prostatic carcinoma, usual variant

PROSTATIC CARCINOMA, USUAL VARIANT

Definition• Acinaradenocarcinomaoftheprostateglandisthe

mostfrequentlydiagnosedformofcancerintheUnitedStates.TheNationalCancerInstituteestimatesthatalmost200,000newcaseswilldevelopin2010.

Clinical featuresEpidemiology• Prostatecanceristhethirdleadingcauseofcancer-

relateddeathinmenindevelopingcountries.• Multiplegeneticandenvironmentalfactorsare

involvedinprostatecarcinogenesis.• Age,familyhistory,andracearedefinitiveriskfactors.• Thedegreeofriskisrelatedtotheageandthenumber

oftheaffectedrelatives,withthegreatestriskconferredbyafatherorbrother,withanonsetbefore40yearsofage.

• Racialbackground,withAmericanblackshavinghigherincidence,highergrade,andmoreextensivecancer,mayberelatedtodifferentgeneticandenvi-ronmentalfactors.

• Dietaryfatandsexhormonelevelsareprobableriskfactorsforprostatecarcinoma.

• Manysusceptibilitylociandseveralcandidategeneshavebeenidentifiedforhereditaryprostatecancer.

• Linkageanalysishasidentifiedfewcandidatelociforhereditaryprostatecancer.Ofthem,threegeneshavebeenclonedasRNaseLon1q24-25,HPC2on17p,andMSR1on8p22-23.

Presentation• Mostprostatecarcinomaisasymptomatic.• Approximately70%ofprostatecarcinomaarisein

theperipheralzone,andsomecanresultinabnormalfindingsondigitalrectalexamination.

• Rarely,prostatecarcinomacanleadtourinaryobstructionwhenalargetumorarisesinthetransi-tionzoneorextendsintothetransitionzonefromtheperipheralzoneorinvadesthebladderneck.

• Locallyaggressiveprostatecarcinomainvolvesthebladderandrectumandcancausehematuria,rectalbleeding,orobstruction.

• Rarely,patientsexhibitsymptomsandsignsthatarerelatedtometastaticprostatecarcinomatodifferentanatomicsites,mostcommonlybone,regionallymphnodes,lung,andbrain.

• Currently,mostprostatecarcinomasareclinicallydetectedbyserumPSAscreeninganddigitalrectalexamination.

Prognosis and treatment• Treatmentforprostatecancerdependsonthestageof

thediseaseandthegradeofthetumor;otherimpor-tantfactorsinplanningtreatmentaretheman’sageandgeneralhealthandhisfeelingsaboutthetreat-mentsandtheirpossiblesideeffects.

• Prostatecancercanbemanagedinanumberofways: • Activesurveillance(watchfulwaiting) • Surgery(radicalprostatectomy)

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• Radiationtherapy(externalbeamradiotherapyorimplantationofradioactiveseeds[brachytherapy])

• Hormonaltherapy(surgicalcastration[orchiec-tomy]orpharmacologicblockadeofandrogeneffectwithlutenizinghormone–releasinghormoneanalogsorantiandrogencompounds)

• Cryotherapy• Radicalprostatectomyisconsideredtobethemostreli-

ablemethodoferadicationoflocalizedprostatecancer.• Locallyadvancedprostatecarcinomaisfrequently

managedbyacombinationofradiationandhormonalablation.

• Theprognosisforpatientswithprostatecarcinomaishighlyvariableanddependsonavarietyofhost,tumor,andtreatmentparameters:

• Forprostatecancer,limitedtotheprostate(stagesIorII)andwellormoderatelydifferentiated(Glea-sonscore3+4=7orless),the5-yearoutcomeisconsideredtobeexcellent.

• Biochemicalrecurrenceoccursinapproximately11%to13%ofpatientswithclinicallylocalizedprostatecancertreatedwithradicalprostatectomy.

• TheoverallPSArecurrence-freesurvivalratesare84%and83%at3and5years,respectively.

• Theactuarialprobabilityofremainingprogression-freeat5and8yearspostoperativelyis78%and71%,respectively.

• Whenstratifiedbypathologicstage,5-yearfreedomfromprogressionofdiseaseafterRPwas83%and69%forpT2andpT3,node-negativeprostatecancer,respectively.

PathologyHistology• Threehistologicfeaturesarediagnostic(cancer-

specific)ofprostatecarcinoma,becausetheyhavenotbeendescribedinbenignglands:

• Mucinousfibroplasia(collagenousmicronodules)occursasdelicatefibroustissuewithingrowthoffibroblastswithinoradjacenttocancerglands.

• Glomeruloidformationiscreatedbyintraluminalcribriformproliferationofmalignantcellsandoftensurroundedbyacrescenticspace,resemblingarenalglomerulus.

• Perineuralinvasionwithcancerglandsencirclingtheentirecircumferenceofanerveispathogno-monicofprostatecarcinoma.(Benignglandscanoccasionallybefoundtoabutanerve;however,circumferentialextensionofbenignglandsentirelyaroundanervehasnotbeendescribed.)

• Prostatecarcinomahasaconstellationofarchitec-tural,cytoplasmic,nuclear,andintraluminalfeatures:

• Architecture • Gland-formingprostatecarcinomasaremore

crowdedthanbenignglandsandtypicallyexhibithaphazardgrowthpatternandinfiltrativegrowthpattern,withmalignantglandssituatedbetweenorflankingbenignglands.

58 Prostatic Carcinoma, Usual Variant

• Incontrasttobenignglandswithirregularandundulatingluminalborders,prostatecarcinomaglandsaresmallerandhavestraightluminalborders.

• Whenprostatecarcinomabecomeslessdifferenti-ated,itlosesglandulardifferentiationandformscribriformstructures,fusedglands,poorlydelin-eatedglands,solidsheetsorcords,orevensingletumorcells.

• Cytoplasm • Prostatecarcinomaglandsmayhaveamphophilic

cytoplasm. • Low-gradeprostatecarcinomaoftenhaspale,

clearcytoplasm,indistinctfrombenignglands. • Prostatecarcinomatypicallylackslipofuscinpig-

ment. • Nuclei • Typically,prostatecarcinomadisplaysenlarged

nucleiandprominentnucleoli. • Someprostatecarcinomaslackprominentnucle-

oliyethaveenlargedandhyperchromaticnuclei. • Cancernuclei,eveninpoorlydifferentiatedones,

showlittlevariationinsizeandshape. • Mitosesandapoptoticbodiesaremorecommon

inprostatecarcinomaandrarelyfoundinbenignglands.

• Lumina • Crystalloidsaredense,eosinophilic,crystal-like

structurescommonlyfoundwithintheglandularlumensofcancerglands.

• Intraluminal,pink,acellular,densesecretionsandblue-tingedmucinareadditionalfindingsseenpreferentiallyinprostatecarcinoma.

• Corporaamylaceaarecommoninbenignglandsandareseenrarelyinprostatecarcinoma.

• Stroma • Ordinaryprostatecarcinomadoesnotelicita

prominentstromalinflammatoryordesmoplasticresponse.

Immunopathology (including immunohistochemistry)• ThemajorityofprostatecarcinomasexpressPSA,

althoughthereisconsiderableintratumoralandinter-tumoralheterogeneity,andtheexpressionisdecreasedinaminorityofhigh-gradeprostatecarcinoma.

• Prostate-specificacidphosphatase(PSAP)hasadiag-nosticutilitysimilartoPSA,althoughitisingeneralmoresensitiveandlessspecificthanthelatter.

• Prostatecancercanoccasionallyshownegativestain-ingforcytokeratin(CK)7,whichcanbeusefultodifferentiateprostatecarcinomafromurothelialcarci-noma,whichistypicallypositive.

• Prostatecarcinomauniformlylacksabasalcelllayerandthereforeisnegativeforhigh-molecular-weightcytokeratin(HMWCK).However,prostatecarcinomacanoccasionallycontainsparsetumorcellspositiveforHMWCK,yetnotinabasalcelldistribution,espe-ciallyafterradiationorhormonaltherapy.

• p63isanuclearproteinexpressedinbasalcellsofpseudostratifiedepithelia,includingtheprostate.p63isnegativeinprostatecancer.

• AMACRisanenzymeinvolvedinthemetabolismofbranchedchainfattyacidsandbileacidintermediates;itisoverexpressedinapproximately80%ofprostatecarcinomainneedlebiopsyspecimens.AMACRisnotentirelyspecificforprostatecarcinoma,asitispres-entinhigh-gradeprostaticintraepithelialneoplasia(>90%),adenosis(17.5%),partiallyatrophicglands,

andoccasionallymorphologicallybenignglands.AMACRcanbeusedasaconfirmatorystaining,inconjunctionwithH&Ehistologyandbasalcellmark-ers,forprostatecarcinoma.

Main differential diagnosis• Partialatrophy• Postatrophichyperplasia• Adenosis• Sclerosingadenosis• Basalcellhyperplasia• Seminalvesicle–ejaculatoryducttissue• Verumontanummucosalglandhyperplasia• Cowperglands• Paraganglia• Mesonephricremnants• Nonspecificgranulomatousprostatitis• Benignprostatichyperplasia• High-gradeprostaticintraepithelialhyperplasia• Radiationeffect

Fig 1. Mucinousfibroplasia(collagenousmicronodules)consistsof delicate loose fibrous tissue with an ingrowth of fibroblastswithinoradjacenttocancerglands.

Fig 2. Perineural invasion with cancer glands encircling theentire circumference of a nerve is pathognomonic of prostatecarcinoma.

59Neoplastic Disease of the Prostate

A

B

Fig 3. A,Glomeruloidformationiscreatedbyintraluminalpro-liferationofmalignant cells.B,Glomeruloid structure isoftensurroundedbyacrescenticspaceresemblingarenalglomerulus.

Fig 4. Benignprostaticglandscanoccasionallybefoundtoabuta nerve; however, circumferential extension of benign glandsentirelyaroundanervehasnotbeendescribed.

Fig 5. Architecturally, gland-forming prostate carcinomas aremorecrowdedthanbenignglands.

Fig 6. Typically, prostate cancer glands exhibit an infiltrativegrowth pattern, with malignant glands situated between orflankingbenignglands.

Fig 7. Incontrasttobenignglandswithirregularandundulat-ingluminalborders,prostatecarcinomaglandsaresmallerandhavestraightluminalborders.

60 Prostatic Carcinoma, Usual Variant

Fig 8. Whenprostatecarcinomabecomeslessdifferentiated,itlosesglandulardifferentiationandformspoorlydelineatedfusedglands,cords,orevensingletumorcells.

Fig 9. Prostatecarcinomaglandsmayhaveamphophiliccyto-plasm.Notice the intensecytoplasmic stainingcomparedwiththesurroundingbenignglands.

Fig 10. Gleasonscore6mayhavepale-clearcytoplasm, indis-tinctfrombenignglands.

A

B

Fig 11. Typically, prostate carcinoma displays nucleomegaly(A)andprominentnucleoli(B).

Fig 12. Poorlydifferentiatedprostatecancershowinglittlevari-ationinnuclearsizeandshape.

61Neoplastic Disease of the Prostate

Fig 14. Intraluminalpinkacellulardensesecretionsarefindingsseenpreferentiallyinprostatecarcinoma.

Fig 15. Blue-tinged mucin can be seen within the lumen ofprostatecarcinomaglands.

Fig 13. Crystalloidsaredenseeosinophiliccrystal-likestructurescommonlyfoundwithintheglandularlumensofcancerglands.

Fig 16. Corpora amylacea are common in benign glands andonlyrarelyseen(asinthiscase)inprostatecarcinoma.

A

B

Fig 17. A, Small glands of prostate carcinoma infiltratingbetween larger benign glands. B, Prostate cancer glands uni-formly lack a basal cell layer and therefore are negative forHMWCK; in contrast, benign glands show strong cytoplasmicstaininginthebasalcells.

62 Prostatic Carcinoma, Usual Variant

A

B

C

Fig 18. A,Smallfocusofprostatecanceronneedlebiopsy(top).B, p63 nuclear staining is expressed in basal cells of benignprostaticglands,but isnegative inprostatecancer.C,Prostatecarcinoma shows strong cytoplasmic staining with AMACR.p63nuclearstainingispositiveinbasalcellsofadjacentbenignglands,butnegativeinneoplasticglands(p63/AMACRcocktail).

A

B

Fig 19. High-gradeprostatecancer.PSAP(A)hasadiagnosticutilitysimilartoPSA(B),althoughitisingeneralmoresensitiveandlessspecificthanPSA.

Fig 20. High-grade prostate cancer. Notice that most of thetumorcellsshownegativestainingforCK7.CK7cansometimesbeusefultodifferentiateprostatecarcinomafromurothelialcar-cinoma,whichistypicallydiffuselypositiveforCK7.

63Neoplastic Disease of the Prostate

Fig 21. ThemajorityofprostatecarcinomasexpressPSAalthoughthereisconsiderableintratumoralheterogeneity.Thereisvariableintensityofstainingintwodifferentareasofthesametumor.