IntroductiontoTissuePathology

DrIanMudway(ian.mudway@kcl.ac.uk;ext3895)

1. 2. 3. 4.

Coursestructure Aimsandlearningobjectives Lectureandp practicalschedule Moduleassessment:examanddissertation

Lectures
25lectures 4revisionseminars 1sessiononthe dissertation

Practicals Generalclassroom, HodgkinBuilding

Microscopebasedhistology Cellularadaptations(today) Immunecells Vascularhistopathology p gy Tumourhistopathology Pulmonaryhistopathology CNShistopathology
Th sessions These i arei important t tto t reinforce i f th thelectures. l t Al Alsosome oftheexamessayquestionswillbeimagebased.

Incourseassessment(30%)
A2,000wordessayonpathologicprocessesindisease:
Youwillneedtoprovideanaccuratewordcountonyourcoverpage PathologicalProcess
Hypertrophy Hyperplasia Metaplasia Neoplasia Atrophy Apoptosis Fibrosis Necrosis

Disease
Asthma Ulcerative colitis Interstitial lung disease Glomerulonephrosis Systemic Lupus Erythematosus Psoriasis y p Lymphoma Cirrhosis

Handindate24th March totheacademiccentreatGuy Guys s campusby4:00

Structureofdissertation
1. Descriptionofthedisease 2. Descriptionofthepathologicalprocess 3. Relevanceofthepathologyunderconsiderationto theaetiology,progressionandseverityofthedisease

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FAQs:
1. Figureandtablelegends,plusthereferencesarenotincludedinthe2,000wordlimit 2. RequiredtousetheHarvardsystemforcitingandformattingreferences: http://www.kcl.ac.uk/library/help/plagiarism/citing/index.aspx p // / y/ p/p g / g/ p 3. Referencesshouldbefrompeerreviewedpapers(originalarticlesandreviews)andbook, ratherthanwebsites,nonscientificliterature.Theuseofrecentpublicationsand particularlyrecentresearcharticleswillresultinabettergrade. 4. Usep pubmed ( (http://www.ncbi.nlm.nih.gov/pubmed), p // g /p ),orsciencedirect (http://www.sciencedirect.com/)tofindsuitablematerial 5. Generalrulesonplagiarismapply bestnottousedirectquotes 6. Academicqueriesaboutessaysshouldbydirectedtome:ian.mudway@kcl.ac.uk 7. FailuretohandintotheacademiccentreatGuys y by y4:00onthe24th ofMarchwillresultin azeromark,unless,youhaveareallygood/validreason&havesubmittedtherequired paperwork.

Exam(70%)
Answer3ofnineessayquestions Approx25minutesperquestion A Answers 23pages

Supportingtextbooks

28.45

31.99

Pathologyisthestudyofstructuraland functionalabnormalitiesthatareexpressedas diseasesororgansandsystems

RudolphVirchow 18211902 The h Father h of f ModernPathology gy

Proposedthatinjurytothe cellisthebasisofalldisease

Pathology gy
Inflammation

Etiology Eti l Pathogenesis Morphology Clinicalexpression

Dise ease

CourseAims
Toprovideagroundinginthegenericprocess (especially ( p yinflammation) )involvedincellinjury/tissue j y/ damageanddisease Tounderstandthegross(cellular)andmolecular mechanismsunderpinningtissueadaptationto toxicity/stressandtheconsequencestheir breakdownorevolutionintopathologicalstates

Histology
Histologyfiguresarenotalwaysreproduced wellinblackandwhitehandouts.Therefore linkswillbeprovidedtothesourcewhere appropriate.

Manifestationsofcellandtissue i j injury
Physical y Chemical Infectious Immunologic g Stress
Atrophy p y Hypertrophy Hyperplasia Metaplasia Dysplasia Intracellularstorage Neoplasia

Adaption
Biochemical C ll l growth Cellular th D

Injury Celldeath Necrosis Apoptosis

Whatiscellularadaptation?
Cellularadaptation p isthebodys y methodfordealing g withstressors(bothphysiologicandpathologic)to maintainhomeostasis Ifthestressorisremoved,allformsofadaptation (hyperplasia, yp p hypertrophy, yp p y atrophy p yandmetaplasia) p arepotentiallyreversible;however,thestressormust beidentifiedandremoved Eventually,ifthestressorissevereenough, adaptationwillfailandorganinjury(celldeath)occurs

Atrophy
Adecreaseinthesizeorfunctionofanorgan underpathophysiologicstress
Reducedfunctionaldemand Inadequatesupplyofoxygen/nutrients Alteredbalancebetweenproteinsynthesisand proteindegradation Interruptions I t ti of ftrophic t hi signals i l Normalphysiologicageing(senileatrophy)

Adaptiveresponsesresultingin reducedtissuemass

Cellularatrophy
Structuralproteinsandorganellesaredestroyedreducingcellsize andthefunctionalcapacity p yofthecell.Theadaptation p allowsthe celltosurvivebyreducingitsmetabolicrequirements.

Autophagy

Lipofuscin incellularatrophy
Myocardiumof90yearoldfemale

Examplesofatrophy
Physiologic Regressioninsizeofbreastsanduterusafter pregnancy Pathologic Disuse(skeletalmuscleatrophy) Lossofendocrinestimulus( (adrenalatrophy p yinpatients p onsteroids) Denervation Inadequatenutrition Ischemia(atrophyofkidneyduetorenalartery stenosis)

Muscularatrophy: d decrease in i muscle l mass

Musculardystrophy y p y Limbinactivity Starvation Ageing:sarcopenia Cachexia comorbidityof: Cancer CongestiveHeartFailure COPD AIDS Burns Liverfailure
Sarcopenia:musclewasting

young

old

Mechanismsofmusclewasting
Distinguishingsarcopenia fromcachexia

ThomasDR.ClinNutr.2007Aug;26(4):38999.

Atropy ofskeletalmusclewith denervation

Normaltissue Denervated muscle

Stevensetal.CorePathology,3rdedition,2009

Cerebralatrophyinapatientwith Al h i Alzheimer disease di (l (lower) )

Thegy gyri arenarrowed andtheintervening sulci widened, particularlypronounced towardthefrontallobe region.

inferiorfrontalgyrus

Hypertrophy
Anadaptivechangeresultinginanincreasein cellularsizeto(a)satisfyincreasedfunctional demand,or(b)inresponsetotrophicsignals
Physiologic
Skeletalmusclehypertrophyassociatedwithexercise Compensatoryhypertrophyofkidneyafterremovalofotherkidney

Pathologic
Cardiachypertrophy yp p yduetohypertension, yp ,valvular stenosis or insufficiency Asthmasmoothmusclehypertrophy Hypertrophyofbladderassociatedwithprostaticglandhyperplasia

Hypertrophyofskeletalmusclein responsetoexercise i
Transversesectionofsoleus muscle Soleus muscleinmarathonrunner

Stevensetal.CorePathology,3rdedition,2009

Myocardialhypertrophy
Leftventricularhypertrophy developsinresponsetosome factor suchashighbloodpressure, factor, pressure thatrequirestheleftventricleto workharder.Astheworkload increases,thewallsofthechamber growthicker,loseelasticityand eventuallymayfailtopumpwithas muchforceasahealthyheart.

Pathologicalandphysiological hypertrophicresponsetostimuli

http://library.med.utah.edu/WebPath/CINJHTML/CINJ005.html

Normalcardiacmuscle

Hypertrophiedmuscle

Hyperplasia
Anadaptiveincreaseinthe numberofcellsinanorgan/ tissue.Oftenoccurs concurrentlywithhypertrophy.
Hormonalstimulation Increasedfunctionaldemand Chronicinjury/inflammation

Hyperplasia
Physiologic: Breastenlargementduringpregnancy(andhypertrophy) Uterineenlargementduringpregnancy(andhypertrophy) Liverregrowth afterpartialresection Inflammation,repair Pathologic: Ductal hyperplasiaofbreast(duetoestrogen) Benignprostatichyperplasia Endometrialhyperplasia(duetoestrogen) Viralinfections Endocrineorganswithincreasedstimulus(e.g.,adrenalgland enlargementduetoACTHsecretingpituitaryadenoma;goiter)

Asthmasmoothmusclehypertrophy yp p y
Healthy bronchiole Fatalasthma

Asthmatic bronchiole

Hyperplasia:Psoriasis
Normalepidermis
Stratumcorneum Stratumlucidum g Stratumgranulosum Stratumspinosum Stratumgerminativum Dermis

Epidermalhyperplasia

FromRubinsPathology

Hypertrophy&hyperplasia
Hyperplasiaandhypertrophycanbedifficultto separatenotpossiblebygrossexam;difficultby microscopicexam.Insomecases,bothhyperplasia andhypertrophyoccurtogether(e.g.,breastand uterusduringpregnancy) pregnancy). H Hyperplasia l i essentially ti ll d doesnot toccuri inth theb brain i andheart

Metaplasia
Anadaptiveresponsetochronicinjuryin which hi hthe h tissue i adopts d the h mostprotective i phenotype: Squamousmetaplasia ofthelungs Glandularmetaplasia oftheesophagus (Barrettesophagus) Metaplasiaisalwayspathologicbutisusually fullyreversibleoncethestresshasbeen removed

Metaplasia oflaryngealrespiratory epitheliumtotobaccosmoke

http://library.med.utah.edu/WebPath/CINJHTML/CINJ009.html Themetaplasic responseprotectstheairwayfromthedamagingactionofcigarette smoke,butimpairsmucusclearanceandthefunctionofthemucociliaryelevator

Metaplasia ofthenormal esophageal h l squamousmucosa

http://library.med.utah.edu/WebPath/CINJHTML/CINJ010.html

Squamous metaplasia ofthebladder

Dysplasia
Thedisorderedgrowthandmaturationof g Oftenviewedas cellswithinatissue/organ. aprecursortomalignancy
Variationincellsizeandshape Nuclearenlargement,irregularityandhyperchromatism Disorganised g arrangement g ofcellswithintheepithelium p

Occursmostcommonlyinareasofsquamous metaplasia,suchasthebronchusorcervix. Likemetaplasia willregressoncestress/ injuriousstimuliisremoved

Dysplasticepitheliumofthe uterinecervix
Cellulardysplasiaofthe uterinecervix. Thenormalcervical squamousepitheliumhas becometransformedtoa moredisorderlygrowth pattern,ordysplastic epithelium. Thisisfartherdownthe roadtowardneoplasia,but dysplasiaisstilla potentiallyreversible process. http://library.med.utah.edu/WebPath/CINJHTML/CINJ011.html

Acutecellular ll l adaptions d i
EffectsofOzone(powerfuloxidizingair pollutant)onthenasalMucosaofa22Year OldMaleMigrantaftermovingtoMexicoCity

FineStructureofthenasalepithelium

EffectsofOzoneonNasalMucosa 22YearOldMaleMigranttoMexicoCity

Meandailymax. O3=260ppb meanmax max. NO2<53ppb meanmax. SO2<30 30ppb b

Intracellularstorageofendogenous /exogenousmaterialmayindicate cellinjury

Degradedphospholipids:lipofucsin Ab Abnormal lf fat taccumulation l ti :diabetes, di b t alcholism, l h li atheroscleroticplaques Substancesthatcannotbemetabolised:protein aggregates,exogenousparticulates,hereditarystorage disorders,endogenouspigments Overloadofnormalbodyconstituents:Fe,Cu,cholesterol Abnormalproteins:Lewy bodiesinParkinsondisease,tau proteininAlzheimerdisease,Malloryhyalineintermediate fil filaments t i inalcoholic l h li li liverdi disease,mutant t t1antitrypsin tit i i in liverdisease

Whydocellsaccumulatesubstances?
Toomuchproduced Tooslowofclearance
Lackofenzyme;decreasedenzymeactivity Blockageofoutlet

Cellularaccumulationsareasignofinjury;cellular accumulationsresultfrominjury,or,their accumulationcancausecellularinjury

Lipidaccumulationinmacrophagesina cutaneous xanthoma

FromRubinsPathology

Cholesterolaccumulationina atheroscleroticplaque

FromRubinsPathology

Lipofuscin accumulationintheliverofan 80yearoldmale

FromRubinsPathology

Prussianbluestainofliverdemonstrating largedepositsofFeinsubjectwith hereditaryhaemachromatosis

FromRubinsPathology

Anthracosis:carbonaceousaccumulation
Alveolaranthracosis

Elementalcarbonaccumulationin amediastinallymphnode

Calcification
Dystrophic y p (local ( causes) )
Patientshaveanormalcalciumlevel Calcificationaffectspreviouslydamagedtissue

Metastatic(systemiccauses)
Patientshaveanelevatedlevelofcalcium
Causes:Hyperparathyroidism Hyperparathyroidism,bonymetastases

Calcificationaffectsnormaltissueandpreviouslydamaged tissue

**Outofallformsofcellularadaptation,calcificationis theonlyonewhichisnotroutinelyreversible

Dystrophiccalcificationinthewallof thestomach stomach.

http://library.med.utah.edu/WebPath/CINJHTML/CINJ047.html

Metastaticcalcificationinthelungofapatientwitha veryhighserumcalciumlevel(hypercalcemia) (hypercalcemia).

http://library.med.utah.edu/WebPath/CINJHTML/CINJ048.html

Cellinjury j y
Causes:hypoxia,ischemia,trauma,infections, autoimmune toxins autoimmune, toxins,immuneconditions, conditions oxidativestress Cellinjuryleadingtocelldeath
DNA Cellmembranes(plasmaandlysosomal) Proteingeneration ATPproduction
Life/viability Death

Subcellular changes
Mitochondria:swelling,amorphousdensitiesrichinphospholipid Plasmamembrane:blebbing Nucleus:fibrillarandgranularcomponentsofthenucleous may segregate Endoplasmicreticulum:Cisternae becomedistendedbyhydropic swelling Membraneboundpolysomes undergodisaggregationand swelling. detachfromthesurfaceoftheroughER

Cellinjury j y
Reversibleandirreversible Irreversibleinjury *DecreasedATPlevels *Amorphous p densities in
*Ionimbalance * Swelling DecreasedpH Fatty F tt change h (liver) (li ) mitochondria *Severemembrane damage *Lysosomal rupture ExtensiveDNAdamage

Reversibleinjury

Mechanismsandmorphologyof cell lli injury j

Reversiblecellinjury
Hydropic swelling:Characterisedbycellswithlarge, pale cytoplasm,reflectingincreasedwatercontent
Liverneedlebiopsyfromapatient withtoxichepaticinjury

MembraneBlebbing

Cellinjury:NecrosisandApoptosis

ApoptosisandNecrosis
Morphologicfeaturesofapoptosisvs.necrosis
Feature Cell size Nucleus Plasma Membrane Necrosis Enlarged (swollen) Pyknosis karyorrhexis karyolysis Disrupted (contents spilled) Enzymatic digestion, extracellular leakage Frequent (see above) The culmination of irreversible cell injury, always pathologic Apoptosis p p Reduced (shrinkage) Fragmentation into nucleosome size fragments Intact with altered structure especially the orientation of lipids (insideoutside) Intact, may be released as apoptotic bodies No Often physiologic (a process for removing unwanted, unneeded or aged cells May be pathologic, a damaged cell (especially DNA damage) g ) may y commit suicide.

Cellular contents Adjacent inflammation Pathologic

Cellulareventsinnecrosis

Morphologicpatternsofnecrosis
Coagulative g necrosisistypically yp yseeninhypoxic yp environments,suchasaninfarction.Celloutlinesremain aftercelldeathandcanbeobservedbylightmicroscopy. Liquefactive necrosisisusuallyassociatedwithcellular destructionandpusformation(e.g.,pneumonia).Thisis typicalofbacterialor, or sometimes, sometimes fungalinfections becauseoftheirabilitytostimulateinflammation. Gummatous necrosisisrestrictedtonecrosisinvolving g spirochaetal infections(e.g.,syphilis). Haemorrhagic necrosisisduetoblockageofthevenous drainageofanorganortissue(e.g.,intesticulartorsion).

Morphologicpatternsofnecrosis
Caseous necrosisisaspecificformofcoagulation necrosistypicallycausedbymycobacteria (e.g., tuberculosis), ),fungi, g ,andsomeforeign g substances.Itcan beconsideredacombinationofcoagulative and liquefactive necrosis. Fattynecrosisresultsfromtheactionoflipasesonfatty tissues(e.g.,acutepancreatitis,breasttissuenecrosis). Fibrinoid necrosisiscausedbyimmunemediated vasculardamage damage.Itismarkedbydepositionoffibrinlike proteinaceous materialinarterialwalls,whichappears smudgyandeosinophilic onlightmicroscopy.

 Coagulative necrosis:
Grossfeatures:Thenecrotic areaisswollen, swollen firmandpale. pale LM:celldetailislost, ,but architecturepreserved.The deadcellsretaintheiroutline butonlyindistinctly. indistinctly Thistypeofnecrosisis frequentlycausedbylackof bloodsupplyandis exemplifiedwellininfarctsof solidorgans. organs

Coagulative necrosis of the left ventricular wall

Early

Late

Special p types yp ofcoagulative g necrosis

Tuberculosis

Caseous necrosis
Grossfeatures: soft,granular,
andfriableacreamcheesy appearance.Granularand eosinophilic.Surroundedby inflammatorycells (granulomatous reaction)

LM: architecturecompletely
destroyed:Tuberculosis, syphilis,somesarcomas.

WETGANGRENE
Conditions:Botharterialand venousobstruction;wet environments
.

Character:wetswollen,foul smelling blackorgreen smelling, green. Commonlyinsmallintestine, appendix,lung,anduterus, alsoinlimbs.

DRYGANGRENE

Conditions:onlyoccursonthe skinsurfacefollowing arterialobstruction. obstruction Itis particularlyliabletoaffect thelimbs,especiallythe toes. Character:mummification

 Liquefactive necrosis:
Soft S f and dli liquid idgrossly. l E Enzymes digestthecellandconvertitto aformlessp proteinaceous mass. Ultimately,dischargeofthe contentsformsacysticspace. i e centralnervoussystem i.e. afterischemicinjury;abscesses.

http://library.med.utah.edu/WebPath/CI NJHTML/CINJ024.html

http://library.med.utah.edu/WebPath/ CINJHTML/CINJ020.html

Liverabscessisanexampleoflocalized liquefactive necrosis

F t necrosis Fat i
Grossly:Opaqueand chalky LM:outlineofnecrotic fatcellsfilledwith amorphousbasophilic material t i l(calcium ( l i soaps). ) i.e.Digestionof peritonealfatby pancreaticenzymesin pancreaticinflammation. p

Peripancreatic adiposetissuefroma patientwithacutepancreatitis

Fibrinoid necrosis

Definition:Fibrinoid necrosis isaform of necrosisinwhichthere isaccumulationof amorphous,basic, proteinaceous materialin thetissuematrixwitha staining t i i pattern tt reminiscentoffibrin. Location:interstitial collagenandbloodvessels (smallarteryandarteriole)

Fibrinoid necrosisinanartery

Patternsoftissuenecrosis
Coaggulative necrosis: kidney Liquefactive necrosis: brain Caseous necrosis: kidney

Gummatousnecrosis: liver

Hemorrhagicnecrosis: testis

Fibrinoid necrosis: artery

Consequencesofnecrosis
1. A 1 Acute or chronic h i inflammation i fl i 2. Immunological reactions to subcellular components released by dead tissue or self antigens altered by denaturation. 3 lysis and absorption 3. 4. Isolation and discharge: ulceration and cavity formation 5. Encapsulation,calcification.

Inductionofapoptosis

Ph i l i apoptosis Physiologic t i
Embryogenesis HormonalInvolution Cellpopulationcontrol,e.g.,crypts PostInflammatoryClean Cleanup up EliminationofHARMFULcells Cytotoxic TCellscleaningup

Histologyofapoptosis

Whatyoushouldknow?
1. Youshouldbeabletodescribethemajorpathologic adaptationsofcells/tissuestostress/injuryandgive examplesoftheirroleinavarietyofdiseases 2. Youshouldbeabletodiscusshowirreversiblecell injuryinducescelldeathandthepathology associatedwithdifferentformsofnecrosis

Additionalreading
1 WhelanRS, 1. RS Kaplinskiy V, V Kitsis RN. RN Celldeathinthe pathogenesisofheartdisease:mechanismsand significance.Annu RevPhysiol.2010Mar17;72:19 44.[Gooddiscussionofnecrosisandapoptosisina varietyofcardiacdisease] 2 Rock 2. R kKL, KL Kono K H The H. Th inflammatory i fl responsetocell ll death.Annu RevPathol.2008;3:99126.[discusses howcelldeathcantriggerinflammationafter necrosisandapoptosis leadsintonextweeks lectures] ]

Previousexaminationquestions
Q)Outlinethevariousformsofnecrosisobservedclinicallyandtheirgrossand microscopicappearance.(25min) Thestudentshouldcoverthefollowingareas:Liquefactive necrosis(brain,lung),wetand drygangrene(extremities,bowel),plusfibrinoid,caseous (tuberculosis),fat(Breast,any fat), ),ischemic( (nonspecific) p )andavascular necrosis.Grossorgan g andmicroscopic p features ofnecrosiswerepresentedinthelectureandpracticalsandthestudentswouldbe expectedtocommentonchangestonuclearmorphology(pyknosis,karyorrhexis and karyolysis),lossoffinestructureandeosinophilicstainingpatterns. Q)Outlinethecellularadaptivechangesthatoccurintheairwayepitheliumasaresult oftheinhalationoftoxicgasesandparticles,suchasincigarettesmoke.(25min) Thestudentshouldcoverthefollowingareas:Inductionofacuteinflammation,celldeath (necroticandapoptotic),lossofcilia,hyperplasia,withlossofcolumnarepithelialcells andtheappearanceofalessstructuredintermediateepithelium,endothelialhyperplasia, thickeningoftheairlunginterfaceandmetaplasia ofgobletcells. cells