentiatednervoustissueresemblingcerebralcortex.Benigntumorstendto appearmoredifferentiatedwitheasilyrecognizablematuretissues.Malignanttumorstendtobelessdifferentiated,with largeareasofnecrosisandhemorrhage,andmaymetastasize.(Gordonetal.1996;Rehmetal.2001;Pathbase2004) Extragonadalteratomasareusuallyinchimericmice,originatingfromEScells.(Blackshearetal.1999) Testes,seminoma Testiculargermcelltumorderivedfromspermatogeniccellsresemblingspermatogoniaorspermatocytes.Thesearevery rareinmice,composedoffairlyuniformlargecellswithclear(glycogencontaining)cytoplasmandwelldefinedcell borders,resemblingprimitivegermcells.(Gordonetal.1996;Rehmetal.2001;Pathbase2004) Testes,Sertolicelltumor Testiculargermcelltumorderivedfromsexcord/stromalcells(Sertolicells).Theseareveryrareinmice,composedof elongatecellstypicallyarrangedindistinctivepalisadesondelicatefibrovascularstroma(picketfencepattern),forming tortuoustubularstructureswithoutdistinctlumina.Apoorlyorganizeddiffusepatternwithfeworindistincttubular structuresislesscommon.Neoplasticcellstendtohaveindistinctborders,palevacuolatedcytoplasmandmanymitotic figures.(Rehmetal.2001;Pathbase2004) HEMATOPOIETIC Histiocyticsarcoma Solidtumormasscomposedpredominantlyofhistiocyticcells(Koganetal.2002)Thesecanbecommonhematopoietic

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(reticulumcellsarcoma orreticulumcell neoplasm,typeA; endometrialsarcoma) neoplasmsinsome strains,andusuallyaremorecommoninfemalemice.Usuallydiagnosedafter12monthsofage.Liver anduterusorvaginaarecommonlyinvolved.Spleen,lymphnode,bonemarrow,lung,kidneyandovariesalsomaybe involved.Noncircumscribed,highlyinfiltrativeaccumulationsofusuallylargehistiocytoidcellswithampleeosinophilic cytoplasm.Theremaybeareasofprimarilyelongatecellsinsarcomatouspatterns,multinucleatedcells,and erythrophagocytosis.Theremaybeareasofnecrosissurroundedbypalisadingcells.Liversinusoidsmaybefilledand expandedbyneoplasticcells,and(metastatic)neoplasticcellsmaybeprominentinpulmonaryvasculature.Thecells shouldbeimmunocytochemicallypositiveforhistiocyticmarkersincludinglysozyme.Eosinophilichyalinedroplets(of lysozyme)arereportedinkidneytubules.Liverhematopoiesismaybeincreased. (Wardetal.1999;Frithetal.2001;LacroixTrikietal.2003) Themajorityoflymphoidleukemiasinmice,asdefinedbyinvolvementoftheblood,representspillover"oflymphoma cellsintotheblood,i.e.notprimaryleukemiasbutratherlymphomaswithleukemicphases.(Morseetal.2002) Nonlymphoidleukemias,myeloiddysplasias,andmyeloidproliferations(nonreactive)includediseasesthatariseprimarily asincreasednumbersofnonlymphoidhematopoieticcellsinthespleenand/orbonemarrow.Leukemiasaredisseminated diseasesthatarerapidlyfatal.Manyleukemiasarecharacterizedbyimpaireddifferentiation,butmyeloproliferative diseaselike(MPDlike)myeloidleukemiasretaindifferentiationtomatureforms.Myeloiddysplasiasarecharacterizedby cytopeniasandabnormaldifferentiation.Nonlymphoidhematopoieticsarcomasarecellularproliferationsthatarise primarilyassolidtumorse.g.histiocyticsarcoma.Myelogenousleukemiasorerythroleukemiasareuncommoninmiceand canbeinducedbysomemurineleukemiavirusesandbygeneticmanipulations.(Koganetal.2002) Malignantneoplasmoflymphoidcells.Thistermusuallydesignatessolidneoplasms.Somestudiesdonotdistinguish hematopoieticneoplasms,oritisnotclearwhatthecorrectcurrentnomenclatureshouldbebasedonthenomenclature used.Immunohistochemistryand/ormoleculartechniquesshouldbeusedtodetermineaccuratediagnosesand subclassifications.Onlyafewofmorecommonspontaneouslymphomasarelistedhere.(Wardetal.1999;Frithetal. 2001;Morseetal.2002) NeoplasmofmatureBlymphocytes.Thishasbeenreportedasaspontaneoustumorinsomecongenicandrecombinant inbredmice.Thereusuallyissplenicinvolvementwithlittleorlatelymphnodeinvolvement,sometimesliverandblood involvement.ThecellsareuniformlysmallBcells.(Morseetal.2002) NeoplasmofmatureBlymphocytes,althoughinfiltrating(polyclonal)Tcellsmaybenumerous.Thesearethemost commonspontaneoushematopoieticneoplasminmanymousestrains.Usuallytheyarediagnosedafter12monthsofage. Thereisprogressiveenlargementofthespleenwithmottlingoncutsectionduetoneoplasticenlargementoffolliclesin whitepulp.Advancedcaseshavemassivelyenlargedmesentericlymphnodesandspleen,andprominentGALT. Histologicallythereisdiffuseinvolvementofsplenicwhitepulpandcellsaresmallorlarge,withcleavedornoncleaved nucleiwithclumpedorvesicularchromatinofapparentlymixedcelltypes,althoughearlytumorsmaybemore plasmacytoid.(Wardetal.1999;Frithetal.2001;Morseetal.2002) NeoplasmofimmatureTcellsthatarisesinthethymus.LymphomasofTcelloriginusuallyariseinthethymus.Clinically micewiththymiclymphomamaybedyspneicduetomassiveenlargementofthethymus.Necropsyfindingscommonly alsoincludeenlargedspleenandlymphnodes.Involvementofliver,kidneysandbonemarrowmayoccurinadvanced

Leukemia,lymphoid Leukemia,nonlymphoid

Lymphoma(anytype)

Lymphoma,diffuselargeB celllymphoma;follicular centercelllymphoma Lymphoma,follicularBcell lymphoma;follicular centercelllymphoma; reticulumcellsarcomaor reticulumcellneoplasm, typeB Lymphoma,precursorTcell lymphoblastic lymphoma;(thymic

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leukemia) stages,ormayrepresentanadditionalneoplasticprocess.Histologicallyneoplasticcellsaremonomorphicandmedium sizedwithscantcytoplasm,andthestarryskypatternisattributedtoscatteredlargerpaler(tingiblebody)macrophages, whichareengulfingapoptoticornecroticcellsanddebris,insheetsofhomogeneousneoplasticlymphoidcells.Thisisthe mostcommonlymphomaaffectingthethymus,isverycommoninAKRmiceandisthemostcommonlyinducedtumorby virusesandcarcinogens.(Wardetal.1999;Frithetal.2001;Karpovaetal.2002;Morseetal.2002) NeoplasmofmaturesecretoryBcells.Itisanuncommonspontaneousneoplasmsinmicebutcanbeinducedbyinduced bypristaneandmineraloil,especiallyinBALB/cmice.Thespontaneoustumorpresentswithsplenomegalyand lymphadenopathy.Thepristaneinducedtumorarisesinperitonealgranulomas.Histologicallyitischaracterizedbymature plasmacytoidcellswithampleamphophiliccytoplasm,frequentlywithparanuclearpallorduetogolgimaterial,andround clockfacenucleiwithcentralnucleoli.Theyshouldbeimmunocytochemicallypositiveforcytoplasmicimmunoglobulins. (Wardetal.1999;Frithetal.2001;Morseetal.2002) Seeabove,CARDIOVASCULAR. Seetable5 HANarecommonpreneoplasticfindingsinMMTVinfectedandMMTVfreemice&incarcinogentreatedmice.Grossly HANare15mmnodules,frequentlyoutlinedbyyellowpigment.Histology:focioflobuloalveolarhyperplasia, characterizedbycloselycrowdedacinilinedbyasinglelayerofepithelium,lackingsignificantdysplasia,inabackgroundof normalfattystroma.Thishyperplasticmammarytissueisimmortalandcanbeseriallytransplanted,withdevelopment intofocalproliferationsandneoplasticlesions.(Medina1982;Rehmetal.1996;Cardiffetal.1999;Cardiffetal.2000) Mammaryplaquesareepithelialproliferationsthatoccurinmousemammaryglandsduringpregnancyorafterhormone induction,butregressafterwithdrawalofthestimulus.ThesewereformerlyknownastypePorpregnancydependent tumors.Histologicallytheyconsistofradiatingductssurroundedbydenseconnectivetissue.(Medina1982;Rehmetal. 1996;Cardiffetal.1999) Mammaryneoplasm,adenomavs.adenocarcinomavs.othernotspecified Benignneoplasmofthemammarygland.Thesearerareinmice,butwelldifferentiatedacinarpatterncarcinomasmaybe referredtoasadenomasinsomestudies.Thesearewelldifferentiated,circumscribedorencapsulatednodulescomposed ofcloselypacked,small,uniform,acinarstructures.(Seelyetal.1999;Bruneretal.2001) Malignantneoplasmofthemammarygland.MostspontaneousorMMTVinducedmammarytumorsinmicehavebeen classifiedastypeA,BorCadenocarcinomasaccordingtoThelmaDunnsoriginal1959classification. TypeA(acinar)ormicroacinaradenocarcinomasarecomposedofsmallacinilinedbyasinglelayerofcuboidalcells.These alsohavebeenreferredtoasadenomaandtubularcarcinoma. TypeB(bizarre)orductaltumorsaremostcommon,havemorevariablehistologicfeatures,withwellandpoorly differentiatedregionsofneoplasticcellsincordsorsheetsorpapillomalikeconfigurations.Theycanrisefromcarcinogen

Plasmacytoma

Spleen,hemangioma INTEGUMENT Mammaryhyperplasia functionalwithoutatypia Mammaryhyperplastic alveolarnodule;HAN

Mammaryplaques

Mammarygland,tumor Mammarygland,adenoma

Mammarygland, adenocarcinoma

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inducedductalhyperplasias. TypeC(cystic)tumorsarelesscommonthanAorBtumors,andfeaturecysticepithelialstructuresinmoreabundant stroma.(Medina1982;Rehmetal.1996;Cardiffetal.1999;Cardiffetal.2000) Mammarygland,carcinoma Thetermadenoacanthomahasbeenusedtorefertobenignandmalignantadenomatousepithelialtumorswithsome withsquamous squamousdifferentiation.Inmicemammaryadenoacanthomausuallyreferstoamalignantmammaryneoplasmwith differentiation, squamouscellareascovering>25%ofthelesion.Whensquamouscomponentis<25%,itisadenocarcinoma.(Bruneret adenoacanthoma, al.2001)Adenoacanthomasaremorelikelytooccurinoldretiredbreedersthaninyounganimals,aremorecommonin adenosquamous BALB/c(andmaybeFVB/Nmice)thaninothercommonstrains,andtheycanhaveahighincidencewithsome carcinoma carcinogenesisprotocols.(Rehm1990;Rehmetal.1996;Cardiffetal.1999;Cardiffetal.2000;Nietoetal.2003) Mammarygland, Benignneoplasmofmammaryepitheliumplusfibrocollagenousconnectivetissue.Commoninrats,butunusualinmice.It fibroadenoma iscomposedofproliferatingductswithinadensefibrousstroma.(Seelyetal.1999;Bruneretal.2001) Skinsubcutis,fibroma Benignneoplasmoffibroblastsorfibrocytes,characterizedbyproductionofcollagen.Presentasfirmroundedskinmasses orelevations..Circumscribedmassesofcollagenousconnectivetissuethatcancompressordistortsurroundingtissues. Spindlecellsareenmeshedincollagenfibersininterlacingbundles.(Sundberg1996;Peckhametal.1999;Ernstetal.2001) Skinsubcutis,fibrosarcoma Malignantneoplasmoffibroblastsorfibrocytes.Tendtohavemoreirregularpatterns,highercellularity,morecellular pleomorphismoratypia,andmayhavelesscollagenthanfibromas.Mayhaveherringbonepatterns,necrosis, hemorrhage,inflammation,andalopeciaandulcerationofoverlyingskin.Localinvasioncanbeextensivebutmetastasis lateandinfrequent.(Peckhametal.1999;Ernstetal.2001) Skinsubcutis,fibrous Neoplasmofpluripotentialmesenchymalstemcells.Shouldexhibitstoriformpatternsandhavehistiocytoidfeaturestobe histiocytoma diagnosed.Theymaybepositiveforhistiocyticenzymessuchaslysozyme,cathepsinB,alpha1antitrypsin,alspha1 antichymotrypsinaswellasmesenchymalmarkers.Theyhavebeenreportedasthemostcommonskin/subcutaneous neoplasminCD1mice.Histologicallybenignfibroushistiocytomaarecomposedofprimarilywelldifferentiatedspindled fibroblastlikecellsinstoriformandcartwheelpatterns,andmayhaveabundantcollagen,butalsohaveahistiocytoid componentofplumpercellsthatmayexhibitphagocytosis.Theremaybeinflammatorycellsscatteredinandaroundthe neoplasm.Malignantneoplasmshavemorevariablepatterns,fibrous,myxoid,pleomorphic,andmixed.Theseneoplasms maybedifficulttodistinguishfrompoorlydifferentiatedfibrosarcomas,andmaybediagnosedasfibrosarcomaor undifferentiatedsarcomainsomereports.(Peckhametal.1999;Ernstetal.2001) Skinsubcutis,hemangioma Hemangiomasinskinorsubcutisaredarkredorpurpleraisedlesionsthatbleedprofuselywhencut.Seeabove (angioma) Hemangioma.(Boothetal.1995;Boothetal.1996)alsoseeaboveCARDIOVASCULAR. Skinsubcutis,lipoma, Lipomaandliposarcomaarerareinmice.Lipomasarewellcircumscribedaccumulationsmatureunilocularadipocyteswith liposarcoma peripherallycompressednuclei.Liposarcomastendtobefirmer,poorlycircumscribed,morecellularwithmorepoorly differentiatedspindlecells,andfewertypicaladipocytes.(Peckhametal.1999;Ernstetal.2001) Skinsubcutis,neuralcrest SubcutaneousspindlecelltumorsoccurringonthepinnaandtailofFVB/Nmicewerediagnosedasneuralcresttumors. tumor TheyresembletheamelanoticmelanomasofthepinnaeofFischer344rats.(Mahleretal.1996) Skinsubcutis,neurofibroma, Seebelow,NERVOUS. neurofibrosarcoma

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Skinsubcutis,Schwannoma, nervesheathtumor Skin,papilloma;Squamous papilloma Seebelow,NERVOUS. Abenignneoplasmconsistingofvillousorarborescentoutgrowthsoffibrovascularstromacoveredbyneoplasticsquamous epithelialcells.Theseareuncommonspontaneousneoplasms,butareinduceinvariouscarcinogenprotocols.Theyare usuallyexophyticorpapillary,butmaybepedunculated(onathinstalk)orsessile(flat).Thebasalcelllayerorborderline shouldbedistinct.Acanthosis,andhyperkeratosisorparakeratosisaretypical.(Bruneretal.2001;Pathbase2004) Malignantneoplasmofstriatedskeletalmuscle.Theseneoplasmsariseasnodulesinskeletalmuscle.Neoplasticcellsare pleomorphic,withelongate,straplikecellswithmultiplenucleiintandemarray,andsmallerplumptospindled haphazardlyorientedcells.Crossstriationsinneoplasticcellsdistinguishesthisfromothersarcomas,butcanbevery difficulttodiscern.Theymaybeenhancedbyphosphotungsticacidhematoxylin(PTAH)stains.(Sundbergetal.1991; Sundbergetal.1996) Neoplasmofastrocyticglialcells.Astrocytomasisevenlesscommonthanoligodendrogliomasinmice.Shouldbeconfined tooneareaofbrainbutmarginsareindistinctandtheremaybeedema,hemorrhage.Cellstendtobemonomorphicbut withindistinctcytoplasmicborder,andlarge,ovalorslightlyfoldednuclei.Hemorrhageandnecrosismaybemoretypical ofastrocytomasthanofoligodendrogliomas.Malignantneoplasmsmaybemulticentricwithinvasionofperivascular spacesandmeninges.Morgan,Frithetal.1984;FrithandWard1988;RadovskyandMahler1999;Krinke,Fixetal.2001) Neoplasmofmeningealcells.Theseusuallypresentasdiscretenodulesonthesurfaceofthebrainorspinalcord.Theyare expansileandcompressadjacentsofttissue,andrarelyexhibitinvasion(malignancy).Thefibroustypehasaregular patternoflooselyinterwovenbundlesofdelicatespindlecells,withsinglesmallhyperchromaticovalnuclei.The neoplasmsmayappearmyxomatouswhenthereisabundantfaintlybasophilicfinelygranulargroundsubstance. Meningothelialtypesarelesscommonandhavelarger,moreepithelioidcellswithabundanteosinophiliccytoplasm formingsheetsorlobules.(Morganetal.1984;Frithetal.1988;Radovskyetal.1999;Krinkeetal.2001) NeoplasmofoligodendrocytesthatnormallyformmyelinsheathsintheCNS.Braintumorsareuncommoninspontaneous orinducedtumorsinmicebutthesearethemostcommonlydiagnosedCNSneoplasms.Itoccursinthecerebrumand/or diencephalon,usuallyisventrolateralandinvolvesmuchofthethalamus,hypothalamusandamygdaloid.Itispoorly demarcatedmassbutexpansileanddistortssurroundingtissues.Itisdistinctfromadjacentneuropilduetodistinctive monomorphiccellpopulationofsmallcellwithsmalldarkroundnuclei,andatypicalperinuclearclearhalo,thatmayresult inahoneycombpattern.Bloodvesselswithintheneoplasmmayhavehyperplasticendothelium..Theremaybenecrosis andhemorrhage.(Morganetal.1984;Frithetal.1988;Radovskyetal.1999;Krinkeetal.2001) Neoplasmderivedfromfibroblastsofperineuralconnectivetissue(perineurium),distinctfromschwannoma.Histologically theyresemblefibromaorfibrosarcoma,withneoplasticspindlecellsarrangedinbundlesofeosinophilicfibers.(Peckhamet al.1999) Neoplasmderivedfromnervesheathcells(Schwanncells),whichnormallyproducetheneurilemmaandmyelinlayers surroundingaxonsintheperipheralnervoussystem(PNS),andareofectodermal,neuralcrest,origin.Theseare

MUSCULOSKELETAL Rhabdomyosarcoma

NERVOUS Brain,astrocytoma

Brain,meningioma

Brain,oligodendroglioma

Neurofibroma, neurofibrosarcoma Schwannoma,nervesheath tumor

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uncommonneoplasms inmicebutmostlikelytobediagnosedinthesubcutisandheart.Benignneoplasmsarediscrete, expansile,compressive.Malignantneoplasmsareinvasive,usuallywithmoreatypiaandmitoticfigures.Thesespindlecell tumorshave2typicalgrowthpatterns.AntonitypeApatternfeatureselongatecellsinwhirlsandbundleswiththeirnuclei palisadinginparallelarray.TheseareasmaybecalledVerocaybodies.AntoniBpatternisalooserpatternwithsparser cellsmorehaphazardlyarrangedinaclearoredematousmatrix.Ultrastructurallythesecellsshouldhavebasallaminae, andimmunohistochemicalstainingforS100indicatingneuralcrestorigin.(Peckhametal.1999;Ernstetal.2001) Hemangiomainthenasalcavity,seeabove,cardiovascular Schwannomaofthenasalcavity.Seeabove,NERVOUS Pulmonaryneoplasm,adenomavs.adenocarcinomanotdistinguished.Usuallyothertypesoftumorsormetastasesinthe lungarenotincludedinthiscategory,unlessdiagnosesweremadebygrossexaminationonly. Seetable5.

RESPIRATORY Nasalcavityhemangioma Nasalcavity;schwannoma, neurilemmoma Lungtumors Lung,bronchoalveolar hyperplasia; TypeIIcellhyperplasia Lung,adenoma(BAA, bronchioloalveolar adenoma)

Lung,carcinoma (bronchioloalveolar carcinoma)

SPECIALSENSES Harderiangland,tumor Harderiangland,adenoma

Harderiangland,carcinoma oradenocarcinoma

Benignneoplasmofairwayepitheliumsupportedonfibrovascularstromainacinarorpapillarypatterns. rightlobesareinvolvedmorefrequentlythantheleft.Themostcommontumortype,previouslycalledbronchoalveolaror bronchioloalveolaradenoma,currentlyisclassifiedsimplyasadenomaofthelung,andtheymayhaveacinar(solid) papillaryormixedpatterns.(NikitinAY2004)Grossly,thesetumorsareyellowwhite,discretenodulesranginginsizefrom 1.010mm.Adenomasareusuallylessthan4mmindiameterwithsolid>papillary>mixedpatterns.(Dixonetal.1991; Festingetal.1994;Dixonetal.1999;Dungworthetal.2001) Malignantneoplasmofairwayepithelium.Carcinomasusuallyareirregularnoduleslargerthan4mmindiameterwith papillary>>mixedpatterns.Carcinomasarelesscommonthanadenomasandmaymetastasizetoliver.Theymaybe difficulttodistinguishfromlargeadenomaswhenthereisnotobviousdestructionofparenchyma,invasionofbronchiolar walls,interstitialtissueorpleura,lymphaticdisseminationordistantmetastasis.(Dixonetal.1991;Festingetal.1994; Dixonetal.1999;Dungworthetal.2001) NeoplasmoftheHarderianglandadenomavs.carcinomanotspecified. BenignneoplasmofacinarepitheliumofHarderiangland.EspeciallycommoninBALB/cfemales.Adenomasaremuch morecommonthancarcinomas.Theymaybeunderreportedbecausetheglandmaynotbeexaminedunlessthereisa grosslyobviouslesion.Usuallywelldemarcatedorencapsulatednodules,withcompressionofsurroundinggland.Patterns maybepapillary,cystic,cysticpapillaryoracinar,andtheneoplasticcellsusuallyarewelldifferentiatedandinasingle layer.(Sheldonetal.1983;Bottsetal.1999;Krinkeetal.2001) MalignanttumorofacinarepitheliumoftheHarderiangland.Theseusuallyarelargerthanadenomasandmaycausefacial sellingand/orexophthalmos.Theyarehighlycellular,anddisorganizedcomparedtoadenomas,withpilingupof

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pleomorphiccells.Areasofmedullaryorsolidgrowthpatternsarecommon.Theremaybenecrosisandhemorrhage, invasionbeyondtheorbitanddistantmetastasistolungs,locallymphnodes,thymus,orliver.(Bottsetal.1999;Krinkeet al.2001) Hyperplasiaorproliferationofrenaltubuleepithelium.Byconventionfociofhyperplasiaare<3timesthediameterofa normaltubule.Theymaybeprecursorsofadenomasorcarcinomas.Thetubulemaybeexpandedbyseverallayersof slightlypleomorphicepithelialcells,orthetubulemaybedilatedwithanexpandedlumenandlinedbyanirregularand crowdedpleomorphicepithelialcells.Crowdedcellswithnuclearcrowdingusuallyisapparent.Tubulestructureis essentiallymaintainedandthereisnocompressionofadjacentparenchyma.(Seely1999;Hardetal.2001) Benignneoplasmofrenaltubuleepithelium.Theseareuncommonspontaneousneoplasmsinmice,withadenomaand carcinomaincidenceusually<1%.Theyusuallyaresolitary,andclassifiedmorphologicallyascystic,papillary,orsolid,with papillarybeingmostcommontype.Theneoplasticcellsareuniformlycuboidalwitheosinophiliccytoplasmandrelatively smallnuclei.Mitoticfiguresarerare.Cysticandpapillaryadenomasusuallyareencapsulated.Solidadenomasusuallyare welldemarcatedfromadjacentparenchyma,butnotencapsulated.(Frithetal.1988;Seely1999;Hardetal.2001) Malignantneoplasmofrenaltubuleepithelium.Theseareuncommonspontaneousneoplasmsinmice,withadenomaand carcinomaincidenceusually<1%.Theymayhavesolid,papillaryortubular,oranaplasticpatterns.Theyarecompressive andmayhavenecrosisorhemorrhage,orcysticareaswithintraluminalpaleeosinophilicmaterial.Neoplasticcellsvary fromsmallanduniformtolargeandpleomorphic,withgranulareosinophilic,clearorbasophiliccytoplasm.Theirnuclei maybeuniformlysmallandroundoroval,orlargeandpleomorphic,andthemitoticindexisvariable.Metastasisisrare andusuallytothelungs.(Frithetal.1988;Seely1999;Hardetal.2001)

URINARY Kidney,renaltubular hyperplasia

Kidney,adenoma(renal tubularcelladenoma)

Kidneyadenocarcinoma; (renaltubularcell carcinoma,renalcell carcinoma)

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