URINARY CYTOURINARY CYTOAND OTHER URIN

OPATHOLOGYOPATHOLOGYE-BASED TESTS

IN ACCORDANCE WITH ACINDIVIDUAL IN A POSITIONCONTROL THE CONTENT OACTIVITY HAS DISCLOSEDACTIVITY HAS DISCLOSEDFINANCIAL RELATIONSHIPMONTHS WITH COMMERCMONTHS WITH COMMERCPROVIDE PRODUCTS ANDTO THE CONTENT OF THISINDIVIDUAL BELOW HAS RNO RELEVANT FINANCIALCOMMERCIAL INTEREST TCOMMERCIAL INTEREST T

WILLIAM M MURPHY MDWILLIAM M. MURPHY, MD,

CCME GUIDELINES, ANY N TO INFLUENCE AND/OR OF THIS ASCP CME

D ALL RELEVANTD ALL RELEVANT PS WITHIN THE PAST 12 IAL INTERESTS THATIAL INTERESTS THAT

D/OR SERVICES RELATED S CME ACTIVITY. THE RESPONDED THAT HE HAS L RELATIONSHIP WITH TO DISCLOSETO DISCLOSE.

FASCPFASCP

URINARY CYTOHAS BEEN USED CLIHAS BEEN USED CLI

NEOPLASMCRYSTALSBK POLYOEOSINOPHMICROORGPARASITESHORMONETRANSPLAHEAVY ME

OPATHOLOGYINICALLY TO ASSESSINICALLY TO ASSESS

MSSOMAVIRUSHILS GANISMSS

E STATUSANT REJECTIONETALS

PROBLEMS WITH URINAIN “BLADDEIN “BLADDE

LOW DIAGNOSTIC YIELD, e

LOW DIAGNOSTIC YIELD F

LOW COMFORT LEVEL AMO

RELATIVELY HIGH INTEROBRELATIVELY HIGH INTEROB

THE INSISTENCE OF UROLUROTHELIAL NEOPLASMS

ARY CYTOPATHOLOGYER CANCER”ER CANCER”

esp. FOR VOIDED URINE

OR LOW-GRADE TUMORS

ONG PATHOLOGISTS

BSERVER VARIABILITYBSERVER VARIABILITY

OGISTS ON LABELING ALL “CANCER”

THE TROUURINARY CYTURINARY CYT

INACCURATE HISTOLOINACCURATE HISTOLO

INAPPROPRIATE CLINI

LACK OF PATHOLOGIS

UBLE WITHTOPATHOLOGYTOPATHOLOGY

OGIC CLASSIFICATIONOGIC CLASSIFICATION

ICAL APPROACH

ST CONFIDENCE

INACCURATEINACCURATECLASSIFCLASSIF

HISTOLOGIC HISTOLOGIC FICATIONFICATION

HISTORICAL THE DEFINITION O

THE “INVASIO

PAPILLARY AND NPAPILLOMAPAPILLOMACARCINOMA

FLAT LESIONSFLAT LESIONSDYSPLASIA - LOWATYPIA - MODERAATYPIA MODERADENUDING CYSTI

PATHOLOGYOF MALIGNANCY

ON” SCHOOL

NODULAR LESIONS

W, HIGH GRADEATE SEVEREATE, SEVEREITIS

HISTORICAL THE DEFINITION O

THE “RECURRE

PAPILLARY AND NOCARCINOMA - GRA

FLAT LESIONSCARCINOMA IN SITDYSPLASIA, ATYPIA

PATHOLOGYOF MALIGNANCY

ENCE” SCHOOL

ODULAR LESIONSADES 0-4

TUA, ???

THE DEFINITION OFTHE DEFINITION OF NEVER DEPENDED OANAPLASIA OF THEANAPLASIA OF THE RATHER THE GROWTHE TUMOR FOR PATHE TUMOR - FOR PAUROTHELIAL NEOPLBEEN TAUGHT TO DBEEN TAUGHT TO DSTALK, NOT ITS CEL

MALIGNANCY HASMALIGNANCY HAS ON THE DEGREE OF TUMOR CELLS BUTTUMOR CELLS BUT

WTH PATTERN OF PAPILLARYPAPILLARY LASMS, WE HAVE IAGNOSE THEIAGNOSE THE

LLS

MODERN PAC SS C OCLASSIFICATION

SCIENCE IS IMPORFACTS ARE IN DISPPATHOLOGY ORGACONSENSUS AND CACHIEVE CURRENT

ATHOLOGYCO S S S BY CONSENSUS

RTANT BUT THE PUTE SO LET’S USE ANIZATIONS FOR COMPROMISE TO T BEST PRACTICE

THE 1973 WHO COF UROTHELIOF UROTHELI

PAPILLOMAPAPILLOMACARCINOMA - PAPILL

GRADE 1GRADE 1GRADE 2GRADE 3GRADE 3

CARCINOMA IN SITU/

CLASSIFICATIONIAL TUMOURSIAL TUMOURS

LARY, NODULAR

/DENUDING CYSTITIS

THE CELLS IN URINABEEN TELLING US ABEEN TELLING US A

OF UROTHELIAL N40 YEARS BU40 YEARS BU

NOT PREPARE

ARY SPECIMENS HAVEABOUT THE NATUREABOUT THE NATURE NEOPLASMS FORUT WE WEREUT WE WERE ED TO LISTEN

EVIDENCE THAT TIS NOT A MAIS NOT A MA

DNA ploidy normaDNA ploidy normaDNA ploidy normaDNA ploidy normaChromosome struChromosome struAlmost no abnormAlmost no abnormBlood group antigBlood group antigBlood group antigBlood group antigCytology normal 4Cytology normal 4LongLong--term survivaterm survivaExperimental lesioExperimental lesioExperimental lesioExperimental lesioNeither invasion nNeither invasion n

TCC-1 (1973 WHO) ALIGNANCYALIGNANCYalal 95%95%al al -- 95%95%cture normal cture normal

malities in genesmalities in genesens retainedens retained 85%85%ens retained ens retained -- 85%85%40 40 -- 70%70%al 95% al 95% (even with “recurrence”)(even with “recurrence”)

ons reversibleons reversibleons reversibleons reversiblenor metastasisnor metastasis

TUMOR-SPEC380 CASES WITH A

CIFIC SURVIVAL (YRS)AT LEAST A 10 YEAR F/U

THE CURRENT CLUROTHELIALUROTHELIAL

(1998 WHO/ISUP, 2004 WH

PAPILLPAPILLPAPILLPAPILLPUNLMPUNLMCARCINCARCIN

LOWLOWLOWLOWHIGHHIGH

CISCISDYSPLADYSPLADYSPLADYSPLAATYPIAATYPIA

LASSIFICATION OF NEOPLASMSNEOPLASMS

HO, 2004 AFIP FASCICLE)

OMAOMAOMAOMAPP

NOMANOMAW GRADEW GRADEW GRADEW GRADEH GRADEH GRADE

ASIAASIAASIAASIAAA

INAPPROPRIATE CLINAPPROPRIATE CL

(MOST) CLINICIANS RE

LINICAL APPROACHLINICAL APPROACH

EALLY KNOW BETTER

TWO PATIENTS WITH U

UROLOGISTS TELL BOTH THAT

UROTHELIAL TUMORS

THEY HAVE BLADDER CANCER

URINARY SPECIMENS FFROM BOTH PATIENTS

BASICALLY, THTWO GRADES O

NEOPLNEOPL

LOW GRADE NOLOW-GRADE - NONOT EASILY DIAGNOS

HIGH-GRADE - AEASILY DETECTED WEASILY DETECTED W

ERE ARE ONLYOF UROTHELIALLASMSLASMS

OT AGGRESSIVEOT AGGRESSIVESED CYTOLOGICALLY

AGGRESSIVEWHEN CELLS PRESENTWHEN CELLS PRESENT

THE PRIMARY CLITHE PRIMARY CLIURINARY CYTOPAIDENTIFICATION OCARCINOMA CELLGLANDULAR, SQUCELLCELL

NICAL VALUE OFNICAL VALUE OF ATHOLOGY IS THE OF HIGH-GRADELS - UROTHELIAL, ,UAMOUS, SMALL

SPECIMEN C

RANDOM VRANDOM V

BLADDER

CATHETER

24 HOUR

EARLY MO

COLLECTION

VOIDEDVOIDED

R WASHING

RIZED

ORNING

VOIDED URINE AND BLADDE

VUVU

R WASHING – SAME PATIENT

BWBW

SPECIMEN PRSPECIMEN PR

REFRIGERAT

ALCOHOL (25(

CARBOWAXCARBOWAX

RECONSTITURECONSTITU

RESERVATIONRESERVATION

TION

5%))

UTION IN SALINEUTION IN SALINE

2 days2 days 9 daysy

16 days

SPECIMEN PSPECIMEN P

CYTOCENT

THIN PREP/

MEMBRANEMEMBRANE

DIRECT SMDIRECT SM

PROCESSINGPROCESSING

RIFUGATION

/NU VIEW

E FILTERSE FILTERS

EARSEARS

CLINICAL INFORMFOR CYTOPATHOLOFOR CYTOPATHOLO

H “BLADDEHx “BLADDE(AND GRADE

HEMATURIA

SPECIMEN SBLADDERBLADDER INTESTINAL NEOBLADDEBLIND URETURETER, RE

MATION HELPFULOGIC CONSULTATIONOGIC CONSULTATION

ER CANCER”ER CANCER”E)

SOURCE

CONDUITERHRANAL PELVIS

DIAGNOSTIC TERURINARY SURINARY S

POSITIVE, HIGH GRADE N

SUSPICIOUS - R/O HIGH-GR

DYSPLASTIC CELLS R/O LDYSPLASTIC CELLS, R/O L

NEGATIVE FOR MALIGNANEGATIVE FOR MALIGNANUMEROUS CELLS (ITSELSCANT CELLS

INSUFFICIENT CELLS FOR

RMINOLOGY FOR SPECIMENSSPECIMENS

NEOPLASM

RADE NEOPLASM

LOW GRADE NEOPLASMLOW-GRADE NEOPLASM

ANCY (INCLUDES REACTIVE)ANCY (INCLUDES REACTIVE)LF ABNORMAL)

R ANALYSIS

INSUFFICIENT FFOR ANALYSIS

WORKING DEFINITIFOR URINARYFOR URINARY

VOIDED URINE OR BLADDER“BLADDER CANCER”BLADDER CANCER

AT LEAST 5 NON-SUPE

VOIDED URINE, HISTORY OF AT LEAST 5 NON-SUPE

BLADDER WASHING, HISTORAT LEAST 15 NON SUPAT LEAST 15 NON-SUP

ION OF ADEQUACYY SPECIMENSY SPECIMENS

R WASHING, NO HISTORY OF

RFICIAL CELLS

“BLADDER CANCER”RFICIAL CELLS

RY OF “BLADDER CANCER”ERFICIAL CELLSERFICIAL CELLS

NORMMAL

TOO MANY

10

Y CELLS

10x

40x

CELLULAR FEATGRADE UROTHELGRADE UROTHEL

INCREASED N:C RINCREASED N:C RINCREASED NUCINCREASED NUCNUCLEAR ECCENNUCLEAR ECCENNUCLEAR ECCENNUCLEAR ECCENNUCLEAR PLEOMNUCLEAR PLEOMNUCLEAR PLEOMNUCLEAR PLEOMIRREGULAR, IRREGULAR, COACOA

TURES OF HIGH LIAL NEOPLASMSLIAL NEOPLASMS

RATIOS (>1:2)RATIOS (>1:2)LEAR SIZELEAR SIZETRICITYTRICITYTRICITYTRICITYORPHISMORPHISMORPHISMORPHISM

ARSE CHROMATINARSE CHROMATIN

HIGH-GRADE NEOPLASM UUROTHELIAL CARCINOMA, HIGH-GRADE,

MTC IN BLADDDER WASHING

HIGH-GRADE NEOPLASM UROTHELIAL CARCINOMA, HIGH-GRADE

10x 40x

COMMON CONFOUFOR HIGH GRADFOR HIGH-GRAD

SCANT CELLS IN VOSCANT CELLS IN VO

TUMOR CELLS THATTUMOR CELLS THAT

REACTIVE CELLS THREACTIVE CELLS TH

UNDING FACTORSDE NEOPLASMSDE NEOPLASMS

OIDED URINESOIDED URINES

T LOOK BENIGNT LOOK BENIGN

HAT LOOK MALIGNANTHAT LOOK MALIGNANT

SCANT MALIGIN URINARYIN URINARY

GNANT CELLSY SPECIMENY SPECIMEN

10x

TYPICAL MTC

10x 40x

C AFTER BCG

40x

CARCINOMA IN SITU UNDERMMINING NORMAL UROTHELIUM

REACTIVE SUPEERFICIAL CELL

REACTIVE CELLS – YOUNG PATIENT WITH BMT

REACTIVE – 33 YO F WITH Tx

TYPICAL (TEXTBBOOK) BK CELLS

BK CELLS IN DAAILY PRACTICE

POLYOMAVIRUSES IN URINE ARE (A

BK IS UBIQUITOUS IN HUMANS BUTWHO ARE IMMUNOCOMPROMIZED.

NUCLEAR INCLUSIONS ARE COMMCONFINED TO SUPERFICIAL CELLS

C O CBK NUCLEI TEND TO HAVE EVEN CCHROMATIN; THEY ARE OFTEN DEG

WHEN BK CAUSES DISEASE THE DWHEN BK CAUSES DISEASE, THE DTHE KIDNEY, NOT THE BLADDER.

IMMUNOCYTOCHEMISTRY IS AVAILAIMMUNOCYTOCHEMISTRY IS AVAILAMOST CASES; IT IS OFTEN EQUIVO

I REPORT BK IN “HEMATURIA” CASIMMUNOCOMPROMIZED OR THERE

ALMOST) ALWAYS BK.

T ONLY PATHOGENIC IN PEOPLE

ON AND ARE ESSENTIALLY S.

O O S S GONTOURS AND SMUDGED GENERATED.

DISEASE IS A MOST A WAYS INDISEASE IS ALMOST ALWAYS IN

ABLE BUT NOT NECESSARY INABLE BUT NOT NECESSARY INOCAL IN PRACTICE

SES ONLY WHEN THE PATIENT IS E ARE RED CELL CASTS.

CELLULAR FEATURUROTHELIAL NEOPLAUROTHELIAL NEOPLA

INCREASEDINCREASED N C (>N C (>INCREASEDINCREASED N:C (>N:C (>INCREASED NUCLEINCREASED NUCLEEXTREME ECCENTREXTREME ECCENTRNUCLEAR BORDERNUCLEAR BORDERNUCLEAR BORDERNUCLEAR BORDEREVENLY DISPERSEEVENLY DISPERSEHOMOGENEOUS CYHOMOGENEOUS CY

NB: ALL FEATURES NB: ALL FEATURES RARELYRARELY

ES OF LOW GRADE ASMS AND DYSPLASIAASMS AND DYSPLASIA

>1 2)>1 2)>1:2)>1:2)EAR SIZEEAR SIZERICITYRICITY

R IRREGULARITIESR IRREGULARITIESR IRREGULARITIESR IRREGULARITIESD, FINE CHROMATIND, FINE CHROMATIN,,YTOPLASMYTOPLASM

YY PRESENT IN EVERY CELLPRESENT IN EVERY CELL

CELLS FROM A LOWCELLS FROM A LOW-DYSPLASTIC CELLS,

R/O LOW-GRADE NEOPLASM

GRADE CARCINOMA-GRADE CARCINOMAUROTHELIAL CARCINOMA, LOW-GRADE

10x 40x

DYSPLASTIC CELLS, R/O LOW-GRADE NEOPLASMR/O LOW GRADE NEOPLASM LOW-GRADE CARCINOMA

LOW-GRADE DYSPLASTIC CELLS,DYSPLASTIC CELLS,R/O LOW-GRADE NEOPLASM

CARCINOMA

LOW-GRADE

DYSPLASTIC CELLS, R/O LOW-GRADE NEOPLAS

CARCINOMA

SM

PUN

DYSPLASTIC CELLS, R/O LOW-GRADE NEOPLASM

NLMP

4x

10x

PU

DYSPLASTIC CELLS, R/O LOW-GRADE NEOPLASM

UNLMP

4x

20x

CYTO - HISTOLOGIUROTHELIALUROTHELIAL

NEGATIVE

DYSPLASTIC

SUSPICIOUS

POSITIVE

IC CORRELATIONS NEOPLASMSNEOPLASMS

PAPILLOMAPUNLMPPUNLMPPUNLMPCa, LOW GRADE,Ca, HIGH GRADECISCa, HIGH GRADECISOTHER TYPES

COMMON CONFOUFOR LOW GRADFOR LOW-GRAD

PAPILLARY AGGREGAPAPILLARY AGGREGA

CAUTERY ARTIFACTCAUTERY ARTIFACT

NEOPLASTIC CELLS TNEOPLASTIC CELLS T

UNDING FACTORSDE NEOPLASMSDE NEOPLASMS

ATESATES

THAT LOOK NORMALTHAT LOOK NORMAL

STONE

57 YO FPELVIC PAIN

XRT EFFECT

24 YO PREGNANT

REACTIVE PAPILLLARY AGGREGATE

LOW-GRADE NEOPLASM ALOW GRADE NEOPLASM AAFTER ELECTROCAUTERYAFTER ELECTROCAUTERY

“NORMAL” CELLS

10x

PUNLMP

40x

AS A PRACTICAL MATPATIENTS DYING OF BPATIENTS DYING OF BSUCCUMB TO A HIGH-WAS PRESENT AT INITWAS PRESENT AT INITTHAN 10% OF PATIENTWITH A PAPILLOMA OWITH A PAPILLOMA OPROGRESSION AND LBLADDER CANCER (NBLADDER CANCER (NPUNLMP).

WHAT THEN IS THE BEOF EARLY DETECTIONOF EARLY DETECTIONGRADE TUMORS?

TTER, NEARLY ALL BLADDER CANCERBLADDER CANCER -GRADE TUMOR THAT TIAL DIAGNOSIS LESSTIAL DIAGNOSIS. LESS TS WHO PRESENT R PUNLMP SUFFERR PUNLMP SUFFER

LESS THAN 5% DIE OF NOBODY DIES OF ANOBODY DIES OF A

ENEFIT TO PATIENTS N OF RECURRENT LOWN OF RECURRENT LOW-

THE PRIMARY CLINICACYTOPATHOLOGY IS TWHO NEED MORE ANAGGRESSIVE EVALUACYSTOSCOPY WITH OVIRTUALLY NO ONE ISSOLELY ON A CYTOPAASSESSMENT OF A U

AL VALUE OF URINARY TO IDENTIFY PATIENTS D/OR MORE ATION, USUALLY OR WITHOUT BIOPSY. S TREATED BASED ATHOLOGIC RINARY SPECIMEN.

CLINICAL RECYTOPATHOLOGCYTOPATHOLOG

U/BWU/BWNegativeNegative**

U/BWU/BW

Dysplastic cellsDysplastic cellsr/o r/o lglg neoplasmneoplasmgg pp

SuspiciousSuspiciousr/o hg neoplasmr/o hg neoplasmr/o hg neoplasm r/o hg neoplasm

PositivePositivehg neoplasmhg neoplasm

*scant or numerous cells - ch

ESPONSE TO GICAL DIAGNOSISGICAL DIAGNOSIS

RESPONSERESPONSENoneNone

RESPONSERESPONSE

CystoscopyCystoscopyw/w/wowo biopsybiopsyp yp y

CystoscopyCystoscopyw/w/wowo biopsybiopsyw/w/wowo biopsy biopsy

CystoscopyCystoscopyw biopsyw biopsy

heck patient status

CYTOPATHOLCYTOPATHOL

RELIABLY DISTIFROM UROTHELFROM UROTHEL

DIFFERENTIATEINVASIVE CARC

LOCALIZE THE L

LOGY CANNOTLOGY CANNOT

INGUISH ADENO LIAL CARCINOMALIAL CARCINOMA

E IN SITU FROM CINOMA

LESIONS

UROTHELIAL CARCINNOMA, HIGH-GRADE

ADENOCAARCINOMA

CARCINOMMA IN SITU

SQUAMOUS CELL CARCINOMA

SQUAMOUS CESQUAMOUS CELL CARCINOMALL CARCINOMA

SMALL CELL CARCINOMA

PCa IN

10x10x

URINE

40x40x

URINARY CYTOURINARY CYTOIN DAILY P

EVEN BELIEVERS HAURINARY CYTOURINARY CYTO

OPATHOLOGYOPATHOLOGY PRACTICE

AVE PROBLEMS WITHOPATHOLOGYOPATHOLOGY

THE AUA DEFINITIOFOR “BLADDFOR “BLADD

HISTORY OF SMOLDER THAN 40OCCUPATIONALGROSS HEMATUHISTORY OF IRRHISTORY OF IRRHISTORY OF UTANALGESIC ABANALGESIC ABHISTORY OF PEHISTORY OF URUSING THIS DEFINITIOHEMATURIA QUALIFIE

ON OF “HIGH-RISK”ER CANCER”ER CANCER”

MOKING0 YEARSL EXPOSUREURIARITATIVE VOIDINGRITATIVE VOIDING

TIsBUSEBUSEELVIC XRTROLOGIC DISORDERON, NEARLY EVERYONE WITH

S FOR ANCILLARY TESTING

DIAGNOSTIC YIECYTOLOGY SPCYTOLOGY SP

Sens SpeA

Sens Spe72 82

B 72 78

C 67 77

D 60 87D 60 87A -D Differen

ELD OF URINARY PECIMENS (%)PECIMENS (%)ec PPV NPVec PPV NPV2 92 51

8 80 69

7 92 34

7 95 327 95 32nt scenarios MALIK, UROLOGY, 1999

DIAGNOSTIC YMULTIGROUP COLMULTIGROUP COL

Group A

Sens S47Group A

Group B 85Group B

Group C 66p

Overall 64Overall 64A = Academe, B= PP,

YIELD OF UC-LLABORATION (%)LLABORATION (%)

Spec PPV NPV98 81 91

74 56 93

98 88 94

95 75 9295 75 92 C= Cancer Center

BASTACKY, CANCER(CANCER CYTOPATHOL), 1999

URINARY CYTOPATHURINARY CYTOPATHCONSIDERED IN TWMONITORED FOR “BMONITORED FOR BARE IN A DIAGNOSTPATIENTS WITH HEMPATIENTS WITH HEMSCREENING MODE.

THE PPV IS VERY DI

HOLOGY MUST BEHOLOGY MUST BE WO MODES – PATIENTS BLADDER CANCER”BLADDER CANCER TIC MODE;MATURIA ARE IN AMATURIA ARE IN A

FFERENT

TRIUMMPHS

TREATMENIN URINARYIN URINARY

ALKYLATING AGALKYLATING AGMALIGNANTMALIGNANT--LOOLOOMALIGNANTMALIGNANT--LOOLOO

XX--RAYSRAYSNONENONE

BCGBCGBCGBCGNONENONE

T EFFECTSSPECIMENSSPECIMENS

GENTS GENTS –– MMC/TTPMMC/TTPOKING SUPERFICIAL CELLSOKING SUPERFICIAL CELLSOKING SUPERFICIAL CELLSOKING SUPERFICIAL CELLS

NECROSIS DDUE TO MMC

COURTESY MS SOLOWAY, MD

NORMAL-LOOKINAFTERAFTER

G CYSTOSCOPYR MMCR MMC

COURTESY MS SOLOWAY, MD

MITOMYCIN EFFECT

HIGH-GRRADE MTC

CIS (LOWER LAYERS) AND MMC EFFFECT (SUPERFICIAL CELL LAYER)

GROSSLY NORMMAL BLADDER

COURTESY MS SOLOWAY, MD

HIGH-GRADEE NEOPLASM

CARCINOMMA IN SITU

CYSTOSCOPY AAFTER BCG

COURTESY MS SOLOWAY, MD

HIGH-GRADDE NEOPLASM

DENUDATION OF UROTHELIUM, L.P. INVASION

URINARY CYTOAFTER CYSAFTER CYS

ILEAL CONEOBLANEOBLA

URETHRAL

OPATHOLOGYSTECTOMYSTECTOMY

ONDUITSADDERSADDERS

WASHINGS

ILEAL CONDDUIT URINE

ILEAL CELLS

MTC

MTC

HIGH-GRADE CARCINNOMA RENAL PELVIS

URETHRAL STU

10x

UMP WASHING

40x

CIS IN PARAUREETHRAL GLANDS

URETHRAL STUUMP WASHING

CIS IN PARAUREETHRAL GLANDS

WHAT ABOUT CEUPPER COLLECUPPER COLLEC

LOW-GRADE NEOPLASMS DOCYTOPATHOLOGIC DIAGNOSIS

IT IS NOT UNCOMMON TO SEESPECIMENS FROM BOTH SIDESEEMS TO BE ON ONLY ONE S

RENAL CELL CARCINOMAS ARRENAL CELL CARCINOMAS ARSPECIMENS

ALL TYPES OF EVALUATION MALL TYPES OF EVALUATION MRESECTION

ELLS FROM THECTING SYSTEM?CTING SYSTEM?

N’T LEND THEMSELVES TO S

E HIGH-GRADE CELLS IN ES EVEN THOUGH THE TUMOR SIDE

RE RARE IN UPPER SYSTEMRE RARE IN UPPER SYSTEM

MUST CORRELATE BEFOREMUST CORRELATE BEFORE

NORMAL CELLS IN RENAL PELVIS WASHING

NORMAL CELLS, LEFT MALIGNANT CELLS, RIGHT

URETERAL WASHING

POSITIVE, HIGH-GRADE NEOPLASM

UROTHELIAL CARCINOMA, HIGH-GRADE

4x

40x

ESTABLISHED METUROTHELIALUROTHELIAL

HEMATURIA (w OR w/o

CYSTOSCOPY (CYSTOSCOPY (w OR w

URINARY CYTOPATURINARY CYTOPAT

THODS TO DETECTNEOPLASMSNEOPLASMS

o IRRITATIVE VOIDING Sx)

/ BIOPSY)w/o BIOPSY)

HOLOGYHOLOGY

TYPICAL CASTYPICAL CASDATE CYSTO CDATE CYSTO C

5/75 POS 5/75 POS

7/75 POS 7/75 POS 10/75 S P10/75 S P2/76 POS 2/76 POS 4/76 S N4/76 S N7/76 NEG 7/76 NEG 11/76 NEG 11/76 NEG 3/77 NEG3/77 NEG3/77 NEG 3/77 NEG 9/77 NEG 9/77 NEG 12/77 S P12/77 S P2/78 NEG 2/78 NEG 3/78 S3/78 S3/78 S 3/78 S 7/78 S P7/78 S P11/78 NEG 11/78 NEG 2/79 NEG 2/79 NEG 6/79 NEG 6/79 NEG 9/79 POS 9/79 POS 1/80 NEG 1/80 NEG 4/80 POS 4/80 POS 6/80 POS 6/80 POS

E – NBCCG-AE NBCCG ACYTO HISTOCYTO HISTO

ND TCCND TCC--II, CISII, CIS

S DYS S DYSPOS CISPOS CISPOSPOS TCCTCC--II, CISII, CISNEG DENUDEDNEG DENUDEDNEGNEG NEGNEGDYS DYS DYSDYSDYS NEGDYS NEGDYS NEGDYS NEG S S ----POS NEGPOS NEGPOS POS ----

SS ---- SSPOS TCCPOS TCC--II, CISII, CISPOS POS ----POS POS ----NEGNEG ---- ---- TCCTCC--II, CISII, CIS S S ----NEG TCCNEG TCC--IIIIIIPOSPOS TCCTCC--IIIIII

OK SO WE NOW KNOOK, SO WE NOW KNOAND CLINICAL USESCYTOPATHOLOGYCYTOPATHOLOGY.

CAN’T WE DO BETTECAN T WE DO BETTEMETHODS?

OW THE LIMITATIONSOW THE LIMITATIONS OF URINARY

ER WITH ANCILLARYER WITH ANCILLARY

ANCILLARY BLADDER NBLADDER N

TISSUE PRODUCTSTISSUE PRODUCTS --TISSUE PRODUCTS TISSUE PRODUCTS BLOOD GROUP ANTIGBLOOD GROUP ANTIGCYTOKERATINSCYTOKERATINS -- CK2CK2CYTOKERATINS CYTOKERATINS -- CK2CK2PROTEINS/MUCINS PROTEINS/MUCINS -- IIENZYMESENZYMES TELOMERTELOMERENZYMES ENZYMES -- TELOMERTELOMERGROWTH FACTORS GROWTH FACTORS --ADHESION MOLECULADHESION MOLECULADHESION MOLECULADHESION MOLECULDNA DNA -- QUANTICYTQUANTICYTCHROMOSOMESCHROMOSOMES URURCHROMOSOMES CHROMOSOMES -- URURGENESGENES

TESTS FOR NEOPLASMSNEOPLASMS

BTA NMP22BTA NMP22 DD23DD23BTA, NMP22, BTA, NMP22, DD23DD23GENS GENS -- ABH, LEWIS XABH, LEWIS X2020 CYFRA 21CYFRA 21--1 TPA UBC1 TPA UBC2020, CYFRA 21, CYFRA 21--1, TPA, UBC1, TPA, UBCIMMUNOCYTIMMUNOCYT, URO II, URO II

RASE HA/RASE HA/HAaseHAaseRASE, HA/RASE, HA/HAaseHAaseEGF, TGF, FGFR3EGF, TGF, FGFR3

LESLES CD44 ECD44 E ddLES LES -- CD44, ECD44, E--cadcad

ROVYSION FISHROVYSION FISH MSMSROVYSION FISHROVYSION FISH, MS, MS

PROBLEMS WITHAPPLICATIONAPPLICATION

VERY FEW MARKERS SPECIFIC (ONVERY FEW MARKERS SPECIFIC (ON((MANY REACT VARIABLY EVEN IN TYPICALMANY REACT VARIABLY EVEN IN TYPICALNO MARKER IS DIAGNOSTIC FOR NO MARKER IS DIAGNOSTIC FOR MALIGNAMALIGNA

IF USED FOR DETECTION, LOW PPV IF USED FOR DETECTION, LOW PPV SENSITIVITY AND SPECIFICITYSENSITIVITY AND SPECIFICITY

IF USED FORIF USED FOR DDDD FOCAL REACTIONFOCAL REACTIONIF USED FOR IF USED FOR DDxDDx, FOCAL REACTION, FOCAL REACTIONINTEROBSERVER VARIATION; IMAINTEROBSERVER VARIATION; IMA

IF USED FOR PROGNOSIS OVERLAPIF USED FOR PROGNOSIS OVERLAPIF USED FOR PROGNOSIS, OVERLAPIF USED FOR PROGNOSIS, OVERLAPLARGE FOR PATIENT CARE; HYPOLARGE FOR PATIENT CARE; HYPO

WITH FEW EXCEPTIONS IMMUNOCYWITH FEW EXCEPTIONS IMMUNOCYWITH FEW EXCEPTIONS, IMMUNOCYWITH FEW EXCEPTIONS, IMMUNOCYTO APPLY IN MOST PRACTICESTO APPLY IN MOST PRACTICESIF MANY ABNORMAL CELLS, IS IT NECESSIF MANY ABNORMAL CELLS, IS IT NECESSIF FEW ABNORMAL CELLS, IS IT RELIABLEIF FEW ABNORMAL CELLS, IS IT RELIABLE

H THE CLINICAL OF MARKERSOF MARKERS

LY PSA, URO)LY PSA, URO)))L CASESL CASESANTANT UROTHELIAL CELLSUROTHELIAL CELLS

LIMITS VALUE EVEN IF HIGH LIMITS VALUE EVEN IF HIGH

NS OFTEN LEAD TO HIGHNS OFTEN LEAD TO HIGHNS OFTEN LEAD TO HIGH NS OFTEN LEAD TO HIGH AGING, HISTORY BETTERAGING, HISTORY BETTER

P BETWEEN GROUPS OFTEN TOOP BETWEEN GROUPS OFTEN TOOP BETWEEN GROUPS OFTEN TOO P BETWEEN GROUPS OFTEN TOO OCELLULARITY LIMITS USEOCELLULARITY LIMITS USE

YTOCHEMISTRY HAS BEEN DIFFICULTYTOCHEMISTRY HAS BEEN DIFFICULTYTOCHEMISTRY HAS BEEN DIFFICULT YTOCHEMISTRY HAS BEEN DIFFICULT

SARYSARYEE

DO YOU NEED IMMUNOOS TO DIAGNOSE THIS?

WOULD YOU BELIEVE THEOR WOULD YOU CALL IT

E IMMUNOS IN THIS CASET SUSPICIOUS ANYWAY?

THE SEARCH FOR BEDETECT UROTHELIALDETECT UROTHELIALNEW - WHAT’S NEW ISAVAILABILITY OF URIAVAILABILITY OF URIAND FDA APPROVAL FINANCIALLY FROM TC O

ETTER METHODS TO L NEOPLASMS IS NOTL NEOPLASMS IS NOT S THE COMMERCIAL NE-BASED MARKERSNE BASED MARKERS (THE ABILITY TO GAIN THE TESTS)S S)

JUSTIFICATIO

C O SEMPIRICAL OBSERABERRATIONS IN C

3 RED3 RED7 GREEN17 AQUA17 AQUA9 YELLOW

COINCIDE WITH THUROTHELIAL NEOP

DIAGNOSTIC YIELDDIAGNOSTIC YIELDTHAN VOIDED URIN

ON FOR FISH

O SRVATIONS REVEALCHROMOSOMES

E PRESENCE OF PLASMS

D IS 15 50% BETTERD IS 15-50% BETTERNARY CYTOLOGY

510k CLINICAL DATA510k CLINICAL DATATMTM

UroVysionUroVysion Bladder Cancer RBladder Cancer RTMTM

SENSITIVITY (SENSITIVITY (SENSITIVITY (SENSITIVITY (

GRADEGRADE nn FISHFISH

11 2222 5555

22 99 7878

33 1818 9494

SOURCE:SOURCE: 2001 AUA Poster 664, Sarosdy2001 AUA Poster 664, Sarosdy

Recurrence KitRecurrence Kit

(%) BY GRADE(%) BY GRADE(%) BY GRADE(%) BY GRADE

BTAstatBTAstat CYTOLOGYCYTOLOGY

2727 1818

7878 4444

7272 4141

y et al.y et al.

DIAGNOSTIC ACCUCYTOLOGY - HIGH GCYTOLOGY - HIGH G

YearAuthorVoutsaSchoonees

1963

1971De VoogtEsposti

19721972Esposti

LoeningRife

197219781979Rife 1979

FriedellMurphy

19821984Murphy

Shenoy

1984

1985*weighted average of grades II & III TC

URACY OF URINARY GRADE CARCINOMA*GRADE CARCINOMA

Patients % Pos

20

102

100

82

+

20274

8571274 7179222

536 72536 7218343

6210043

26

100

100 +

CC and CIS +only CIS evaluated

SO YOU WAFOR BLADDFOR BLADDEQUIPMENT ($90 0EQUIPMENT ($90,0

SUPPLIES (>$125

LOGISTICS (PREP

PERSONNEL (TECHCOM

SPACE (FOR DARK

RECORD MAINTEN

ANT TO FISHDER CANCERDER CANCER

00 plus)00 plus)

5/TEST)

PARATION, TRANSPORT)

H LICENSED FOR HIGHMPLEXITY)

K FIELD MICROSCOPE)

NANCE (COMPUTER, CAMERA)

ESTIMATING INCESTIMATING INC

SPECS/YR % BlCa F/U% BlCa F/U % HEMATURIA # ELIGIBLE FOR FISH LESS 20%(FEW CELLS, ETC)LESS 10%(POS CYTO) LESS 2% (POS CYTO)

INCOME (@ $200/SPEC)INCOME (@ $200/SPEC) SCENARIO 1: ONLY BLCA F/U; SCENA

OME FROM FISHOME FROM FISH

1 21 2 2000 2000

25 N/A 25 N/A N/A 100 500 2000

) 400 1600 360 N/A

N/A 1568

$72 000 $313 600 $72,000 $313,600ARIO 2: ALL HIGH-RISK HEMATURIA

DEFINITION OFDEFINITION OF

AT LEAST 25 EPITHELIAAT LEAST 25 EPITHELIA

AT LEAST 4 NUCLEI WIT>2 SIGNALS OF 3&7,

OR>11 NUCLEI LACKING>11 NUCLEI LACKING

(SOME ALSO INCLUDE TRISIN AT LEAST 10% OF NUCL

IN PRACTICE MOST ABNORIN PRACTICE, MOST ABNORABNORMAL 9 IS UNUSUAL (ALL NUCLEI MUST BE ASSE

POSITIVE FISHPOSITIVE FISH

AL NUCLEI ON THE SLIDEAL NUCLEI ON THE SLIDE

TH:3&17, 7&17

G 9G 9

SOMY 3,7, OR 17LEI)

RMALS ARE IN 3&7RMALS ARE IN 3&7<10%)SSED

PROBLEMS WITH

SPECIMENS WITH 1 3SPECIMENS WITH 1-3WEAK/ABSENT YELLNON SPECIFIC SIGNANON-SPECIFIC SIGNAWIDELY SPLIT SIGNATETRAPLOID SUPERTETRAPLOID SUPER>2 RED/GREEN, RETEAUTOFLUORESCENCAUTOFLUORESCENCNUCLEAR CLUMPINGNEUTROPHILSNEUTROPHILSPPV BlCa 50%, PPV H

H FISH ANALYSIS

3 ABNORMAL NUCLEI3 ABNORMAL NUCLEI LOW SIGNALS ALS ESP REDALS, ESP. REDALSRFICIAL CELLSRFICIAL CELLSENTION OF YELLOWCECE G

HEM 3% - 24%

FIS(NOV 05(NOV 05 -

TOTAL SPECIMENTOTAL SPECIMENFISH NOT DONE

POOR PRESERVAPOSITIVE CYTOL

FISH PERFORMEUNINFORMATIVENEGATIVE POSITIVEABNORMAL (2,3 C

SH JUNE 08)JUNE 08)

NS 1278NS 1278

ATION LOGY

268 (21%)78 ( 6%)

D E

93248 ( 5%)

( )

768 (82%)57 ( 6%)

CELLS)( )

60 ( 7%)

CASES WITH P35 PATIENTS35 PATIENTS;

TUMOR AT FOLLOWUP CYTOLOGY SUSP/DYCYTOLOGY NEGATIC O OG O OCYTOLOGY NOT DO

NO TUMOR AT FOLLOWNO TUMOR AT FOLLOW

NO FOLLOWUP

DIAGNOSTIC YIELD = 31%

POSITIVE FISH57 SPECIMENS57 SPECIMENS

(1-32m) 11( )YS/POSIVE

O

1153

ONE

WUP (1-32m)

3

24WUP ( ) 24

0

% (of 6% = 1.8%)

CASES WITH AB46 PATIENTS 646 PATIENTS; 6

TUMOR AT FOLLOW-CYTOLOGY SUSP/DYCYTOLOGY SUSP/DYCYTOLOGY NEGATIVCYTOLOGY NOT DONCYTOLOGY NOT DON

NO TUMOR AT FOLLONO TUMOR AT FOLLO

NO FOLLOW-UPNO FOLLOW UP

DIAGNOSTIC YIELD = 28%

BNORMAL FISH60 SPECIMENS60 SPECIMENS

-UPYS/POS

135YS/POS

VENE

562NE

OW-UP 29

2

OW UP

4

29

4% (of 7% = 2%)

THE PRIMARY JUSTIFICATION FSENSITIVITY, USUALLY COMPACYTOPATHO OGYCYTOPATHOLOGY.

THIS SENSITIVITY IS ACQUIREDPREDICTIVE VALUE (ABOUT 50FOLLOWED FOR “BLADDER CAPEOPLE WITH HEMATURIA) THPEOPLE WITH HEMATURIA). THWITH MULTIPLE TESTS AND WABNORMAL BUT SO CAN THE

FISH CANNOT DISTINGUISH AGNEOPLASMS AND UROLOGISTTREAT SOLELY ON THE BASIS

PATIENTS BENEFIT PRIMARILYPATIENTS BENEFIT PRIMARILYFREQUENCY AND/OR AGGRESEVALUATIONS.

FOR FISH IS ITS HIGH ARED TO VOIDED URINARY

D AT THE COST OF POSITIVE 0% FOR PATIENTS BEINGANCER” AND 3-25% FOR HE PPV CAN BE INCREASEDHE PPV CAN BE INCREASEDHEN CYTOPATHOLOGY IS RESULTS OF CYTOPATHOLOGY.

GGRESSIVE FROM INDOLENT TS ARE VERY UNLIKELY TO

OF FISH.

Y FROM CHANGES IN THEY FROM CHANGES IN THESSIVENESS OF THEIR

SO, WHAT CHANGES IN EVALUATION OR FOA POSITIVE TEST THAT IS LIKELY TO BE CO(MONITORING) OF THE TIME?

PATIENTS WITH HEMATURIA AND A POSITIV(?AGGRESSIVELY) FOR A UROTHELIAL NEO(?AGGRESSIVELY) FOR A UROTHELIAL NEOFOUND HAS NOT BEEN ADDRESSED.

PATIENTS WITH HEMATURIA AND A NEGATIEVALUATIONEVALUATION.

FOR PATIENTS WITH UROTHELIAL NEOPLABE JUSTIFIED IF THE INITIAL TUMOR WERE

CYSTOSCOPY AT EACH VISIT COULD DEPE

MORE FREQUENT AND AGGRESSIVE FOLLOMORE FREQUENT AND AGGRESSIVE FOLLOBE HARD TO JUSTIFY CONSIDERING THE LTO IDENTIFY HIGH-RISK LESIONS.

LESS FREQUENT MONITORING WOULD BE HIGH-RISK NEOPLASM.

OLLOWUP ARE LIKELY WHEN A PATIENT HASORRECT ONLY 3-25% (HEMATURIA) OR 50%

VE FISH COULD BE EVALUATED OPLASM. HOW OFTEN IF NO LESION ISOPLASM. HOW OFTEN IF NO LESION IS

IVE FISH COULD AVOID A BLADDER TUMOR

ASMS, LESS FREQUENT FOLLOWUP MIGHT E LOW-RISK (PUNLMP/LOW-GRADE,Ta)( , )

END ON FISH REMAINING NEGATIVE.

OWUP SOLELY FOR A POSITIVE FISH WOULDOWUP SOLELY FOR A POSITIVE FISH WOULDLOW PPV AND THE INABILITY OF THE TEST

HARD TO JUSTIFY FOR ANY PATIENT WITH A

FISH FAFISH FA

SAME AS UC - LONG LEAD TIMTO INTERPRET RESULTING IN HIGH ICOMPLEXITY TECHNOLOGISTS REQ

DIFFERENT FROM UC - HIGLESS RELIABLE RESULTS (LOWER PREIMBURSEMENTREIMBURSEMENTIF PATIENTS PRESCREENESHOULD BE COMPARED WCOST EFFECTIVENESS VSFISH BEST (cf VU) FOR LONEOPLASMS BUT NEED FONEOPLASMS BUT NEED FOQUESTIONABLE

ACTORSACTORS

E, FLUCTUATING RESULTS, DIFFICULT NTEROBSERVER VARIABILITY, HIGH UIRED

HER SENSITIVITY, SPECIFICITY BUT PPV), HIGHER COSTS AND

ED WITH CYSTO, FISH WITH BW, NOT VU

UC NOT ADDRESSEDW-GRADE, NON-INVASIVE OR EARLY DETECTIONOR EARLY DETECTION

WHO SHOULDWHO SHOULD

PATIENTS WHOSE MPATIENTS WHOSE MBE CHANGED BY THBE CHANGED BY TH

-- “BlCa” F/U WITH NON“BlCa” F/U WITH NONABNORMAL CYSTOABNORMAL CYSTO-- ABNORMAL CYSTO, ABNORMAL CYSTO,

-- SPECIAL PROTOCOLSPECIAL PROTOCOL

D GET A FISH?D GET A FISH?

MANAGEMENT WILLMANAGEMENT WILLHE RESULTHE RESULT

NN--POSITIVE CYTOLOGYPOSITIVE CYTOLOGYNONNON POSITIVE CYTOPOSITIVE CYTONONNON--POSITIVE CYTOPOSITIVE CYTO

LS OF THE PRACTICELS OF THE PRACTICE

“BlCa” PATIENT - CYTOLOGY SUSP, CYSTOSCOPY NEG

WHO SHOULD N

PATIENTS WHO WILL BE FOANYWAY i e THEY HAVE AANYWAY i.e. THEY HAVE A (HIGH-GRADE UCa, CIS, TI-

PATIENTS WITH A POSITIVE

PATIENTS WITH A POSITIVEPATIENTS WITH A POSITIVE

PATIENTS WITH VERY LOW(PUNLMP PAPILLOMA DYS(PUNLMP, PAPILLOMA, DYS

OT GET A FISH?

OLLOWED AGGRESSIVELY HIGH RISK INDEX TUMORHIGH-RISK INDEX TUMOR -2, NON- UCa)

E CYSTOSCOPY

E CYTOLOGYE CYTOLOGY

W-GRADE INDEX LESIONSSPLASIA)SPLASIA)

URINARY CYTOPATHOLCURRENTLY AVAILABLCURRENTLY AVAILABLCAN DISTINGUISH AGGCARCINOMAS FROM NCARCINOMAS FROM NUROTHELIAL NEOPLAS

IT REMAINS THE BEST PATIENTS FOR RECURPATIENTS FOR RECURDISEASE.

LOGY IS THE ONLY LE METHOD THATLE METHOD THATGRESSIVE UROTHELIAL ON-AGGRESSIVEON-AGGRESSIVE SMS.

WAY TO MONITOR RENT/PERSISTENTRENT/PERSISTENT