I

Title:

Quality design in Anatomical Pathology byDr. Anil Malleshi Betigeri 978-1466256972 1466256974 ElizabethLog elizbeth.log@hotmail.com Internet Medical Publishing info@imedpub.com http://imedpub.com/ 2011

ISBN-13: ISBN-10: CoverdesignandLayout: Publisher: First edition:

isclaimer:ThisbookcontainsarticlespublishedunderCreativeCommonsAttributionLicense. D CreativeCommonsAttributionLicenseallowscommercialre-useofallcontent.

II

IV

Index
Index V

Butterfly effect and quality

Butterflyeffectandquality Conclusions References

1
2 3 4

Quality by design concept

Qualitybydesignconcept References

5
6 8

Pre-analytic phase
Pre-analyticphase Specimencollection Specimenlabelling Specimenfixation Grossing Tissueprocessing Embeddingandsectioning

9
10 11 11 12 12 13 14

Mounting Conclusion References

15 15 16

Analytical phase
Analyticalphase Cognitivedomain Communicativedomain Normativedomain Medicalconductdomain Conclusion References

17
18 20 20 21 22 22 23

Standardization of immunohistochemistry
Standardizationofimmunohistochemistry Specialstains Clinicalquestionandtestselection Specimenaquisitionandmanagement Reagentvalidation Useofcontrols Analyticskills Conclusion References

25
26 27 28 29 29 30 30 30 31

Classification in surgical pathology

Classificationinsurgicalpathology Precisionandaccuracy Typesofclassification Whatisthebestclassification?

33
34 35 36 36

VI

Thedesignofclassifications 1.Datalimitations 2.Self-interest 3.Consensus 4.Compliance Conclusion References

37 37 38 38 38 38 39

Postanalytic phase
Postanalyticphase Qualityassuranceconsultation Effectivecommunication Differentreviewmethods Conclusion Reference

41
42 43 44 45 47 47

Error taxonomy and validation

Errortaxonomyandvalidation Conclusions References

49
50 55 55

Structural component of a quality

Structuralcomponentofaquality 1.Workforce 2.Continuouseducationandtraining 3.Theabilitytochange 4.Comprehensivecomputersystem 5.Standardisedtasksandlanguage 6.Regulatorycompliance References

57
58 59 59 59 60 60 61 61

VII

VIII

Butterflyeffect
and quality

Butterflyeffect
and quality
Thebutterflyeffect,asdefinedintheChaostheoryisaninteresting phenomenon characterized by the sensitive dependence oninitialconditions,whereinasmallinitialchangeataplacein anon-linearsystemcanresultinmassivedifferencestoalater state.Theclassicalexamplequotedisthatofabutterflyflapping its wings and causing a hurricane. Edward Lorenz popularized thisterminweatherforecastingwhichhadalreadybeendescribedintheliteratureinaparticularcaseofthethree-bodyproblembyHenriPoincarin1890.(SomeHistoricalNotes:History ofChaosTheory)Heobservedthataveryminutechangesinone ofthevariables(insteadofenteringavalueas0.506127,hechose0.506)inacomputermodelforweatherforecastingaffected thewholesystemtremendously.

Thebutterflyeffecthasbeenwellappreciatedinweatherforecasting.However,inmedical science,itspotentialhasremainedlargelyunexplored.Pathologistsfamiliarwiththeintricaciesofqualityprocessinanatomicalpathologywouldcertainlyrelatetothiseffectwhenit comestoprecisionandaccuracyintheirpathologyreports. This is all the more important since the biological system follows non-linear dynamics wheretheoutputmaynotbedirectlyproportionaltoitsinput.Toacertainextentthough,the biologicalsystemalsofollowslawsofphysicsandbiologistsbelievethatexactmodellingofa cellorbiologicalsystemispossible.Thefractalmodelofcancergrowthhasbeengenerated byvariousscientists[2].Differentcellmodelsandbiologicalsystemshavebeengeneratedby researchersbasedonenormousdataandfindings[3,4]. Thepredictionofdifferentphysiologicalandpathologicalphenomenaispossibleusing non-lineardynamicssuchasdeterministicchaosthoughitmustnotbeforgottenthatchaoticsystemsarehighlyresponsivetoinitialconditionsandanegligibleinputorapparently minorvariationinthemeasurementofthebasalstateofsystemmayproduceanunexpected output;thebutterflyeffect. Forinstance,thenucleusisthecentreofallgeneticmaterialandthisiswheretheinitial geneticorepigeneticchangesmayoccurintheeventofanon-lethalcellularinjury[5].As hasbeendocumentedduringtheprocessofcarcinogenesis,mutationsmayhappenwithin thenucleiofasingleorahandfulofcells.Thesemayappeartobeminorchangesofnegligiblesignificanceintheoverallcontextoftheorgansystem.However,theresultingcascade offunctionalderangementscouldleadtoseriousconsequencesandwiththeprogression of time, affect the system tremendously culminating in the ultimate collapse of the entire systeminamannerreminiscentofthebutterflyeffect[6]. Inpracticinganatomicpathology,thepathologyreportisareflectionofthepathologists competence,basedontheprecisionandaccuracyinvolvedinfinalizingit.Whiletherecanbe nodoubtthatthedataprovidedbypractitionersofanatomicpathologyishighlyrelevantand valuabletothepracticeofevidencebasedmedicineintheclinicalarenaonewoulddowell tokeepinmindthattheknowledgebaseinthisspecialityispredominantlyobservational; whichcancreateabutterflyeffectinclinicaloutcome.Moreover,fromaphenotypic-clinical frameworkofdiagnosis,weareshiftingintoaphenotypic-molecular-clinicaldimension[7].

Conclusions
The majority of studies on the quality of oncologic pathology diagnoses have focused on patient safety and have documented a variety of causes of errors that occur in the clinical andanatomicpathologydepartmenttestingphases.Clinicalpractitionersplayanessential roleinerrorreductionthroughseveralavenuessuchaseffectivetestordering,providingaccurateandpertinentclinicalinformation,procuringhigh-qualityspecimens,providingtimely follow-upontestresults,effectivelycommunicatingonpotentiallydiscrepantdiagnoses,and advocatingsecondopinionsonthepathologydiagnosisinspecificsituations. Thisisindeedtherighttimetoconsiderare-lookintothefunctioningofouranatomic pathology departments, especially in light of litigation threats looming large over todays medicalpractice.Althoughdesigningcomprehensivequalitysystempoliciesandprocedures atthedepartmentlevelwouldappeartobethelogicalapproachintherightdirection,precision&accuracymaynotbeeasytoachieveduetovariousfactors.

Aninterdisciplinaryapproachwouldbemandatorytoformulateeffectivetreatmentplans toresolvethepressingproblemsinmedicalscience,particularlycancermanagement.

References
1. orenzEN(1963).Deterministicnonperiodicflow.JAtmosSci20:130-141. L 2. aishJW,GazitY,BerkDA,NozueM,BaxterLT,etal(1996).Roleoftumorvasculararchitecture B innutrientanddrugdelivery:aninvasionpercolationbasednetworkmodel.MicrovascRes51: 327-346. 3. DeyP(2010).Cellmodellingandsimulation:Fantasytofact.BullMedEduRes42:170-176. 4. omitaM,HashimotoK,TakahashiK,ShimizuS,MatsuzakiY(1999).E-cell:Softwareenvironment forwholecellsimulation.Bioinformatics15:72-84. 5. eyP(2006).Chromatinremodelling,cancerandchemotherapy.CurrMedChem13:2909-2919. D 6. JoshiA,CaoD(2010).TGF-betasignalling,tumormicroenvirnmentandtumorprogression:The butterflyeffect.FrontBiosci15:180-194. 7. Salto-TellezM(2007).Acaseforintegratedmorphomoleculardiagnosticpathologists.ClinChem 53:1188-1190.

Qualityby design concept

Qualityby design concept

Qualityisapervasivetermwhichisoftenoverusedandseldom achieved. Dr Walter Shewhart invented the statistical control chartin1930s[1]whichwasutilizedbytheUnitedStatesduring worldwar-IItheUnitedStatesalongwithbasicqualitycontrol methodstoproducemilitarysuppliesinlargequantitiescheaply,butwithgoodquality.

In manufacturing, quality is a measure of excellence or a state of being free of defects, deficiencies,andsignificantvariation,broughtaboutbythestrictandconsistentadherence tomeasurableandverifiablestandardstoachieveuniformityofoutputthatsatisfiesspecific customeroruserrequirement. ISO8402-1986standarddefinesqualityasthetotalityoffeaturesandcharacteristicsofa productorservicethatbearsitsabilitytosatisfystatedorimpliedneeds. Inmanufacturing,onetypicallyaddspriceorcostintotheexpectationofquality.However, inmedicine,pricemustbeaccordeddiminishedweightageinconsiderationofquality.AccordingtoAmericanNationalStandardsInstitute,thedefinitionofquality,acceptedbythe CAP (College of American Pathologists), isThe totality of features and characteristics of a productorservicethatbearonitsabilitytosatisfygivenneeds.Somehavedefinedquality asConformancetospecification,othershavesuggestedthatqualityismeetingorexceeding customerexpectations.Thereforequalitymeasuresneedstobecustomized[2].Accordingto ISO9001definition;itissetofagreedstandardsthatprovideguidelinesforaQualityManagementSystem. In January 2003, the International Organization for Standardization (ISO) published the worldsfirstharmonizedclinicallaboratorypracticestandard.Sinceitspublicationthisstandardhasgainedrapidandwidespreadacknowledgementandadaptationinmanycountries. In2007,thesecondeditionofISO15189waspublished,withintenttoalignitfurtherwith ISO17025[3].Thenhowdowedefinequalityinsurgicalpathology?Onemajoraccreditationbody,theJointCommissiononAccreditationofHealthcareOrganizations(JCAHO),calls for incorporating comparison of organizational performance with that of others, so-called benchmarkingofperformances[4].Inotherwords,howdoesoneknowthatoneisasgood asonesaysandwhatcanonelearnbycomparingoneselfwithothersincompetitionoreven thebestinotherunrelatedbusiness. TheInstituteofMedicine(IOM)qualitymetricdefined6domainsofquality:safety,effectiveness,efficiency,timeliness,equity,andpatientcenteredness[5].Toaccomplishthis,basic notionssuchasqualityandproductmustbedefinedandunderstood.Elementsofquality that are important in generation of the end product i.e. surgical pathology report include accuracy,timeliness,reproducibility,andcompleteness.Theaimofqualityshouldfocuson measuringthecompleteprocessfromthecliniciansperspective. TheentireprocessofQualityAssuranceandImprovement(QA&I)shouldfocusontheprocessofproductgeneration(surgicalpathologyreport)andproductimpact(customerorcliniciansatisfaction).Mostwouldagreethatitiseasytodefineproductqualityratherthanproductimpact.Figure1showsadiagrammaticrelationbetweenproductrequirement(accuracy, timeliness,reproducibility,andcompleteness)inhavingappropriatecharacteristics(clinician satisfaction and patients safety).The existence of relationships between requirements and characteristicsmakesstatementsaboutthequalityofproduct(surgicalpathologyreport). In surgical pathology, perhaps the worst consequence of poor quality reporting is the inevitable negative outcome resulting from misinformation that may be acted on by the clinician.Someofthesereportsmaybebroughttothelaboratorysnotice,havingsomehow escapedlaboratoryattentionandfortunatelyidentifiedbyclinicalpersonnelbeforewreaking anyhavoc.Nevertheless,thesetypesoferrorsarequitedamagingnotonlytothelaboratorys reputationbutalsotothecliniciansfutureconfidenceinthelaboratory. Themajorproductinsurgicalpathology,thatofadiagnosis,resultsfromnumerouscomplex,oftenmanual,sequentialprocesseswithinterimworkproductsandmanyhumanhand-

Fig. 1

offpoints[6].Oneshouldfocusonqualityproductbyredesigning,simplifying,andeliminating processes that may have accumulated or been adopted over the years without much thought to efficiency or effectiveness.This quality by design, is nothing but our ability to modifysystemprocessesthatenhancediagnosticaccuracy,informationcontentandcompletenessaswellastimelinessofreportingwithreproducibility.

References
1. estM,NeuhauserD(2006)WalterAShewhart,1924,andtheHawthronefactory.QualSafHealth B Care15:142-143. 2. NakhlehRE(2006)Whatisqualityinsurgicalpathology?JClinPathol59:669-672. 3. KawaiT(2010)HistoryofISO15189anditsfutureperspective.RinshoByori58:64-68. 4. RadeckiRP,SittingDF(2011)ApplicationofelectronichealthrecordstotheJointCommissions 2011NationalPatientSafetyGoal.JAMA306:92-93. 5. RaabSS,GrzybickiDM(2010).SecondarycasereviewMethodsandAnatomicPathologyCulture. AmJClinPathol133:829-831. 6. Zarbo RJ (2000) The oncologic pathology report. Quality by design. Arch pathol lab Med 124:1003-1010.

Pre-analytic
phase

Pre-analytic
phase
Pre-analytical phase is multifactorial and involves many individualsoutsidethelaboratory.Inaddition,asthetraditionalmorphologicalclassificationisgivingwaytoanewermolecularbased classification,thegoalistoeducatethebiomedicalcommunity inanefforttoimprovethequalityofRNAthatcanberecovered fromformalin-fixed,paraffin-embedded(FEPE)tissue[1].

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In the pre-analytical phase of test cycle, several elements may be monitored including patientsatisfactionwithcollectionprocess,trainedprofessionalstaffinspecimencollection &transport. Table 1.Giveslistofpre-analyticalimprovementmonitors. Table 1. Pre-analyticimprovementmonitors DirectlyrelatedtoLaboratory Specimenfixation Specimendelivery Specimenidentification Grossing Tissueprocessing Tissueembedding Cuttingsection Staining,Mounting&Labelling Indirectlyrelatedtolaboratory Fillingrequisitionform dequacyofclinicalhistorywithdifferential A diagnosis Imagestudyreports Biopsyprocedure&primaryfixation Orientationmarksforspecimen

Specimen collection
Thefirststepsintheprocessofsamplehandlingarechallengingtocontrol,butsignificantly impactthequalityofthespecimen.Theseincludetimeofanaesthesiaadministration,ligation ofvessels,andspecimenremovalfromthepatient[2].Thesefactorscannotbestrictlycontrolledbecausetheyinfluencepatientcare;however,adetailedrecordingofthesetimesare animportantmetricoftissuequalityastheyaffectthequalityoftheresultantbiomolecules, ifnotcytomorphologydirectly.Themostcommonlydescribedimpactontissuequalityisthe warmischemiatimefromwhenthebloodsupplyisligateduntilthespecimenisreceivedby thepathologistforprocurement.Thistimevariesfromminutestohoursdependingonorgans, thesurgicalapproach,thesurgeon,nursingstaff,andstandardoperatingproceduresofthe institution[3].Themagnitudesofthesechangesarepoorlyunderstood.Allprotocolsshould include the recording of the times for administration of anesthesia, ligation of the vascular supply,andremovalofspecimenfromthepatientsbody.Thesetimesshouldbeincludedas recordsubmissionofthesurgicalspecimentothepathologydepartment.Forbiopsies,time ofspecimenremovalshouldberecordedandcommunicatedtothepathologydepartment.

Specimen labelling
Labellingerrorscanresultininappropriatetherapyorwithholdingoftherapyinpatientswith unrecognizedmalignancies.Labellingerrorsmaybedetectedbylaboratorystaff,pathologist oraclinician.Labellingerrorsdetectedbeforecausingharmorinconveniencetopatientsare frequentlydesignatedasnearmisses.[4] Identification errors involving surgical specimens may involve misidentification of a patientorthepatientsspecimenorthesitefromwhichthespecimenwasobtained.

11

Specimenlabellingerrorswithinthelaboratorycanoccuratseveralpointsofspecimen processing.Withinthegrossroom,specimencontainerscanbepairedwithcassetteslabelled withanincorrectcasenumber(wrongpatient)oranincorrectpartnumber(wrongsite).In thehistologylaboratory,cassettesatthecuttingstationcanenduppairedwithincorrectly pencil-labelledslides(wrongpatientorsite),oracorrectlypencil-labelledslidecanhavethe wrongpaperlabelapplied(wrongpatientorsite). Asurgicalpathologistmaypickupanincorrectslideanddictateareportwithincorrect diagnosisforthepatientslaboratorydatabeingreviewed.Errorsmayalsooccurduringtranscriptionwhendictationsaretranscribedtothewrongreportnumberandpatient[5]. Identificationoferrorsfallinto2categoriesrepresentedbypatientidentificationerrorsand specimenidentificationerrors.Inpatientidentificationerror,aspecimenislabelledwiththe incorrectpatientnameoridentificationnumber.Inaspecimenidentificationerror,aspecimen is misidentified as to site of origin or time of collection but the specimen is correctly associatedwithcorrectpatientnameoridentificationnumber. Identificationerrorscanbeclassifiedaspre-analytic,analytic,andpost-analytic.All3types areofconcerntopathologistreputation.Pre-analyticorclinicalerrorscanbeaddressedby standardizationofspecimencollectionprocessandfeedbacktoclinicalstaff.Onlytheanalytical errors are directly addressable by laboratory professionals and surgical pathologists. Themajorityofroutinepracticesfortheidentificationoflabellingandspecimenidentificationerrorsprobablyunderestimatesthefrequencyofoccurrenceofsucherrors,andmaygo undetected[4].

Specimen fixation
Themannerinwhichthespecimenispreparedhasadramaticimpactontheresults.Thefailuretoappreciateandstandardizethesestepsposesproblemsforboththepathologist&researcherwhoworkswiththeresultantRNA.Thefixationstepentailsthreeelements:thickness oftissue,volumeoffixative,andtime.Failuretooptimizeall3oftheseelementscanresultin eitherunderfixationoroverfixationofthetissue.Bothoverfixationandunderfixationresultin degradationofthespecimenafterparaffininfiltration,andtheyhindercorrectdiagnosisby thepathologistbyalteringthehistomorphologyandimmunoreactivity[6]. Formalinpenetratestissueatanaveragerateof1mm/hour,butthisratecanvarydependingontissuetype.Standardfixationtimesareaminimumof5hoursforneedleandendoscopic biopsy specimens and 12 or more hours for sections from larger specimens.These times are required for complete fixation of the specimen. There is unjustified pressure to decreasethetimefromwhentissueisremoveduntilitsfinaldiagnosis,whichputsthequalityofhistomorphoogicaldiagnosisatrisk.Reportshavedescribedmicrowaveandultrasound fixationwithavarietyoffixativestospeedupthefixationoftissue[7].

Grossing
Grossing can contribute to prevention of erroneous specimen identification. The classical patternofgrossingis:

12

1. handleonespecimenatatime; 2. atchtherequisitionformwiththecontainerandtheprocessingcassette; m 3. ouble-checktheidentityofthespecimenduringdictation. d If the biopsies contain many parts, they should be lined up to check completeness of the case with all possible discrepancies in specimen identification. However, the principle ofprocessingeverypartofthespecimenasaseparateentitymustbehonoured.Although practicesometimesmakescorrectiontothisgeneralrule,everygrossingpersonrealisesthat violationofthisgrossingcentraldogmaisdangerousandcanleadtoaspecimenmix-up. Althoughsomeinstitutionsdonotusedictationwhilegrossing,itisacommonlyaccepted practice.Dictationsmustinclude,withclearpronunciation,thesurgicalnumber,thepatients name,andspecificidentifiersonthecontainer(number,site,content,etc). Frozensectiongrossingispronetospecimenmisidentificationbyspecificsoftheprocessing.The frozen section area is especially vulnerable if the specimens arrive simultaneously fromdifferentpatientsoraspartsofthesamepatientsspecimen,butinbulk.Detailsofthe grossing table configuration are very important for preventing specimen mix-up. Unfortunately,sometimesthegrossingpersonmaygrabawrongcontainerorprocessingcassette. Additionalspecimenidentificationonthecassetteiscommonpractice. Defininglaterality,typeofspecimen,ortypeofproceduresometimescanbeusefulnot onlyforembeddingorientationbutactasasafeguardinpreventingspecimenmix-up.The grossingpersonmustconfirmorcorrecttheidentifierplacedduringaccession.Thisisavery importantpartofpreventingspecimenmisidentification. The next step, with digital imaging in grossing pathology, can be an additional in preventing erroneous specimen identification. The pathologist would see on the screen not only the specimens identification documents but actual specimen features (shape, color, size,etc.).Histologyinformationmustbeenteredintothecomputerbythegrossingperson, whosolelyknowsalldetailsofthespecimen,byusingthebarcodedrequisitionformsasthe maindocument. Anotherperspectivemightbeaninterfacebetweenelectronicmedicalrecords,anatomic informationsystemandaspecimenbar-codingsystem.Thiswouldenabletrackingaspecimens surgical number, grossing cassettes, embedded blocks, and even microscopic slides duringprocessingcycles.Thebreakinsequenceofthesurgicalnumbersorpartsofthespecimen,doublenumbers,unexplainablediscrepanciesbetweenthecolourofthecassetteaccordingtolog,areallsafeguardsinpreventingspecimenmisidentification[8].

Tissue processing
The process of embedding tissue with paraffin impairs the recovery of biomolecules but appearstohavelessimpactontheirquality,asdeterminedbytheprocessofhandlingand fixation [9]. General recommendation is that detailed records of processing procedures be maintained.Detailsaboutthetimes,temperatures,presenceofvacuumandinstrumenttype, as well as the reagent should be included. Accelerated tissue processing protocols require adequate studies to measure their impact on biomolecule recovery and stability. Reagent qualityandreplacementshouldbemonitored.Studiescomparingalternativereagentsand processingconditionsshouldbecarriedoutandreported.

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Thegeneralprocessingstepsincludesequentialdehydrationfromanaqueousenvironmenttoanalcoholenvironment(mostoftenethanol),subsequentreplacementbyxylene(or xylenesubstitute)inaprocessreferredtoasclearing,andreplacementofxylenewithparaffin (impregnation).Typically,thisprocessiscompletelyautomated,butitlacksstandardization and depends on the instrumentation, specimens, and reagents used. Quality of reagents, time,andtemperaturearesuretoimpactsampleintegrity[2]. Thedurationforcompleteprocesscanvaryfromlessthan4hourstomorethan12hours.In general,needlebiopsiesandbloodyspecimensshouldbeincubatedconservatively,whereas fattyspecimencanbeprocessedforlongerthanaverage.Itiscrucialthatreagentsbeofhigh qualityandbereplacedonaregularbasis.Thealcoholsandxylenesusedinprocessingbecomedilutedwithcarry-overfrompriorsteps;asaresult,tissueprocessedatalatertimemay notbecompletelydehydrated.Theimpactoftimeissimilartothatofpoorqualityexhausted reagents.Itisessentialthattissuebecompletelydehydratedduringprocessing,asresidual waterwillnotbereplacedbyparaffin,thusmakingthetissuesusceptibletodegradation[2]. Themechanismisprobablyrelatedtoincompletecoagulationofproteins;asaresult,water getstrappedwithinthetissue. Data concerning alternative reagents and a comparison to the common protocols are lacking.Controlledstudiesofalternativealcoholsandclearingagentshavenotbeencarried outfortherecoveryofnucleicacids.Studiesonproteinsuggestthatdifferencesdoexistthat requiremodificationofdownstreamprotocols.

Embedding and sectioning

Thepathologistmayguideembeddingbynotchingorinkingoneorseveralsurfacesofthe specimenandprovidingamapinaccompanyingpaperworkthatindicateswhetherthese shouldbeplacedface-down,face-up,orinparallelwiththelateralaspectsofcassettes.The embedding step is a potential source of great irritation (and medico-legal liability) for the pathologistifitisdonebyaninexperiencedorcarelesslaboratoryworker.Smallbiopsyspecimensthatareorientedimproperlycannotbeinterpretedmicroscopically,necessitatingthat theblockbere-meltedandre-embedded.Thistakestime,andintheprocessoffacingthe poorlyorientedspecimenforpreparationofinitialsections,valuabletissuemaybelost[10]. Theparaffinusedinimpregnationandembeddingvariesandischosentomeetthedemandsoftheindividuallaboratory.Paraffinwaxeshavedifferentmeltingpointsandtextures thatimpactthesectioningcharacteristicsofthefinalblocks.Notonlyareadiversityofparaffinsused,theirexactcompositionsareoftenproprietaryand/orcontainbeeswaxofmarked variation[11].Syntheticparaffinswithlowmeltingtemperatures(55-63oC)aretypicallyused in the United States and Western Europe.These formulations may contain latex, dimethyl sulfoxide,andproprietaryplasticizersthatmodifytextureandmalleability.Beeswax,containing pollen and other contaminants, is routinely used in Eastern Europe, Africa, and South America to modify the melting temperature and improve the malleability of poor-quality paraffin.These interfere with the recovery of biomolecules [12].The use of higher melting temperatureparaffinresultsindecreasedandinadequatede-paraffinizationandreduction intheamountofnucleicacidsrecovered[13].Low-melting-temperatureparaffinisrecommendedforimpregnationoftissue.Thetypeofparaffinshouldberecorded.Avoiduseofa additivesuchasbeeswax.

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Histo-microtomyisaseeminglystraightforwardprocess,representingthecuttingofserial paraffin-embeddedsectionswithtissuemicrotome.Nevertheless,thistechniquehasmany hiddentrapsthatrelatetopropermaintenance,calibration,andorientationofcuttingblades; preparationforparaffinblocks;anddexterityofthetechnologist.Microtomebladesthatare dull loose or nicked will producechatter orvenetian blind artefacts in tissue sections. In addition,theclearanceangle(anglebetweenthetissueblockandthemicrotomeknife)is crucialtogoodtechnique.Itshouldbeapproximately3-8o.Iftheangleistoonarrow,alternately thick and thin sections are cut, or they are folded on themselves [10]. An excessive clearanceanglecauseschatteredorotherwisehideoussectionsandmayprecludetheability ofthetechnologisttoobtainatissueribbon.Evenworsearetheeffectsofloosemicrotome bladesortissueblocksinmicrotomechuck.Thesedeficienciesmayshattertheparaffinblock entirelyordeeplygroovethetissuespecimen.Ablockthatismountedcrookedlyinthemicrotomechuckwillproduceirregularribbonsorcauseindividualsectionsintheribbonsor causeindividualsectionsintheribbontobreakfreefromoneanother.Warmblockswillyield wrinkledribbonsorcausesuccessivesectionstoannealtooneanother.Inadditionfailureto moistenthesurfaceofblockedtissuesuitablybeforecuttingwillyieldsanexcessivenumber ofknifemarksorfragmentedsections.Anotherproblemthatissometimeseenatthisstep istendencyforribbonstoflyontotheknifeblade.Thisisresultofstaticelectricitybetween thewaxortissueandmetalblade,andalsomaybeavoidedbyslightlymoisteningtheknife andblocksurfacebeforeeachribbonisprepared.

Mounting
The temperature of water bath at the cutting station should be cut at 5-10 oC below the meltingpointoftheembeddingwax.Ifitistoohot,desiccated-lookingsectionswillresult;in contrast,coolfloatationbathsproduceexcessivewrinklingofthetissue.Theribbonsmustnot beleftinthebathformorethan1or2minutes,orelsewillresultinspuriousoverhydrationof thetissue.Thiseffectsimulatestheappearanceofoedemafluidmicroscopically.Oneofthe mostdangerousofallmistakesinthehistologylaboratorycantakeplacewhenmounting sectionsfromfloatingbaths.Friabletissuemayshredsmallfragmentsthatfloatfreeonthe surfaceofthewater,andthesemaybeinadvertentlypickedupwhenmountingslidesfrom subsequentlyprocessedunrelatedcases.Derisivelyknownasfloaters,theseroguepiecesof tissuecommonlycauseagonizinginterpretiveproblemsforthepathologist[10].Analternativesourceoffloater-typeartefactsisthetongueblademetastasis,whereintissueadheres to a wooden applicator stick that is used to float successively prepared ribbons from two differentcases.

Conclusion
As morphological classifications are gradually being replaced by molecular classification, it has become imperative to preserve & recover nucleic acids.The final product of quality is enhanced by better defining the processes, setting specifications, and approaching tissue asananalyteformolecularanalysis[10].Oneshouldencourageastandardizedapproachfor reporting&documentingpre-analyticindicators.Inclusionoftheseinthechecklistoffinal reportwillfurtherenhanceaccountability.Thebiomedicalcommunitywillbenefitfromad-

15

ditional recommendations based on research results demonstrating the quality of nucleic acidsrecoveredfromFFPEtissues.Infutureonecananticipatethatthebodyofknowledge onthisimportanttopicofmolecularanalysiswillcontinuetogrow.

References
1. ewittSM,FraserLA,YanxiangC,RichardCC,MaureenC,etal.(2008)TissuehandlingandspeciH menpreparationinsurgicalpathology.Issuesconcerningrecoveryofnucleicacidsfromformalin-fixed,paraffin-embededtissue.ArchpatholLabMed132:1929-1935. 2. CCLS (1999) quality assurance for Immunocytochemistry. Approved guidelines. Wayne, N Pa:NCCLS;1999.NCCLSdocumentMM4-AC. 3. DashA,maineIP,VaramballyS(2002)Changesindifferentialgeneexpressionbecauseofwarm ischemiatimeofradicalprostatectomyspecimens.Amjpathol161:1741-1748. 4. ValenstainPN,SirotaRL(2005).Identificationerrorsinpathologyandlaboratorymedicine.Clin LabMed.24:979-996. 5. LayfieldLJ,AndersonGM(2010).Specimenlabellingerrorsinsurgicalpathology:an18-months experience.AmJClinPathol134:466-470. 6. eMarzoAM,FedorHH,GageWR(2002)Inadequateformalinfixationdecreasesreliabilityofp27 D immunohistochemicalstaining:probingoptimalfixationtimeusinghigh-densitytissuemicroarrays.HumPathol33:756-760. 7. ChuWS,FurusatoB,WongK,(2005)Ultrasound-aceleratedformalinfixationoftissueimproves morphology,antigenandmRNApreservation.ModPathol18:850-863. 8. DemensteinIB(2008).Rootcauseanalysisofspecimenmisidentificationinsurgicalpathology accessionandgrossing.Labmedicine39:497-502. 9. GoldsteinNS,HewittSM,taylorCR,YazijiH,andtheMembersofAd-HoccommitteeonImmunohistochemistry standardization (2007). Recommendations for improved standardization on immunohistochemistry.ApplImmunohistochemMolMorphol15:124-133. 1 M 0. arkRW,MillsNC,WilliumKB(2008).Tissueprocurement,Processing,andstainingtechniques. In:MarkRWediditor.DiagnosticHistochemistry.Cambridgeuniversitypress.Pp.1-27. 1 F 1. ricainJC,RouaisF,DupuyB(1996).Atwo-stepembeddingprocessforbetterpreservationof softtissuesurroundingcoralimplants.JbiomedMaterRes33:23-27. 1 2. FergenbaumJH,Garcia-ClosasM,HewittSM,LissowskaJ,SakodaLC,etal.(2004)Lossofantiginicityinstoredsectionsofbreastcancertissuemicroarray.CancerEpidemiolBiomarkersPre. 13:667-672. 1 3. ChungJ-Y,BraunschweigT,HewittSM(2006).OptimizationofrecoveryofRNAfromformalinfixed,paraffin-embeddedtissue.DiagnMolPathol15:229-236.

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Analytical
phase

17

Analytical
phase
Apathologicdiagnosisistheresultofacomplexseriesofactivities,masteredbythepathologist.Manyelementsculminatein adiagnosis,includinggrossdissectionandsection,embedding, histologicalsectioning,possibleotherancillarystudies,andmicroscopicinterpretation.Mostcriticalinthisphaseistheactof diagnosisitself(OtheranalyticindicatorsaredepictedinTable1).

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Error-reductioninitiativesshouldtargetthecognitivecomponentofinterpretationerror includingtheimplementationofstandardizeddiagnosticcriteria,educationalinitiatives,and thedevelopmentofredundantsystems[1].Diagnosticinterpretationerrorsmaybeclassified intothecategoriesofslipsandmistakes,andstudiesofcognitionhavehelpedtodefinesome errortypes. Table 1.AnalyticIndicators. S.No 1. Intra-operative Frozensectionpermanentsectionconcordance Histologyandgrossroommonitors Blocklabellingerrors Slidelabellingerrors Slidequality Technicalskillsofhisto-technicians Immunohistochemistry Frequencyofrepeatslides Annualinventoryofantibodiesandfrequencyofuse Externalvalidationofselectedantibodies Technicalskillsoftechnician Others Interpersonalrelationbetweenlaboratorystaff Ancillarystudymonitors(FISH,EM,Othermolecularstudies) Managementscommitmenttoquality

2.

3.

4.

Therootcauseofinterpretationerrorsgenerallyincludesacognitivefailureinconjunction withupstreamfailuresorwithsystemfailures.Forexample,poor-qualityspecimenmaybe over-interpretedorunder-interpreted,andlatentsystemproblemsmayincludepathologist overwork,lackofexperience,lackofappropriateredundantsystems,etc.Theaccuracyofthe finaldiagnosisisameasureoftheeffectivenessofallofthesesequentialsteps.Unfortunately amedico-legalsystemoftenignoressystemproblemsandfocusesonindividualculpability, whichisacontraryapproachtoimprovingsafetysystems. An understanding of the diagnostic process from a theoretical perspective will benefit pathologyasascienceandasamedicalspecialitybecauseitprovidesthebasisforunderstandingdiagnosticvariationsanddiscrepancies[2].Thediagnosticprocesscanbeviewedas aproblemsolvingstrategy.Inresolvingtheproblemspresentedbythecase,thepathologist mustelaborateanactionplan,contemplatingfourdifferentdomains:cognitive,communicative,normative,andmedicalconduct.

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Cognitive domain
Pathologists use cognitive process, such as perception, attention, memory, and search, to collectdatafromthecase,includingmacroscopicandmicroscopicfindingsandclinicalor radiologicalinformation.Theprocessofthinkingisconsciouslyguidedinthedirectionofsolvingproblem.Metacognitiveskillsincludeplanningthewaytoapproachatask,beingaware of internal or external distracting stimuli, evaluating progress toward task completion, and maintainingmotivationuntilthetaskhasbeencompleted[3]. Whenlookingatahistologicslide,thepathologistcanmakeadiagnosis,basedonastrategycalledpatternrecognition.Patternrecognitionistherealizationthatthehistologicpicture conformstoapreviouslylearnedpictureofthedisease.Multiplestrategiesareemployedby pathologiststoarriveatadiagnosissimilartotheirclinicalcounterparts[4]. Anotherstrategyiscalledmultiplebranchingorarborisation.Inthis,thereisprogressionof thediagnosticprocessdownoneofalargenumberofpotential,presetpaths,byamethodin whichtheresponsetoeachdiagnosticinquiryautomaticallydeterminesthenextinquiryto becarriedoutandwhich,ultimatelyleadstothecorrectdiagnosis.Thealgorithmmustspelled outinitsentirety,beforethecasearrives,andmustincludeallrelevantfindingsorclues,linking thembypathwaysthatrepresenttheidealizeddiagnosticprocessoftheexpertpathologist. In exhaustive strategy, the pathologist accumulates all possible data (scrutinizes all the sections, reviews all available clinical data and x-ray, evaluates special stains and immunohistochemistryslides)andproceedstothesecondstageofsearchingforthediagnosis.With experiencethepathologistmayresorttousingshortcuts.However,everynowandthen,the exhaustivestrategymayreappear,toaidinrulingoutremotediagnosticpossibilities,tojustify adelayinsign-outwhilethepathologistconsidersotherrelevantpoints,ortoestablishrapportwiththepatients,theclinician,orareferringpathologistinaconsultingcase. Thehypotheticalanddeductivestrategycomprises2elements:hypothesiscreationand hypothesisverification.Hypothesiscreationisahighlyindividualisticprocessanddependson masteryofthedynamicmodelsofstructure,function,andresponsetostimulithatcomprise the knowledge from basic science disciplines, such as anatomy, biochemistry, physiology, genetics,basicpathology,andmicrobiology,aswellasclinicalmedicine,surgery,anddermatology,amongothers.Thesecondelement,hypothesisverification,isamasteryofselection, acquisition,andinterpretationofpathologicandpara-pathologicdatathatwillbestshorten thelistofhypothesis. AccordingtoreviewsbyFoucar[5,6]decisionmakingisanimmaturescientificfield,and it slips into poorly defined, almost transcendental factors, such as intuition, flair, luck, gut impression, and others, which might be related to an implicit or tacit knowledge that pathologistsuseinmakingdiagnoses,butwhichareformallyexpressed.Accordingtohim,the pathwaytothisscientificapproachistoprogresstowardevidence-basedmedicine.Although notconformingtomanyofthebeststandards,thepathologicdiagnosis,moreoftenthannot, isconsideredagoldstandardtowhichotherstandardsarecompared.

Communicative domain
20
The written report is a conglomeration of relevant communicative activities like receiving adequateclinicalorsurgicalinformation,conversingwiththeclinicianorpatient,preparing

acaseforpresentationorpublication,andimagedocumenting.Thenatureofwarrantsand backingswilldeterminetheacceptabilityandcertaintyofthepathologicalconclusions.Even ifsensitivityandspecificitystatistics(aswellaslikelihoodratiosandpredictivepositiveand negative values) were to be available for every possible pathologic finding in relation to a diagnosis, such external evidence could never replace individual, pathologic expertise. Put into the context of the dispute between individuality and standardization, the pathologist individually has to choose which standards must be applied in a given case.The available evidence does not always necessitate a particular conclusion; in most cases, the evidence providessomedegreeofconfidence,notabsolutecertainty.Boththecertaintyofthescientificknowledgeinpathologyandthefirmconvictionofabeyond-a-doubtdiagnosisreston thereasonsthepathologistcanadduceinrefutingobjectionsagainstthem.Previousexperienceservesasawarrantinanargument.Inaparticularcase,theideaoftheobjectivityofthe histologicperceptiondoesnotensurethetruthofthecorrespondingdiagnosis;instead,it representsonlyoneinstanceofanexperienceinthediversityofitspossibleinterpretations. Intheabsenceof(andsometimesdespiteof )goodqualityresearchdata,pathologicreasoning may be guided by medical heuristics. Of course, medical heuristics may be passed frompathologisttopathologist,intrainingactivities,consultations,books,andmeetings,and theyformpartofbackgroundknowledgethatpathologistusetomakediagnosis,butthey arenotusuallyreflectedonormadeexplicit. Heuristicswillalwaysbeusefulinactivatinghypotheses,butasanatomicpathologyadvancesasascience,theiruseisexpectedtodecreaseasmorphologicfindingsandmolecular techniquesareestablishedasmorereliablewarrantsauthorizingdiagnosticconclusions.Thus argumentisusefulbecauseithelpstomakeexplicitmedicalreasoning[7]. Becausetherearegreyzonesinmedicalpractice,uncertaintyshouldbeclearlyacknowledged.This might be a source of considerable epistemological and ethical tension [8].The validityofapathologicreport,dependson2conditions: 1. tmustbegroundedinexperience,meaningthatitisnotdissonantwithexperience; i and 2. hestatementmustholdupagainstallcounterarguments,i.e.itmustbediscursively t recoverable[9]. Apathologicreport,toreachconsensus,mustbeintelligible,musthavenormativerightness,mustnotraisedoubtsaboutthepathologistssincerity,anditspropositionalcontent mustbevalidatedastruth.

Normative domain
Aswitheveryhumanactionthathasmeaning,pathologyisdrivenbyrulesandnorms.The instrumentalactionisgovernedbytechnicalrules,whicharebasedonempiricalknowledge andwhichcanbeprovedtobecorrectorincorrect.Thepurposive,rationalactionisgoverned by strategies (rules of rational choice), which are based on analytic knowledge and which are derived from preference rules and decision-making procedures. Classification schemes shouldbe,asmuchaspossible,basedonstrategicrules,andthedecisiontochoosewhich classificationismostappropriateforagivencasereliesontheobjectiveswehaveinmind whenclassifying.Thecommunicativeactionisgovernedbysocialnormsthatdefinereciprocal expectations and that must be accepted by at least 2 acting subjects. Whereas the effectivenessoftechnicalrulesandstrategiesdependsonthevalidityofempiricallytrueor

21

analytically correct propositions, the validity of social norms is ensured by inter subjective recognitionthatisbasedonconsensusormutualunderstanding. Failuretofollowproventechnicalrulesorcorrectstrategiesmayresultinlackofsuccess. Learningtherulesofinstrumentalandpurposive,rationalactionsstrengthensthepathologistsskillsandenableshimorhertomakediagnosesor,inMurphys[10]view,tobecome themedicalconsultant.Actinginconformitytothenormsofcommunicativeactiondepends onmotivations. Threekindsofrulesmustbefollowed(toinstrumentalaction,rationalaction,andcommunicativeaction),withdifferentconsequencesiftheyaredisrespected[11].Suchrulesguide actionsthatarenotopposedtoeachother;instead,theyarecomplementaryandrelevant topathologicpractice.

Medical conduct domain

Theactionsthatshouldbe,orareexpectedtobe,carriedoutbypathologistandtheclinician have to be evaluatedbefore thefinaldiagnosis issignedout.The pathologist must clearly knowtheconsequencesofadiagnosisinthemanagementofacase,andthereportshould makeclearboththediagnosisandtheexpectedconductderivedfromit.Thepathologistis technicallyresponsibleforthediagnosticinterpretationheorshemakes.Thisresponsibility islinkedtothemedicalconductconsequentonthediagnosis.Asapracticingmedicalspecialist,thepathologistisassumedtobeacquaintedwiththepracticalimplicationsofhisor herdiagnoses,therebyadmittingresponsibilityfortheactionsresultingfromthem.Medical conductquestionsmayguidediagnosisandmayalsocontributetovariation,asinthecase of a pathologist who feels more comfortable, and therefore more liberal in diagnosing an endometrialcurettagespecimenfromawomeninher50sorolder.

Conclusion
Mostcliniciansseethediagnosisasaninstanceofproblemsolving.Intheintervalbetween receivingaspecimenandsigningoutareport,thepathologistexecutesaseriesofactions andoperations.Beforeproceedingtotheactionsrelatedtodiagnosis,thepathologistshould elaborate a plan of action for the problematic case.The implicit knowledge in pathology, comprisingmanyofthetasksinvolvedindiagnosis,involvesaninteractionamongdifferent domains.Inadiagnostictask,the: 1. ognitivecapabilitytorecognizeahistologicfindingandtoestablishaconclusionmust c beintegratedwith 2. hecommunicativeabilitytoappropriatelydescribeandinterpretfindingsandtoprot videadequatewarrantstoaconclusion,with 3. obediencetoappropriatenormativeguidelines,and 4. o evaluate the whole task with respect to the conduct that may be instituted as a t consequencetothediagnosis. This know-how in pathology aids in the solution of the case, even if a diagnostic label cannot be applied. When such situation occurs, the pathologist is expected to present a communicationstatingthefactsthatprecludedafinaldiagnosis,tofollowadequaterules,

22

and also, to propose a managerial approach to the case.The end resultpathology report shouldoriginateintheinterestandrespectforthepatient,andtheclinician,aswellasother pathologists.

References
1. RaabSS,GrzybickiDM(2010).Qualiyincancerdiagnosis.CacancerJClin60:139-165. 2. PenaGP,Andrade-filhoSA(2009).Howdoesapathologistmakeadiagnosis?ArchPatholLab Med133:124-132. 3. PenaGP,Andrade-FilhoJS(2006).Implicacoescognitivas,filosoficaseeducativasdotrabalhodo patologista.RevBrasEducMed.30:76-86. 4. Sackett DL, Haynes RB, Guyatt GH, Tugwell P (1991). Clinical diagnostic strategies. In: sackett Dl,HaynesRB,GuyattGH,TugwellP,Editors.Clinicalepidemiology.AbasicscienceforClinical Medicine.2nded.Boston,mass:Little,brownandCo;pp3-18. 5. FoucarE(1996).Diagnosticdecision-makinginsurgicalpathologyIn:WeidnerN,editor.Thedifficultdiagnosisinsurgicalpathology.Phildelphia,Pa:WBSaunders;pp1-10. 6. FoucarE(2001).Diagnosticdecision-makinginanatomicpathologist.AmJClinpathol.21-33. 7. UpshurREG,CloakE(2003).Argumentationandevidence.TheorMed.24:283-299. 8. PellegrinoED(1999).Theethicaluseofevidenceinmedicine.EvalhealthProf.22:33-43. 9. HabermasJ.(2001)Teoriasdelaverdad.In:HabermasJ,editor.TeoriadelaAccionComunicativa: ComplementosyEstudioPrevios.4thed.Madrid,Spain:catedra;pp113-160. 1 0. MurphyWM(2002).Theevolutionoftheanatomicpathologistfrommedicalconsultanttoinformationspecialist.AmJSurgPathol26:99-102. 1 1. HabermasJ(2001).Leccionessobreunafundamentaciondelasociologiaenterminosdeteoria dellenguaje.In:HabermasJ,editor.TeoriadelaAccionComunicativa:ComplementosyEstudios Previos;4thed.Madrid,Spain:Catedra,2001:19-158.

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24

Standardizationof

immunohistochemistry

25

immunohistochemistry

Standardizationof
From the beginning there has been concern relating to the relatively poor reproducibility of immunohistochemical (IHC) methodasappliedtoformalin-fixedparaffinembedded(FFPE) tissuesections,reproducibilityonadaytodaybasiswithinasinglelaboratory,andreproducibilityamongdifferentlaboratories. Inrecentyearstheseconcernshave,ifanythingincreasedand thelackofstandardization isnowrecognizedasamajorimpedimenttobasicresearch,clinicaltrials,anddirectpatientcare.

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Atotaltest approachwasadvocatedin1992(Tayler1992),whichinessence,embraces allproceduresperformedtoaccomplishanimmunohistochemistry(IHC)stain,fromsample collectiontowritingafinalreport[table1]. Table 1.Processcycle. S.No PREANALYTICAL Testselection Specimentype Acquisition,pre-fixationandtransport Fixation,typeandtotaltime Processingandtemperature ANALYTICAL Antigenretrievalprocedure Selectionofprimaryantibodies Protocol;labellingreagents Reagentvalidation Controlselection Technicaltrainingandcertification LaboratorycertificationandQAprograms POST-ANALYTIC Assessmentofcontrolperformance Descriptionofresults Interpretation/reporting Pathologist,experienceandCMEspecifictoIHC

1.

2.

3,

Immunohistochemistry(IHC)isessentiallyanELISAmethodappliedtoatissuesection.In thisrespect,whencorrectlyperformed,IHChasthepotentialtoperformasreproducibleand quantitativetissuebasedELISAassay;muchmorethanasimplestain.ThattheIHCmethod mostlydoesnotperformtothislevelreflectsfaultsintheapplicationofthemethod,specificallyinconsistentsamplepreparation,lackofreferencesorcalibrationstandards,andinadequatevalidationofreagents[1].TheuseofReadytouse (RTU)doesnotfinallysolvethese problems,butdefinitelywillleadtoincreasedreproducibilityandconsistencyinapractical sense,inlargepartbyforcingtheuseofexternalstandards,externalreagentvalidation,and defined,extensivelytestedprotocolupontheuserlaboratory.

Special stains
The first special stains were variations of the basic biological dyes. Specific histochemical stainssoonevolvedbasedontheinsituidentificationofactiveenzymeswithincellsbythe

27

applicationofcolorigenicsubstrates[2].Manyhistochemicalmethodswere,however,technicallyexacting,bothintermsoftissuepreparationandstainingprotocol,asituationthatled to recognition of the critical importance of appropriate positive and negative controls for interpretationofthefindings.Althoughthemethodswerechallengingenough,thereagents themselves were often poorly characterized and somewhat variable from manufacturer to manufacturerandlottolot.Howeveroutdateditmayseemtotheyoungergenerationpathologist,specialstainsaidinminimizingthedifferentials.InUnitedStates,theBiologicstain Commission(BSC)wasfoundedin1944asanon-profitcorporation,achievedconsiderable successwithregardtobiologicaldyes,butwiththeadventofimmunohistochemistry,special staintechnologyhastakenanewleapforward,withgreatopportunitiesandnewchallenges instandardization.

Clinical question and test selection

Inthefaceofthediagnosticconundrumthatcannotberesolvedbyorthodoxmorphologic criteria,thepathologistresortstohislifelineintheformofancillarytechniques.Thereisalso animportantongoingshiftinemphasisintheuseofimmunohistochemicalstainsfromprimaryfocusoncellandtissuemarkersasanaidtotherecognitionandclassificationoftumors tothedemonstrationofcellproducts,receptors,oroncogenesofpossibleprognosticvalue, andidentificationofinfectiousagentsinsitu[3]. The first option that a pathologist has, which is the more common modus operandi, is toselectstainsfromapanelthat,intheexperienceofthepathologist,haveproventobeof valueinaparticulardiagnosticarea.Thesecondapproachusesanalgorithmwithsequential panelsofselectedstainsthatindroducesacertaindegreeoflogicandthroughnessintothe processbutmaycompromisetheturnaroundtimeduetosequentialstaining. Foreachstainusedinaparticularcase,thepathologistshouldask,andanswer,thequestion,Willapositive/negativeresultaddtothediagnosis?Iftheanswerisnotknowninthe fieldofpathologyortotheindividualpathologist,thenthestainshouldnotbeperformed, becauseitwillnotaddtothediagnosticequation.Thehugevarietyofreagentsavailablefor IHC,andthelargenumberofdifferentvendors,inawaycontributestolackofstandardization;almostthereistoomuchchoice[4].Apolyclonalantibodyorantiserumisproducesby traditionalimmunizationtechniques,withboosterinjectionstomaximizereactivityagainst the target antigen. Such antisera in fact contain many different antibodyspecies, having varyingspecificityformanyantigens,butareeffectivelyenrichedforhighaffinityantibody molecules that target the antigen of interest (while antibodies to other antigens, to other antigens,notofinterest,arepresentatlowlevels,orareoflowaffinity,ormaybeselectively depletedbyabsorptionmethods).Monoclonalantibodies,preparedbyhybridomamethods, orbymolecularengineering,containasinglespeciesofantibodymolecule,whereeveryantibodymoleculeisidenticalbyidiotype,withasingleaffinity.Bothpolyclonalandmonoclonal antibodyreagentsmustbeaddedtothetissuesectionatanoptimalconcentrationorworkingdilution,definedasthatgivingthehighestintensityofspecificreaction,withthelowest levelofnon-specificbackgroundstaining:i.e.thehighestsignaltonoiseratio.

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Specimen aquisition and management

Pathologistshavesoughttoundosomeoftheadverseaffectsofformalinfixationeitherby the use of controlled enzymatic digestion or the antigen retrieval technique [5].The latter method(sometimesknownasheat-inducedepitoperetrievalorasunmasking)subjectssectionstomicrowaveheatinginthepresenceofaretrievalsolutionthatmayservetostabilize orpostfixtheantigenspresent.Althoughvigorousheatinginamicrowaveovenoffendsbasic instincts,themethodhascontributedtothereproducibilityofimmunostainingbyproviding a more uniform presentation of antigens in tissue sections than is otherwise present followinginconsistentfixationinformalin.However,onesignificantcaveathasbeenissued[6] namelythatasdifferentantigenretrievalapproachesareexploredandpropagated,thereis adangerthatadifferentprocedure,producingvaryingdegreesofrestorationofantigenicity, willaddyetanothervariabletotheoverallprocess.Unfortunatelythiswarninghascometo pass[5].Clearly,thepreferenceisforanatomicpathologisttoadoptmoreuniformandrigorousproceduresforthefixationandprocessingoftissues,extendingfromthemomentthat thespecimenisremovedfromthebodytotheendoftheembeddingprocess,particularly controllingthetotaltimeinfixativeitself.Thepressureforconsistencyinstaininghasgrown evenfurtherbecauseoftheincreasingfocusonprognosticmarkers,wheregreaterstringency isrequired[2].

Reagent validation
Whilechoiceandvalidationofreagentsarecriticalissues,byfarthemostimportantcontributory factor to variable performance of IHC worldwide, as well as in individual laboratories, relatestothepre-analytic phase[7,8].InthisrespectthemorewidespreaduseofRTUsmay havebenefit,notsolvingtheproblemofstandardization,butperhapscontributingtosome practicalimprovement.Thelaboratoryshouldfocusuponselectingtheoptimalconcentration(orworkingdilution)ofprimaryandsecondaryreagents,orelectinginsteadtouseRTUs withdefineddetectionsystemsandprotocols.Itmustbestressedthatotheraspectsofthe IHCprotocolarealsoofcriticalimportanceinachievingconsistency,includingselectionand validationofanyantigenretrievalprocedure,precisioninvolumeofreagentsappliedtothe slide,choiceandpHofdilutionbuffers,optimizedincubationtimes(atdefinedtemperature), number and effectiveness of wash cycles, and concentration, temperature and incubation timeofthechromogenofchoice. There are at least 25 separate steps in a typical IHC assay. All must be optimized and performedinanidenticalmanner,runafterrun,dayafterday;andideallyfromlaboratoryto laboratory.Inthisrespect,useofanautomatedsystemcangreatlyenhancereproducibility withinalaboratory,whetherusingconcentratedreagentsandselfoptimizeddetectionsystems,orRTUs.TheuseofRTUshasanadditionalbenefitformanylaboratoriesinthatitforces standardizationofreagents,dilutions,detectionsystems,andoverallprotocolamongdifferentlaboratoriesusingthesamesystem[4].Internalconsistencyismorereadilyachievedwith RTUsthanwithuseofconcentratedreagents,becauseoftheinherentvariabilityinoptimizationofthelatteramongdifferentlaboratories.Furthermore,asseverallaboratoriesadoptthe sameRTUs,detectionsystemsandprotocols,improvedstandardizationwillresult,againstthe remainingmajorvariableofsamplepreparation.

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Use of controls
TheproperuseofappropriatecontrolsisvitaltoallIHCassays,andshouldincludeapositivecontrol,andanegativecontrol.Inpracticethepositivecontrolisusuallyatissuesection fixedandprocessedinsimilarmannertothetestsectionandknowntocontainthetarget molecule,ideallybaseduponindependentassay,butmoreoftenbaseduponpresumptive presenceofthetargetmoleculederivedfromknowledgeoftheliteratureandpriorexperience.Positivecontrolsideallyshouldbeselectedforgivingarangeofintensityofreaction, fromstrongtointermediatetoweak;useoftissuecontainingveryhighamountsofantigen mayleadtoselectionofoptimalworkingdilutionsthatfailtodetectlowerlevelsofthetarget antigenfoundinother(pathological)tissues.Thetermnegative control,coverstwocontrol concepts;anegativereagentcontrol,typicallyomittingtheprimaryantibodyonaparalleltissuesectionthatotherwiseistreatedidentically,andanegativetissueorcellcontrol,typically omittingtheprimaryantibodyonaparalleltissuesectionthatotherwiseistreatedidentically, andanegativetissueorcellcontrol.Inpracticethelatterrequirementisinmostcasesfulfilled by identification of non-staining cell types within the test section, that is cells that do not containthetargetmolecule,anddonot,thereforegivepositivereaction[4].

Analytic skills
Theexperienceandtrainingofthetechnologistwhoisperformingthestainclearlyarecritical to this process. One major factor in ensuring reproducibility may be the growth of automation, with the extended capability for consistency and control that is inherent in the automatedprocess.Theavailabilityofautomatedimmunostainerhasprovenoverallbenefit inmanysmallerlaboratories,ifnotsomelargerones,thatdonothavetheluxuryofhighly skilledstaffswhoareexperiencesinreagenttitrationandqualitycontrol[2]. Theinterpretationandsignificanceofthefindingshouldbepresentedinthecontextof theoveralldifferentialdiagnosis.Interpretationofthepresenceofspecificpositivestaining,or lackthereof,is,ofcourse,acomplexissue.Itisafunctionoftheperformanceandexamination ofthepropercontrolsandexaminationofthepropercontrolsandtheexperienceofthelaboratoryperformingthestains,especiallythepathologistresponsibleforevaluatingthestained slides.Asecondaspecttointerpretationrelatestothewaywearriveatanopinionregarding thesignificanceofaparticularsetofstainingresultsinrelationtodiagnosisorprognosisof the patient. Most surgical pathology publications now incorporate immunohistochemical findingstosomedegree.Tokeeppacewiththerelevantliteratureisachallengethatisimpossibletomeetinbroadperspective.TheprototypicWebsite,pioneeredbyDennisFrisman[9], mayprovideprecedentforthefuturebutsuffersfromselectivityofcontentandplacesgreat demandsontheWebmasterformaintenanceofcurrency.

Conclusion
TherehavebeenseveralschoolsofthoughtastothereasonwhyIHCstains aredifficultto runinareproducibleorconsistentmanner.Ifthereisaconsensusastothecauseoflackof standardization,itisthatseveralreasonsconspiretogether.Resolutionofpre-analytic issues

30

(samplepreparation,fixation)willrequireanorderofgeneralcollaborationhithertounseen, evenshouldtherebeagreementastowhichnewandbetterfixativetouse. IHCmustbeperformedonlywithadegreeoftechnicalrigorandcontrolthatmatchesany otherimmunologicallybasedassayoflikeprinciple(namelyELISA).LikeELISA,RTUscoupled withprovendetectionsystems,fixedprotocols,recommendedcontrolsandautomation,representananalogouspathwaythatcanleadtoimprovedlevelsofreliabilityandperformance ofIHC.Collectively,theseprocessesalmostcertainlywillelevatestandards,buttoadegree theyareperipheraltotheproblem.

References
1. TaylorCR(2006).Quantifiableinternalreferencestandardsforimmunohistochemistry:themeasurementofquantitybyweight.AppliedimmunohistoMolMorph14:253-259. 2. Taylor CR (2000). The total test approach to standardization of immunohistochemistry. Arch PatholLabMed124:945-951. 3. TaylorCR,CoteRJ(1997).Immunohistochemicalmarkersofprognosticvalueinsurgicalpathology.HistolHistopathol12:1039-1055. 4. TaylorCR(2009).Immunohistochemicalstandardizationandready-to-useantibodies.In:George LK,RudbeckL,editors.IHCstainingmethods.Dako,Northamerica;California.pp21-28. 5. ShiSR,CoteRJ,ChaiwunB,YoungLL,ShiY,et.al(1998).Standardizationofimmunohistochemistry based on antigen retrieval technique for routine formalin-fixed tissue sections. Appl Immunohistochem89-96. 6. ShiSR,KeyNE,KalraKL(1991).Antigenretrievalinformalin-fixed,paraffinembeddedtissue:An enhancementmethodforimmunohistochemicalstainingbasedonmicrowaveovenheatingof tissuesections.JHistochemCytochem39:741-748. 7. TaylorCR(2006).Standardizationinimmunohistochemistry:theroleofantigenretrievalinmolecularmorphology.Biotechnic&Histochemistry.81:3-12. 8. MillerRT,SwansonPE,WickMR(2000).Fixationandepitoperetrievalindiagnosticimmunohistochemistry:Aconcisereviewwithpracticalconsiderations.ApplImmunohistochemMorphol 8:228-235. 9. FrismanD.Immunohistoquery.Availableat:http:/immunoquery.com.

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32

Classificationin
surgical pathology

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surgical pathology

Classificationin

Classificationistheactivitythatallowspathologiststoarrange the bewildering morphologic manifestations of disease into comprehensibleorder.However,inspiteoftheamazingsuccess ofpathologyclassification,itisapparenttoeveryonethatdiagnosticdisagreementsarecommon,andthatthatpatientswho exactlyfitintoadiagnosticcategoryoftenhavemarkedlydifferentdiseasecoursesandresponsetotherapy.Thishaspartlyled us shift from phenotypic- clinical framework of diagnosis, into phenotypicmolecular-clinicaldimension[1].

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Asaresultofthisshift,theprocessleadingfrompathologicaldiagnosistotherapeuticdecision making includes an area of increasing molecular diagnostic complexity that, in most instances,isnotdirectlyaddressedbysurgicalpathologists.Thefutureconsequenceofthis trendisclear:conventionalsurgicalpathologywillnotbelessimportant(themorphological characterizationofthediseasewillalwaysbeastartingpointofthediagnosticprocess),but moleculartesting,ratherthanmorphologicalcharacterization,mayprovidethedecisiveinformationfordiagnosisandtreatment.Itisclearthatthepathologyclassificationwillundergo substantial changes to include molecular dimension (e.g., Breast malignancies, Leukemias, Braintumors,etc.),andmoleculartestingwillaffectareasofdiagnosticdecision-makingthat arecurrentlywithintheexclusiverealmofmorphologists[2]. Geneticstudieshaverevealedthattherearedifferentpathwaystoasuccessfulphenotype, and, therefore,looks like does not always mean geneticallyclosely related to [3,4]. Diagnosticresolutionischangingfromcomparisonsofcellsizetoidentificationofsinglenucleotidepolymorphisms(variationsharedbyatleast1%ofthetargetpopulation).However,new moleculartechnologywillreplacethemicroscopebasedpathologistonlyiftheknowledge produced by this technology is more valuable in clinical setting and more cost effective. Unless political or economic pressures force diagnosis into selected centres of excellence, aclassificationsystemcanbeconsideredsuccessfulonlywhenitcanbeusedcorrectlyina broadrangeofpracticesettings.

Precision and accuracy

Despite the availabilityof miraculous new tools to assistinclassification, pathologists continuetostrugglewithissuesthatareanalogoustothosefacedbyancientandmoremodern taxonomists.Measuresofaccuracyandprecisionaretwoquitedifferent,basicmethodsofassessingtheclinicalusefulnessofaclassificationsystem.Precisionisthemeasureofthedegree ofintraobserverandinterobservervariationinassigningacasetoagivendiagnosticcategory, whileaccuracyistheclosenessofthediagnosistothetrueclinicalstate,encompassingsuch featuresasclinicalmanifestations,clinicalcourse,andresponsetotherapy. Itisimportanttorecognizethatwhetherdiagnosticagreementiswithpeergrouporwith oneormoreexperts,agreementissimplyagreement,andnolevelofagreementtransforms precisionintoaccuracy.Acceptingagreementisnothingmorethanadangeroussubstitute foraccuracy.Whenobjectiveclinicaldatasuchasadistinctiveclinicalcourseoradistinctive responsetotherapyarenotavailabletoestablishaccuracy,pathologyprecisionmayhaveto serveasasurrogateforhowthepatientfeels,functions,orsurvives[5].Ifsupposeallpathologistsagreewithacertaindiagnosisonacase,butthebiologyofthepatientsdiseasedoes notconformtothatofothermembersoftheassigneddiagnosticcategory,thediagnosisis precisebutnotaccurate.Incontrast,adiagnosticcategorythatlacksprecisioncannotbeaccuratebecausepatientsarenotassignedtothecategoryinaconsistentfashion.So,imprecise categoriescanexistintherealmoftextbooksorclassificationschemes,butwithoutprecision, theydonotexistasaclinicalreality. Inasense,theyarepathologyfiction,whichisasubtypeofsciencefiction.Itisonlythrough thepossessionofdiagnosticprecisionthatatheoryistransformedintoadiagnosticcategory thatcanbethenstudiedandclinicallydefined.Asetofrulesfordiagnosisdoesnotestablish ascientificpedigreeforacategory,becausetheapplicationofrulestoproblemsiscommon

35

to both scientific and non-scientific activities.True scientific rules should not be falsifiable, andbecausetheydonotrequireanyprivateinterpretationordivineinspiration,shouldgive similarresultswhenusedbytrainedindividuals.Mostimportant,thereisnostandardforjudgingwhatlevelofdiagnosticdisagreementisclinicallyacceptable.Thecentralityofprecision toscienceishighlightedbytheannualIgNobelPrizeceremony,whichshowcasesworkthat eithercannotorshouldnotbereproduced[6].

Types of classification
Tounderstandclassification,thepathologistmustunderstandthefundamentaldistinctions betweendifferenttypesofclassification.Oneimportantsubtypeofclassificationiscategory assignment.When performing diagnostic category assignment, the pathologist deals with categoriesthataregiven,andtherulesforsortingareunambiguousandinplace.Thecommondenominatorofassignmentisnotthatitissimple,butratherthatoncethediagnostic dataiscollected,theyareunambiguousandleaddirectlytoonediagnosis. Incontrastwithcategoryassignment,othertypesofclassificationrequirethepathologist todealwithexceptionsornewconfigurationofdata.Atoneextreme,classificationrequires thatbothcategoriesandtherulesforassignmentbedevelopedfromscratch;thereareno establishedassignmentrulestoviolate[7].Attheotherendofclassificationisstructuredclassification,whichbeginswiththeacceptanceofasetofcategoriesanddiagnosticrules.When casesareencounteredthatdonotfollowtherulesorfitthecategories,thepathologistmakes modificationsintheexistingframework. Pathologistsusuallyareengagedinassignmentbehaviourbutmustoccasionallyswitch to structured classification activities when rules must be modified before assigning an unusual case to an existing category. In pathology, as in other branches of science, the truth lies somewhere in sociology and science, Understanding pathology classification requires understandingthatthesesystemsaredevelopedthroughapoliticalprocess.

What is the best classification?

Epidemiologistswillbeinterestedinetiologyandepidemiology;pathologistsinmorphology, postulatednormalcellularcounterpart,immunophenotype,andgenetics;cliniciansinprognosis,distinctiveresponsestotherapy,andclinicalfeatures.Surgicalpathologyhasremained heavilydependentonexpertstoprovideagoldstandardforwhatiscorrectandwhatisincorrectclassificationassignment.Thisproblemofidentifyingvalidclassificationgoldstandards hasprovenparticularlychallengingforthespecialityintheareaofearlydiagnosis,wherelinks betweentissueclassificationandoutcomeareincreasinglyobscuredbythemurkyconcepts ofpredispositionandrisk[8,9,10]. Predispositiondiagnosesaredesignedtoreducetheincidenceofadvanceddiseaseina population, not to predict the specific outcome for an individual patients.When increases inscreeningsensitivityabruptlypresentedsurgicalpathologistswithlargenumberofcases withearlychangesofmalignancy,thespecialityhadthestarkchoiceofeitheradmittingthat even experts did not really understand the significance of these new lesions flooding into theirlaboratoriesorcontinuingtoclassifypoorlyunderstoodlesionsasmalignancybasedon

36

historicdiagnosticcriteria[5].Ashort-termchoicetoclassifylesionsofloworuncertainbiologicalpotentialascarcinomawhilethingsgotsortedoutwouldhavebeenunderstandable becausesurgicalpathologyisafieldwithnofoundationinstatisticsorepidemiology.Inthe future,diagnosticadvancesmaypresenttheoncopathologistwithmoreexamplesofclinicallyhealthyindividualsfoundtohaveafewcellsthatsharesomemorphologicormolecular featureswithestablishedmalignantcellpopulation[11]. Neitherthepatientnorthecliniciancareswhetheratumourformsglandsormakeskeratin,butbothwouldlikeinformationthatleadswithhighestdegreeofcertaintytocurrently availableefficacioustherapy,i.e.,apatientmanagement-drivenclassificationsystem.Pathologistratherthanbeingsimplyataxonomist,shouldactasapatientadvocatesensitivetothe clinicalimplicationsofdiagnosticcategories.However,onefindsthatinpractice,agoldstandardthatheavilydependsonclinicalrelevanceisquitedifficulttomaintain.Inapatientcare environmentwheretherapyiseitherchangingorvariablefromcliniciantoclinician,clinical relevancecanbeonemorefactoraddingemptycomplexitytotheclassification.Evenwhen largelybasedonthefeaturesofcells,aclassificationsystemmustacknowledgeandaccommodatethistruththatthetaskathandispatientcare.

The design of classifications

Inthepast,individualsintroduced,promoted,anddefendedclassificationsystems,andsometimesthereseemedtobemoreattentionpaidtodocumentingpriorityorjoustingwithrivals thantodocumentingeitherprecisionoraccuracy[12].Ideallyexpertgrouponclassification, should be multidisciplinary, should base recommendation on a systematic review of publishedwork,andshouldexplicitlystatetherationaleandthestrengthoftheevidencethat supportseachrecommendation[13].Stilltherecouldbelimitationtoclassificationsystem; foursuchimportantlimitationsare

1.Datalimitations
One of the most basic problems that must be confronted in classification is that the data themselvesdonotresolvetheconflictbetweenlumpersandsplitters.Theonlyrationallimitationonthesplittersisthatthenumberofcategoriesshouldnotexceedthenumberofcases availableforclassification.Incontrast,thelumpersarelimitedonlybytheconceptualproblemofhavinglessthanonecategory.Whendevelopingclassificationschemes,oneoptionis tonarrowlyfocusthedefinitionofcategoriessothatdonoteverycasemeetsthecriteriafor inclusionisverysimilartoeveryothercase.However,giventhenatureofbiology,thisoften eitherwillleavemanycasesthatdonotpreciselyfitthecriteriaforanycategoryorwillrequirelargenumberofcategorieswiththeattendantcomplexityandimprecision.Incontrast, ifthecriteriaforcategoriesarebroad,almosteverycasewillfindacategoryhome,butthe categorieswilloftencontainaveryheterogeneousgroupofpatients,essentiallydefeating thepurposeofclassification.

37

2.Self-interest
Like all other aspects of science, classification systems are the products of individuals who haveastakeintheoutcomeoftheirwork.Thedegreetowhichaclassificationsystembecomesinfluentialcontributesdirectlytotheprofessionalstatusoftheindividualsinvolvedin thesystemsdevelopment.Onemechanismtodecreasetheimportanceofself-promotionis toincludeasparticipantsinthedevelopmentofclassificationsasubstantialpercentageof individualswhoarenewtotheprocess[5].

3.Consensus
Achievingconsensusisasmuchasocialasascientificprocess.Sinceeventhebestevidence includeselementsofuncertainty,consensusconclusiondemandsjudgement.AWHOcommittee on Histologic typing of tumours includedmany years of unsuccessful negotiations anddeliberationsaccordingtooneoftheparticipants[14].Whenconsensusisagoal,then lackofconsensusisfailure.Alogicaltechniquetoavoidfailureistoexcludeindividualsknown tohaveopinionsoutsidethemainstreamorcontrarytothoseofthegrouporganizingthe conferences.Butthisconsensusmaybeasimplificationofthecurrentstateofknowledge. Thosewhobelievethattheirinputwasnotgivensufficientweightwillperceivetheconsensuscommitteesconclusionasillegitimate[14].

4.Compliance
Howdoesanexpertcommitteeconvincethousandsofgeographicallydispersedindependentpractitionerstoadoptthenewsystem?Clinicalstudieshavesuggestedproblemswith complianceifthereisalackofanaccountabilitycomponentorifthereisarelianceonvoluntarychangewithoutaccompanyingincentives[15].

Conclusion
Inouropinion,thetermFinalDiagnosisbestsuits,wellwrittennovelscriptsratherthana pathologyreport.ThefinalwordshouldalwaysendwithImpressionorOpinionjusttoaccommodatetheriskofjudgementalerror.Adiseaselabelledcanperhapsbeconsidereda diseasehalfconquered,butadiseasemislabelledissurelyadiseasethatwillremainmisunderstood.Aspecialitysweaktiestothescientificmethodareprovidedbyveryslowrecognitionoferror[16]. Aclassificationofeacherarevealjusthoweffectivelypathologistsworkingatthattime wereabletoseparate,precedent,contemporarypolitics,andsuperstitionfromscientificevidence.Ideasshouldbejudgedbywhethertheywerereasonableinthehistoriccontextin whichtheywereproposed.Successfuladvancesindiseaseclassificationareachievedthrough theevolutionarymechanismsofselectionactingonvariation.

38

References
1. Salto-TellezM(2007).Acaseformorphomoleculardiagnosticpathologists.Clin.Chem.53:11881190. 2. HeffnerDK(2001).Theendofsurgicalpathology.AnndiagnPathol5:368-373. 3. KenrickP(1999).Thefamilytreeofflowers.Nature.402:358-359. 4. SrinivasanMV(1999).Whenoneeyeisbetterthantwo.Nature.399:305-307. 5. FoucarE(2001).ClassificationinAnatomicpathology.AmJclinPathol116:S5-20. 6. NadisS(1999).IgprizesspawnanewgenerationofNobels.Nature401:518. 7. HandDJ(1997).ConstructionandAssessmentofclassificationrules.NewYork,NY:Johnwiley& Sons.Pp1-20. 8. Evans JS (1999). Reviewer. Calculating the chances. Review of: kammen DM, Hassenzahl DM. Shouldweriskit?Science.285:1857. 9. FoucarE(1996).Carcinoma-in-situofthebreast:havepathologistsrunamok?Lancet347:707708. 1 0. FoucarE.Dopathologistplaydice?Uncertaintyandearlyhistopathologicaldiagnosisofcommonmalignancies.Histopathology.31:495-502. 1 1. SchnittgerS,WormannB,HiddemannW,(1998).PartialtandemduplicationsoftheMLLgene aredetectableinperipheralbloodandbonemarrowofnearlyallhealthydonors.Bllod92:17281734. 1 2. DorfmanRF(1974).Classificationofnon-Hodgkinslymphomas.Lancet.2:961-962. 1 3. MillerJ,PetrieJ(2000).Developmentofpracticeguidelines.Lancet355:2172. 1 4. SusterS,MoranCA(1999).Thymomaclassification:therideoftheValkyries?AmJClinPathol. 112:308-310. 1 5. SmithTJ,HillnerBE(2001).Ensuringqualitycancercarebytheuseofclinicalpracticeguidelines andcriticalpathways.JClinOncol.19:2886-2897. 1 6. PlattJR(1964).Stronginference.Science146:347-353.

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40

Postanalytic
phase

41

Postanalytic
phase
Post-analyticphaseofthetestcyclebeginswithdictationofthe grossandmicroscopicexaminationandthefinaldiagnosisand includestranscription,reportcorrection,verification,andreport delivery [1].The use of summary checklist has been shown to beveryeffectiveinprovidingmorecompletereports[2].TATis acriticalelementofqualityandusuallycoversallaspectsofthe laboratory test cycle.WhileTAT may be fragmented into smallercomponents,thetotalTATistheonlymeasurebywhichthe clinician or customer will judge the pathology report. Smaller components, however, are important to understand when an intervention is planned to improve the totalTAT. Post analytic parameterscanbegroupedintothreeindicators:

42

a.Technicalissuesrelatedtolaboratory b.Totalturnaroundtime(TAT) c.Cliniciansatisfactionand/orcomplaints(table1). Table 1.Postanalyticindicators. S.No Technicalissuesrelatedtolaboratory Transcriptionerrors Verificationerrors Reportdeliveryerrors Incompleteerrors Diagnosticfindingcorrelationwithancillarystudies(IHC,EM,FISH) Turnaroundtime(TAT) Frozensection Biopsy Largespecimen Preliminaryandfinalnecropsyreports Cliniciansatisfactionand/orcomplaints Interpersonalrelationbetweenclinician&pathologist Diagnosticaccuracy Frozensectiontimelinessandaccuracy Reporttimeliness Reportcompleteness Pathologistavailability Recentchanges

1.

2.

3.

Customerorcliniciansatisfactionisprobablyoneofthemostimportantmeasuresofqualitybecauseitlendsinsightintoacliniciansperceptionofthepathologyreport.Whilethere aremanyelementsthatwhencombinedadduptoaqualityreport,cliniciansatisfactionis alsobasedontheadditionalfactorofexpectation[3].Thusalaboratorymayhaveaccurate, timely,andcompletereports,yetaclinicianmaystillhavetheperceptionofpoorqualityif they have unrealistic expectations. Therefore, in addition to managing and monitoring all elementsofquality,thepathologistmustalsomanageclinicianexpectationsandmakesure thattheyarerealistic.Withoutsomeefforttoobtainclinicianfeedback,someproblems,at leastfromthecliniciansperspective,mayneverbeidentified.

Quality assurance consultation

Theexperienceofthepathologisthasanimpactontheprecisionofthepathologyfindings. Pathologistschoosingtopracticewithinadistinctsub-specialityacquireafundofknowledge

43

during fellowship training that extends beyond anatomic and clinical pathology residency training. Additionally, sub-speciality pathologists, when defining their practice exclusively within their area of expertise (accepting specimens limited to their area of speciality) may review significantly greater numbers of cases over a shorter period of times as compared to general pathologist - complementing deeper fund of knowledge with rapidly acquired experiencemeasuredintenstohundredsofthousandsofcases. Withinageneralpathologysetting,anindividualpathologistmayreviewatotalof6000 caseseachyeardistributedamongeachoftheorgansystems:30%gastrointestinal,25% skin,20%urologic,15%breastandgynaecological;and10%amixtureoftheremainingorgan systems.That translates to an approximate case experience of 1,800 gastrointestinal; 1,500 skin;1,200urologic;900breastandgynaecological;and600othercaseseachyear.Forcomparison, experienced gastrointestinal pathologists who selectively practice gastrointestinal pathologymayreview10,000caseseachyearwithall10,000casesgastrointestinalspecimen[4].Interpretiveerrorreductionstrategyshouldbepartofqualityassuranceprogramme (Table2).

Table 2.Interpretiveerrorreductionstrategies:typesofobserverredundancy.

ouble-read:generalsign-outwithintradepartmentalconsultvoluntary,individualdiagnostic D thresholdsmandatedbyorgan,diagnosis,orpercentofcasesblindedorpublicreview,by individualorpanelselectedslideorentirecase Correlationreview Conference/Tumourboardreview Extra-departmentalconsult Institutionalreview(Outsidecases)

Effective communication
Evidencesupportingthehighvalueofclinician-pathologistcommunicationforplanningthe bestclinicalmanagementforpatientswithmalignantdiseaseofallstagesmayconsistently befoundinstudiesevaluatingtheimpactofmultidisciplinaryconferences(MC)ortumour boards (TB) [5,6]. Consultative discussions among all physicians (including radiologists and pathologists)onthepatientcareteamtakeplace,withapatientmanagementplanasthe outcome.Thespecificactivitiesshouldinclude,reviewofpreviousradiologicandpathologic testresultswithreviewofoutsidematerialsbyin-houseradiologist,pathologistandamultidisciplinarydiscussionaboutthediagnosticandmanagementaspectsofcase. Thisenhancedcommunicationamongmultiplespecialityphysicianshasbeenshownto resultinsignificantnumbersofchangesinboththetypeandstageofreviewedcases.The occurrence of these discussions in cancer centre settings has also shown to positively impactpatientreceiptofmanagementbestpractices[7].Patientsshouldbegivenopportunity todiscusshis/herdiagnostictestinganddiagnosiswiththeparticipatingpathologist(s)and radiologist(s)[8].Therefore,duringfacetofaceverbalcommunicationamongphysician,clini-

44

calinformationalsoappearstobeexchanged,andthatexchangecontributestochangesin diagnosticandprognosticinformation,whichthenmayproducechangesinpatientmanagement.Thereisadefinitepositiveimpactononcologicdiagnostictestaccuracyandpatient managementdecisionsmadeinformal,structuredforumforinterdisciplinaryphysician-physiciancommunication[7].Noevidenceiscurrentlyavailablethatdescribestheimpactofindividualclinician-pathologistdialogueduringroutinedailypracticeonpathologicdiagnoses orclinicalmanagementplansforpatientswithmalignancies.

Different review methods

1. ubspecialistreviewmethod S Manylaboratoriesandhealthcareinstitutes,inanefforttoincreasequalityandreducediagnosticinaccuracy,haveadoptedpartialorcompletesub-specialitypathologistsign-outcases. This distribution and review of cases represents a significant cultural and system change fromthegeneralpathologist-drivenpathologypractice,inwhicheverypathologistsignsout everytypeofcase.Manycliniciansacceptsub-specialitysign-out,thepatientandclinicianexperiencethebenefitofpathologistspracticingwithalimited,butspecializedskillset,generallycomplementedbytheuseofstandardizedterminologycommontoboththepathologist andtheclinicianspecialist.Sub-specialitypathologistreviewofcasesmayresultinconsistent adherencetoestablisheddiagnosticcriteria,pathologistsabilitytocorrelateobjectivepathologictissuedatawithsubjectiveandobjectiveclinicalinformation,andtheabilitytoprovide acommonlanguagetofacilitateeaseofcommunicationofthepathologyreport. 2.Consultativereview Consultativereviewofpathologymaterials(secondopinions)isanessentialcomponentof totalqualityassuranceprogramsindiagnosticsurgicalpathologyandcytopathology[9].This keyaspectintheassuranceofpatientssafetyfortissue-andcytology-baseddiagnosesislikely tobethemostaccurateandcost-effectivewhenaprogramcombines: rospectiveintradepartmentalreviewofcases, P etrospectiveintradepartmentalreviewofdiagnosesrendered, R elected utilization of inter-institutional second opinions referred to pathologist with S sub-specialityexpertisewithinspecificorgansystemanddiseasecategories,and andatory review of pathology materials in which the diagnosis was reported at exM ternal institutions when patients are referred for definitive therapy within thehome institution[10]. Whilethesecomponentsofqualityassuranceprogramsmayappearself-evidentoruniversallyaccepted,self-reportingsurveysofacademicandcommunityhospitalsdemonstrate thateachofthesemeasuresisperformedconsistentlywithinthepathologydepartmentof only30%to65%ofinstitutions[11].

45

3.Intra-departmentalconsultation The elements of quality assurance consultation is most essential within department, institution, or organization can be assessed by compiling and/or requesting specific reports of consultationactivitiesbypathologists;policiestoincorporate: andatorysecondpathologistreviewwhenindicatedbycurrentstandardofcare(any M malignancy,highgradedysplasiainBarretts,anydysplasiainIBD,andothers). onsensusconferenceactivitieswithinthedepartmenttosetstandardsandthresholds C for diagnosis. Documenting altered judgemental reports based on clinical findings & patientssafety. rospectivedocumentedandconfidentialpeerreviewofchallengingcasesrecording P minorandmajordiscrepancieswithinthedepartment. etrospectivereviewof2%ofallcases,randomlyselected,orselectedbyorgansystem R forsystematicreview. nquiriestothepathologistanddepartment: I 1. hich pathologists have subspecialty expertise in which organ system and/or disW ease?Isthisformalorinformaltraining? 2. stheintradepartmentalconsultationdirectedtopathologistswithsub-specialityexI pertiseordistributedamongthepathologistsinanothermanner? 3. hataretheratesofminorandmajordiscrepanciesamongthepathologist? W 4. Howarethediscrepanciesresolved? 4.Extra-departmental(Inter-institutionalreview) andatoryreviewofanyoutsidepathologymaterialsuponwhichadefinitivetherapyis M plannedwithinareferralinstitution. xternalconsultationbysub-specialitypathologistsrequiredonnolessthan0.5%ofall E cases.Withinacommunityhospitalwith20,000caseseachyear,thisresultsin100cases forconsultationeachyear;roughly2casesperweek[4]. nquiriestothepathologistanddepartment: I 1. hatistheratioofinter-institutionalconsultationperformed(a)attherequestofthe W patient;(b)attherequestoftheclinicians;(c)attherequestofthetreatinginstitution and(d)attherequestofthepathologistrenderingtheoriginaldiagnosis? 2. oesthepathologydepartmentutilizeaspecificsetofpreferredconsultantswhoare D recognizedexpertswithineachsubspeciality? 3. lternately,dothereferralcasesgetsenttotheuniversity,withoutspecifyingaconA sultantpathologist? 4. hatistherateofdiagnosticagreement?Minordisagreement?Majordisagreement? W Withtheconsultingpathologist? 5. redisagreementsdiscussedwithin-housepathologist?ArehisexplanationsdocuA mented? 6. owarethesediscrepanciesresolved? H

46

Conclusion
Clinicalcolleagueshavetwobroadexpectationfromtheanatomicpathologist.Firstisverificationofdiagnosis.Cliniciansexpectpathologyconsultantstohavereviewedandcorrelated previouspertinentdiagnosticmaterialandtoinformthemofclinicallyimportantdiscrepancies or clinical opportunities.The second major expectation is that pathologist will consistentlyprovideinformationtoroutinelysatisfyclinicalneeds[12]. Inmanycases,aclinicianwantstheresultinblackorwhite,whichmaynotbepossible withpresentknowledgeofparticulardisease.Therefore,simplificationoftheresultissometimescalledfor,despiteallskillsandknowledge,thepathologistisexpectedtoknowofthe artandsciencebehindthepathologyreport.Documentationoftheseartsonlongrunwill addvalueinhealthcaredeliverysettingandformulatinglegalboundaries.

Reference
1. Fitzgibbons PL (2005). Post analytic variables: report adequacy and integrity. In: Nakhleh RE, FitzgibbonsPL,editors.Qualitymanagementinanatomicpathology:promotingpatientssafety throughsystemsimprovementanderrorreduction.Northfield:thecollegeofAmericanpathologists,pp61-65. 2. Branston LK, Greening S, Newcombe RG, et al (2002).The implementation of guidelines and computerized forms improves the completeness of cancer pathology reporting. The CROPS project:arandomizedcontrolledtrialinpathology.EurJCancer38:764-772. 3, ZarboRJ,NakhlehRE,WalshM(2003).Customersatisfactioninanatomicpathology;aCollege of American Pathologist Q-probes study of 3065 physician surveys from 94 laboratories. Arch pathollabMed.127:23-29. 4. DahlJ(2006).Quality,Assurance,Diagnosis,Treatment,andPatientCare.Patientssafety&Quality healthcare.http://www.psqh.com/. 5. GatcliffeTA,ColemanRL(2008).Tumorboard:morethantreatmentplanning-a1yearprospectivesurvey.JcancerEdu.23:235-237. 6. PettyJK,vettoJT(2002).Beyonddoughnuts:tumorboardrecommendationsinfluencepatient care.JcancerEdu.17:97-100. 7. RaabSS,GrzybickiDM(2010).Qualityincancerdiagnosis.CaCancerJClin60:139-165. 8. NewmanEA,GuestAB,HelvieMA,RoubidouxMA,ChangAE,etal(2006).Changesinsurgical managementresultingfromcasereviewatabreastcancermultidisciplinarytumorboard.Cancer.107:2346-2351. 9. TomaszewskiJE,BearHD,ConnallyJA,EpsteinJI,FeldmanM,etal.(2000).Consensusconference onsecondopinionsindiagnosticanatomicpathology:Who,whatandwhen.AmJClinpathol. 114:329-335. 1 0. SarewitzSJ(n.d.)Laboratoryaccreditationprograminspectionchecklists.CollegeofAmerican pathologist.http://www.cap.org/. 1 1. GuptaD,LayfieldLJ(2000).Prevalenceofinter-institutionalanatomicpathologyslidereview:a surveyofcurrentpractice.AmJSurgpathol.24:280-284. 1 2. ZarboRJ(2000).Theoncologicpathologyreport.ArchpatholLabMed124:1004-1010.

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48

Errortaxonomy
and validation

49

Errortaxonomy
and validation
There are four general types of errors, with 3 sub-types in the categoryofdefectiveinterpretation[1]. 1. hefirstsubtypeisafalsenegativediagnosisorundercallof T theextentofseverityofalesion. 2. Thesecondisafalse-positivediagnosisoranover-call. 3. Thethirdsubtypeismisclassification(Table1).

50

Whenerrorisdetected,amendmentoptionsincludechangesin(a)theprimarydiagnostic characteristics(eg,changefromnegativetopositive,benigntomalignant,orinadequateto adequate);(b)theseconddiagnosticcharacteristics(eg,tumourgrade,stage,margin,ornode status);(c)diagnosticreclassification(eg,thefibrosarcomachangedtomalignantfibroushistiocytomainwhichprimaryorsecondarydiagnosticchangedoesnotaltertheprognostic impactoftheclassification);(d)patientorspecimenre-identification;(e)reportofadditional specimensamplingthathadresultedinthechangedreport;and(f )othereditsofthereports thatdonotchangeprimaryorsecondarydiagnosticinformation,patientorspecimenidentification,orinvolvespecimencharacteristics. Table 1.Commonerrortypesinalltotaltestcyclephase. S.No DefectiveIdentification Patient Tissue Laterality(rightvs.left) Anatomiclocation DefectiveSpecimen ostspecimen,inadequatevolume,size,grossdescription,erroneousmeasurementor L extraneoustissue. Inadequaterepresentativeness/sampling(tissue,blocks,levels) Pertinentancillarydiagnosticstudynotinitiallydone. Defectivereport Erroneous/missingnon-diagnosticinformation Dictation/Typingerror Reportdelivery Computer/format,transmission,uploaderror DefectiveInterpretation FalsenegativeUndercall FalsepositiveOvercall Mis-classification:notalteringprimaryorsecondarydiagnosticcharacteristics -Primary=Positive/negativeorbenign/malignant -Secondary=Grade,stage,margin,ect.

1.

2.

3.

4.

Timingofdiscoverysegregatesintothosecasesdetectedbeforesign-out(beforecaseis finalized)andthosedetectedaftersign-out(afterareporthasbeenproduced). Forchangesdetectedbeforesign-out,fourmechanismsarepossible:theeffectof(a)additionalinformationormaterial;(b)intradepartmentalreviewbeforesign-outordoubleread ofthecurrentcase;(c)preparationforpresentationataconferenceoratreviewwithclinician; and(d)anexternalconsultation. For the revisions after sign-out, possible mechanisms are: (a) The responsible pathologistsreviewofarecentcasewithoutadditionalinformationormaterial;(b)theresponsible

51

pathologistsreviewofarecentcasewithadditionalinformationormaterialbutwithoutclinicalprompting;(c)atpreparationorpresentationatconferencewithclinicians(e.g.,tumour board);(d)clinician-initiatedrevieworreconsiderationofacase;and(e)astheresultofan externalconsultation. A single classification system cannot adequately fulfil the differing needs of these two purposes.Temporalconsiderationsforceasubdivisionoftheevaluationintoaninitialassessment at the time of discovery and follow-up assessment after 3 months of discovery.The classificationofdiscrepancies/errorsprovidedintheRoyalcollegeofpathologistpublication (2006),entitledconcernsaboutperformanceinpathology:guidanceforhealthcareorganizationsandpathologists(Table2). Table 2.Terminology. S.No 1. Adiagnosticerror,whichislikelytohaveadefiniteinfluenceonclinicalmanagement andpossibleoutcome Amisinterpretationoroversight,whichhasthepotentialtoaffectclinicalmanagement oroutcome Aminordiscrepancyofdiseasecategorisation,whichislikelytobeoflittleclinical significance.

2.

3.

However,inNovember2007,Theprofessionalperformancepanel,submittedrecommendationstotheprofessionalStandardsUnit[2].Thesummariesofthatproposalwereasfollows: Definitions discrepancycanbedefinedasadifferenceofopinionbetweentheoriginalinterpretaA tionatreview discrepancycanonlybeconsideredanerrorwhenthediscrepancyisconfirmedby A twoindependentreviewers hatisthepurposetoevaluatediscrepancies? W esponsetoanexpressionofconcernaboutadoctorsperformance:toascertainifthere R is substance to the concerns about a doctors performances, to identify where these concernslieandwhatcouldbedoneabouttheseconcerns. uty care review: to identify patients whose care may have been sub-optimal with a D viewtorectifyanydeficienciesincare.Thisisusuallyundertakenwhenconcernsabout performanceshavebeenestablished. Errorratescanbeheavilyinfluencedbyclassificationsystembutalsointerpersonalrelation withauditingauthority.Performanceandartofpracticearemultifacetedskillsacquiredand influencedbynumeroussocialandscientificfactors.Thus,errortaxonomyandtheclassificationofdiscrepancy(Table3)mayonlyhelptoidentifyproblemsandredesignqualityprocess. Pathologists should recognise that they may be unable to provide a reliable evaluation of patientimpactifworkinginisolationfromtheclinicalcontext;collaborationwithorreviewby relevantclinicianswillbeneededbeforeplansforremedialactionareinitiated.Inthissetting itisimportanttoconsiderallavailableinformation,includinginformationthatbecomesavail-

52

Table 3.Descriptionasperdutyofcarereview Category Noimpactoncare Noharm:erroneousreportnottransmittedorreceived NearMiss:erroneousreportreceivedbutignoredordiscarded Minimalharm(nomorbidity) Delayindiagnosisonly,<3months nnecessarynon-invasivefurtherdiagnosticefforts(e.g.Bloodsampling,radiograph, U computedtomography) Delayintherapyonly,<3months Unnecessarytherapybasedondiagnosticerrorwithoutmorbidity Minorharm(minormorbidity)* Delayindiagnosisonly,>3months Unnecessarynon-invasivefurtherdiagnosticefforts(e.g.biopsy,angiogram) Delayintherapyonly,<3months Delayintherapywithminormorbiditye.g.unnecessarytherapy Moderateharm(Moderatemorbidity)** Moderatemorbidityduetodelayindiagnosisortherapy Moderatemorbidityduetootherwiseunnecessarydiagnosticefforts Moderatemorbidityduetootherwiseunnecessarytherapeuticefforts Majorharm(majormorbidity)*** ossoflimboranorganorfunctionofanorgansystemduetounnecessary L diagnosticefforts Severemorbidityduetodelayedorunnecessarytherapeuticefforts Death

1.

2.

3.

4.

5.

* inormorbidityindicateseffectsandeventsthatcanbedemonstratedobjectivelyandthatdonotrequire M admissiontohospitalorsurgicalinterventionforexample,fever,thrombocytopenia,wounderythema,swelling. ** oderatemorbidityindicateseffectsandeventsthatrequireadmissiontohospitalorsurgicalintervention,but M donotresultindismembermentorlossoflife. *** ajormorbidityindicatesdismemberment,lossofanorganorthefunctionofanorgansystem-anarm/limb, M eye/sight,ear/hearing,speech,ortheuterusofawomanofreproductiveage.

ableaftertheoriginalreportwasproduced.Theevaluationshouldbebasedoninformation andmaterialavailableatthetimethatthereportwasissued. In the context of the evaluation of a doctors performance, information which became availablelaterisirrelevant,unlessthisinformationshouldhavebeenactivelysoughtbeforea reportwasissued;otherwiseexercisetoevaluatepathologistperformance(table4)ismore futileexerciseoffindingscapegoat.

53

Table 4.Descriptionwithregardstopathologistsperformance. Category Inadequatedissection,samplingormacroscopicdescriptionwhererelevant,this shouldbeassessedagainstguidancesuchasthecollegedatasetsandtissuepathways. Itshouldberememberedthatthepathologistissuingthefinalreportmaynothave dissected,describedandsampledthespecimen. Discrepancyinmicroscopy diagnosiswhichoneissurprisedtoseefromanypathologist(e.g.anobvious A cancerreportedasbenign) diagnosiswhichisfairlyclearlyincorrect,butwhichoneisnotsurprisedtoseea A smallpercentageofpathologistssuggesting(e.g.amoderatelydifficultdiagnosis,or missingasmallclumpofmalignantcellsinanotherwisebenignbiopsy) diagnosiswhereinter-observervariationisknowntobelarge(e.g.disagreements A betweentwoadjacenttumourgrades,oranyverydifficultdiagnosis)
(Note:Indecidingwhereaspecificdiscrepancyliesinthisclassification,considerationshould begiventotherangeofresponsesthatmightbeexpectedifthecasewasusedinarelevant interpretiveexternalqualityassessmentscheme.(1)wouldbesurprisingdiagnosisevenfromone participant;(2)wouldbeunsurprisingfromasmallminorityofparticipants;(3)wouldgenerate diagnosessovariedthatthecasecouldnotbeusedforscoring

1.

2.

3.

Discrepancyinclinicalcorrelation Thiswouldrepresentafailuretoanswertheclinicalquestion(ifclearlyexpressedon requestform),despitethatanswerbeingevidentfromthematerialavailable;ora failuretoindicatethataspecimenisclearlyinadequatetoanswertheclinicalquestion.

4.

Failuretoseekasecondopinioninanobviouslydifficultcase Thiswouldimplyover-confidence

5.

Discrepancyinreport Thiswouldincludetypographicalerrorsandinternalinconsistenciesorambiguitiesin thereportwhichshouldhavebeencorrectedbeforeauthorisation.

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Conclusions
In trying to define surgical pathology error, most published studies have focused on diagnosticaccuracy.However,thereiswidespectrumofclinicallysignificanterrorsoccurringin surgical pathology with potential underlying and contributory causes. Examination of the datathatthetaxonomyuncovers,inrootcauseanalyses,maywellrevealthatcasesofmisdiagnosis (the wrong diagnosis for the patient in question) is less often an indictment of thepathologistsdiagnosticacumenthanproblemwithimplementingandanalyzingquality bydesign.Diagnosticerrorsmayalsoresultfromapathologistmakingdiagnosesoninadequately sampled tissue, either at the gross or microscopic level, when additional material provesdiagnostic. Mostoftenclinicianslooktotheirparticularpathologydepartmentalexpertasthegold standard,pathologistsoftenviewextra-departmentalexpertsofchoiceastheultimatemeasureofdiagnosticaccuracy.Extra-departmentalconsultationislimitedasanerrorsurveillance tool,giventhefocusonout-of-theordinarycasesthatmightbefalse-negativediagnoseson review.Itisimportantforanatomicalpathologydepartmenttodocumentandvalidateerror taxonomyinpresentlitigationworld.

References
1. ZarboRJ,MeierFA,RaabSS(2005).ErrordetectioninAnatomicPathology.ArchPatholLabMed. 129:1237-1245. 2. Publications(2006).Concernsaboutperformanceinpathology:guidanceforhealthcareorganizationsandpathologists.www.rcpath.org/publications

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Structural componentofa
quality

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Structural componentofa
quality
A quality assurance and improvement plan is merely a small component in maintaining a quality pathology report. Quality inalaboratory depends ona hostofstructuralandpersonnel factorsthatarenecessary,regardlessoftheQA&I(qualityassurance&improvement)plan.Evenbetter,qualityassuranceand improvementmustbeweavedintoalltheothersystemsofthe laboratorytoachievetheabsolutebestresults.Healthcareorganizations should recognize that an accurate pathology report requiresthecollaborationofpathologists,oncologyspecialists, andotherclinicians[1].

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The eventual performance outcome of anatomic pathology report is highly dependent notonlyontherolesofpathologistsduringtheanalyticphasebutalsoontherolesclinical practitioners play in pre-analytic and post-analytic phases of the total testing process. It is self-evidentthatqualitygapsstillexistduetohumanfactorsinvolvedintheprocess[2].Inthe end,pathologyreportisbasedonhumanjudgementandisnotacomputergeneratedresult. Hence, a healthcare organization should concentrate on human structural components of qualityinsurgicalpathology(Healthcareisbusiness;buttakingcareofapatientishumannature).Thefollowingisadiscussionofcriticalelementsneededtomaintainaqualitylaboratory.

1.Workforce
Flexible, well trained, knowledgeable staffs is key to the success of any organization. This applies to all levels of work within surgical pathology, including pathologists, pathologists assistant,histologystaff,andthesecretarialstaff.Importantaspectofbuildingthestaffare qualification, suitability, sufficient redundancy, and the ability to work with others [3]. Of course, individuals must have the appropriate qualification for the job they are doing, but moreimportantlypeoplemustbesuitedtotheirduties.Individualwiththesamequalificationmayhavevastlydifferentstrengthsandweaknessesandmustbeplacedinpositionsto takeadvantageoftheirstrengths,doingtheoppositeisasurerecipeforfailure.Inbuilding a workforce, sufficient redundancy in skill is critical to assure continuity or work functions arenotaffectedduringanindividualsabsence.Finally,thestaffshouldworktogetherasa team.Theabilitytoworkwithothersiscriticalformaintainingahealthyenvironmentandis beneficialtopatientsafety[4].

2.Continuouseducationandtraining
Medicalknowledgeandtreatmentisconstantlychanging.Themedicalstaffmustconstantly seek out new knowledge and adopt new practices as they become available.These new conceptsshouldbesharedanddiscussedwithcolleagues,andcollectivelyeitheradoptedor rejected.Asindividualsarehiredtheyshouldbetrainedtothespecificpeculiaritiesoftheir jobswithinaparticularorganization.Individualsshouldalsohaveregulartraininginahost ofotherareas,suchassafetyandqualityimprovement,aswellasanyimpendingchangesin theirjobduties.

3.Theabilitytochange
Keytothesuccessofmostorganizationsistheirabilitytorespondtochangesquicklyand effectively.Inherentintheseorganisationsisanabilitytoadaptandchange.Whilethebasis of anatomic pathology practice has not changed significantly over the past half century, changes in the approach to individual diseases are occurring at a much more rapid pace. Breast cancer is a prime example of this evolution.Thirty years ago a pathology report on abreastcancerincludedadiagnosisandlymphnodestatus.Todayareportshouldinclude

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a diagnosis, tumour grade, tumour size, vascular involvement, lymph node status, margin status,anddistancetomarginifnegative,estrogenandprogesteronereceptorstatus,Her2/ neuimmunostain,andpossiblyaFISHresult.Alongthewayseveralotherfactorssuchasflow cytometryandproliferationmarkerswereatonepointthoughttobeimportantandwereincludedinpathologyreports,buthavenowbeenshowntobelesssignificantindetermining outcomeortreatmentandthereforemaynotneedtobeincluded.Althoughatvariablerates, thistypeofevolutionisoccurringinmanydiseaseprocesses.Aqualityanatomicpathology laboratorymustremaincurrentwithallinformationtocliniciansservedbythatlaboratory.

4.Comprehensivecomputersystem
Acomprehensivecomputersystemcangreatlyenhancethequalityofaanatomicpathology laboratory[5].Whileallthenecessarytechnologyisavailable,comprehensivecomputersystemsarerare.Theidealsystemhastheabilitytopulltogetherallthecomponentsofsurgical pathologywithintegratedqualityassuranceandqualitycontrolchecks.Onemayenvisiona systemthatallowedphysicianremoteorderentrysothattheclinicalhistoryismandatedand specimensareaccountedforastheyarrive.Acomprehensivesystemwouldbetiedwithan institutionaldatabasetoconfirmthepatientsidentityataccessionnumberandthepatients nameandanyotheridentifyinginformation.Thesystemwouldprovidetrackingmechanisms throughtheuseofbarcodeorsimilartechnology,sothatallcases,blocks,slides,andreports areaccountedforthroughouttheprocess.Inaddition,barcodetechnologyifusedtoinput dictation and transcription so that misidentification errors are reduced. A comprehensive computersystemcouldcheckandalertifreportshaveincompleteelementsorifcasesare notcompletedwithinareasonabletime.Suchsystemcouldthendeliverreportselectronicallytotheorderingphysicianaswellastoothervenuessuchastumourregistries.Finally,a comprehensivecomputersystemcouldgeneratenumerousqualityreportsinrealtimeand couldofferalertswhensetparametersarenotmet.

5.Standardisedtasksandlanguage
Qualitylaboratorieshavesetpredeterminedstandardisedproceduresthatareeasilyaccessibleandwellknownbythestaff.Akeytoqualityistheeliminationofcompetingprocedures [3].Thisisbeneficialinreducingconfusionoverwhichproceduresshouldbefollowed,but more importantly it leads to tremendous efficiencies in laboratory operations. Employees must be trained in accepted procedures as they are hired, but also regularly updated as proceduresaremodified. Justasimportantisthestandardisationoftermsusedwithinthelaboratoryandincommunicationwithcliniciansandphysiciansofficeoutsideofthelaboratory,includingdiagnostic terminology. Diagnostic terminology is constantly being revised and laboratories must havemechanismstoreviewandupdatediagnosticcriteriaandterminologyannually.Bythe token,thisneedstobecommunicatedtoallwhoarelikelytoencountertheseterms.Toreduceconfusionandenhancecustomersatisfaction,cliniciansshouldbeincluded.

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6.Regulatorycompliance
Finally,itmaybesuperfluoustosaythatalaboratorymustbeinregulatorycomplianceto operate.Ofcoursethisisnecessaryforlicensure,butmoreimportantly,regulatorystandards arehelpfulinguidinglaboratoriestosetuppoliciesandprocedures[6].Forthemostpart regulatory requirements are minimum standards necessary and serve as a foundation for systemsandorganizationalstructurestoachieveahigherlevelofquality.

References
1. NakhlehRE(2006).Whatisqualityinsurgicalpathology?JClinpathol59:669-672. 2. Crawford JM (2007) Original research in pathology: judgement, or evidence based medicine? LabInves87:104-114. 3. SpathPL(1999).Reducingerrorsthroughworksystemsimprovement.InSpathPL,editor.Error reductioninhealthcare.SanFrancisco:Jassey-Bass,pp199-234. 4. Grumbach K, Bodenheimer T (2004). Can healthcare teams improve primary care practice? JAMA.291:1246-1251. 5. BatesDW(2000).Thequalitycaseforinformationtechnologyinhealthcare.BMCMedInformaticsDecisionMaking2:7-16. 6. CarterDK(2005).Regulatorycompliance.In:NakhlehRE,FitzgibbonsPL,editors.Qualitymanagementinanatomicpathology:promotingpatientssafetythroughsystemsimprovementand errorreduction.Northfield:ThecollegeofAmericanPathologists,pp9-31.

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