Tumour markers in urology

Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai

Moderators:
Professors:
 Prof. Dr. G. Sivasankar, M.S., M.Ch.,
 Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
 Dr. J. Sivabalan, M.S., M.Ch.,
 Dr. R. Bhargavi, M.S., M.Ch.,
 Dr. S. Raju, M.S., M.Ch.,
 Dr. K. Muthurathinam, M.S., M.Ch.,
 Dr. D. Tamilselvan, M.S., M.Ch.,
 Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

PROSTATE TUMOUR MARKERS
Prostatic acid phosphatase: high
concentrations in semen, prostate
 Neither protate tissue nor tumour specific
 Increased in prostate,breast,stomach,colon ca
 Less stable than PSA
 Overall poor specificity
3
Dept of Urology, GRH and KMC, Chennai.

PROSTATE-SPECIFIC ANTIGEN
 34-kD glycoprotein /237 aminoacids
 Produced by epithelial cells forming acini/ducts of
prostate gland
 Chromosome 19
 Proteolytic enzyme of kallikrein family-liquify human
semen
 First identified in 1969-Hara-seminal fluid
4

 Free /complexed form –α₁-anti chymotrypsin,
α₂ macroglobulin
• Free:complexed PSA=1:4
 Tissue specific but not cancer specific
 Periurethral glands,some breast cancers also produce
PSA
5

 BPH/protatitis/significant elevations in older men
after ejaculations
 No studies have shown significant elevation in serum
PSA after routine DRE
 Four fold rise in serum PSA after cystoscopy with
prostatic massage (stamey )
6

PSA-SCREENING GUIDELINES
 Men >50 yrs with >10 yrs life expectancy
 Men >45 yrs considered at high risk (african descent
,family h/o cancer in first degree relative )
7

 In early detection of prostate cancer
 PSA>4 ng/ml-detected 82% of tumour
 DRE detected 55%
 75% of tumour detected by PSA –organ
confined ,56% by DRE ,78% if both are
used
 (Catalona,J Urol 1994;151:1283-90 )
8

 Carter and colleagues concluded that curable
prostate cancer is not likely to be missed with
2 year testing interval, in men >55 yrs having
normal DRE and initial PSA <2ng/ml
 Carter,JAMA 1997;277,1456-60
9

AGE-SPECIFIC PSA REFERENCE
RANGES
 40-49 yrs -0 to 2 ng/ml
 50-59yrs- 0 to 3 ng/ml
 60-69yrs- 0 to 4 ng/ml
 70-79yrs- 0 to 5 ng/ml
 Detected 18% more tumours in men< 60 yrs
 81% of tumours detected in young had favourable
patologic findings
 Partin,J Urol 1996:47:518-24
10

FREE/TOTAL PSA
 % of free PSA of <25% in men with total PSA
between4-10ng/ml was 95% sensitive and had
improved specificity for detecting ca and avoiding
biopsies in 20% BPH
 Catalona,JAMA 1998;279:1542-7
11

FREE/TOTAL PSA
 Complexed PSA has superior specificity over total PSA
and free to total PSA with only slight reduction in
sensitivity (81% vs 83% )
 Brawer ,Urology 1998;52;372-8
12

PSAV
 Carter in 1992
 Most useful for assessing risk of prostate cancer in
individual with normal yet rising total PSA
 PSAV-0.75 ng/ml/year (sensitivity 72%,
specificity 90% )
13

PSAV
 3 consecutive PSA measurements over 1.5 -2 year
period
 PSA2-PSA1/time in years+PSA3-PSA2/time in years
 Overall <5% of men without prostate ca will have
PSAV 0.75 ng/ml/yr and 70% of men will have
prostate cancer (UCNA 1993,20;653-63)
14

PSA-DENSITY
 Total serum PSA(ng/ml)/prostatic volume cm³
 >0.15 enhanced prostate cancer detection in men
between 4-10 ng/ml (52% sensitivity )
 PSAT-0.35 ng/ml/cc
 Limitations-operator dependant
15

HUMAN KALLIKREIN 2
 Hk2 and PSA share 80% amino acid homology
 Activate Ppsa to active PSA
 IHC revealed differential expression pattern for hk2
and PSA
 Hk2/fPSA ratio
16

Kallikrein markers
 KLK4
 KLK11
 KLK14
 KLK15
17

PSMA
 Folate hydratase found in cell membrane of prostate
epithelium,brain small bowel
 PSMA m RNA expression within protate cancer
,highest in hormone deprived state
 PSMA/PSM’ ratio upregulated 3-6 fold in prostate
cancer
 Immuno-SELDI assay
18

NEW MARKERS
 Ki-67 labelling index (LI )
 P53 and BCL2 staining
 MVD-CD31 staining
 AMACR staining
19

AFP
 70 kD glycoprotein first found normal human fetal
serum in 1954
 Dominant serum protein of early embryo
 Concentrations peak at 12-14 wks ofgestation, decline
after 16 wks,fall by 1 year of age <10ng/dl which is
usually seen in adults
21

AFP
 Cells of yolk sac origin is responsible for its production
 Elevated in benign liver disease, pregnancy,ataxia
telangiectasia , tyrosenemia and in HCC ,ca
pancreas,stomach and lung
 Elevated in embryonal carcinoma, teratocarcinoma
and yolk sac tumours
 Never present in pure seminoma or choriocarcinoma
22

HCG
 38kD hormone - by syncitiotrophoblasts
 α and β subunits
 β subunit is antigenically and structurally
distinct /biologically active
 Only minute amounts are detectable in healthy adults
( <5 IU/ml )
23

HCG ELEVATIONS
 Pregnancy ,gestational disorders
 Hepatic, pancreatic, gastric, pulmonary, breast, renal,
bladder tumours and in multiple myeloma
 In GCT, 40-60% of patients will have elevated levels
• All pts with choriocarcinoma
• 80% of pts with embryonal carcinoma
• 10-25% of those pts with seminoma
24

LACTATE DEHYDROGENASE
 134 KD cellular protein
 Expressed in skeletal, cardiac, smooth muscle, liver,
kidney and brain
 Specificity for testicular tumours is extremely poor
,not particularly useful in diagnosis
 Extremely useful prognostic marker
25

LACTATE DEHYDROGENASE
 Important role in monitoring response to treatment &
recurrence in pts with advanced disease
 Five isoenzymes
 LDH-1 MC elevated isoenzyme
26

PLACENTAL ALKALINE
PHOSPHATASE
 Fetal isoenzyme of adult alkaline phosphatase
 Normally expressed in utero,children < 1 yr
 Protein phosphotyrosine phosphatase
 Widely accepted as a reliable histologic marker for
seminoma
 Merit as a serum tumour marker is uncertain
 Elevated in 50-72% of pts with higher stages of
seminoma
27

PLACENTAL ALKALINE
PHOSPHATASE
 PLAP have higher sensitivity for detecting metastases
/specificity is poor
 Elevated in smokers, ca lung ,ovary, breast, GI
malignancies
 Overall,not a proven beneficial serum marker for
testicular neoplasms
28

OTHER SERUM MARKERS
 Neuron specific enolase
 Carcinoembryonic antigen
 Pregnancy specific B1 glycoprotein (SP-1 )
29

OTHER SERUM MARKERS
 Terato-related antigen (TRA )-1-60
 Keratan sulphate proteoglycan
 Expressed on surface of embryonal carcinoma
progenitor cells
 Elevated in 80% of disseminated GCT,fall with
chemotheraphy
 Failure to return to normal 17% of NSGCT &13% GCT
30

CYTOGENETIC MARKERS
 ATKIN & BAKER -1983
 Duplication of short arm of chromosome 12 designated as
i(12p)
 Found in 83% male GCTs (89% SGCT, 81%NSGCT) in all
histologic types
 Presence of more than 3 copies of i(12p) predicts poor
response to chemotheraphy
 Exact clinical value is still evolving
31

PROTO-ONCOGENES
 hst-1 gene-long arm of chromosome 11
 Encodes FGF
 Expressed in 63%NSGCT, 4% seminomas
 c-kit gene –expressed in 80% seminoma,7% NSGCT
32

.TUMOUR SUPPRESSOR GENE
 Retinoblastoma gene (RB)
 Mutated p53 protein –detected in 77% of GCT
33

CLINICAL APPLICATIONS
 Diagnosis-screening not practical –poor specificity
 Extragonadal GCT –positive IHC staining for
AFP/HCG
 i(12p) expressed in >80% GCT
 NSGCT-↑AFP or HCG in 85% (AFP alone 40%,HCG
alone 50-60%)
 Seminoma-no AFP,10-25%HCG
34

 PROGNOSIS: LDH acts as a prgnostic factor for
growth rate and disease specific survival
 STAGING
 RISK STRATIFICATION
35

 MONITORING RESPONSE TO THERAPY
 After surgery -4.5 days-AFP
 16-24 hours for HCG
 1 day-LDH
 After chemotheraphy -10 fold decrease in markers over
3 week period is consistent with good response
36

 Recurrence-AFP and HCG –first indication in 50%
(sensitivity 86%,specificity-100%)
 LDH-in 10% NSGCT
37

URINE BASED BLADDER TUMOUR
MARKERS
 Non invasive
 Rapid
 Objective
 Easy to perform & interpret
 High sensitivity & specificity
38

NMP22
 Evaluates urinary levels of nuclear mitotic apparatus
protein, found in nuclear matrix of all cells
 Quantitative analysis-ELISA or point -of –care test,
bladderchek test
 10 IU/ml is the threshold for a positive test
39

NMP22
 False positive in
 Cystitis
 Haematuria
 Pyuria
 NMP22 BladderChek had higher sensitivity than
cytology (55% vs 16% ) but less specificity (86%vs
99%)
40

NMP22
 In combination with cystoscopy it detects 99% of
recurrence,during surveillance .
 NMP22 always best used as an adjunct and might not
have the ability to fuction as stand alone test in place
of cystoscopy
41

BTA –STAT & BTA TRAK
 Enzyme immuno assays to measure human
complement factor H-related protein in urine by
using MAB X13.2 & X52.1
 BTAstat is a qualitative point of care diagnostic test
(sensitivity-68% ; specificity 74% )
 BTA TRAK –quantitative test-sensitivity62% ;
specificity 74%
42

BTA –STAT & BTA TRAK
 More sensitive than cytology for low grade tumours ;
equivalent sensitivity for high grade tumours
 False positive in
 Haematuria
 Nephrolithiasis
 Recent instrumentation
 Intra vesical BCG /inflammation /
43

IMMUNOCYT
 Fluorescent labelled antibodies to three cell surface
glycoprotein antigens commonly found on malignant
urothelial cells
 M344 (71% Ta-T1 tumours )
 LDQ10
 19A211 (90% Ta-T1 tumours )
44

IMMUNOCYT
 Sample is positive –if atleast one cell has red or green
fluorescense
 Negative declared only after countig 500 cells
 Usually used with cytology to improve sensitivity
 Limitations: 500 cells/slide ,difficulty in detecting
green fluorescence,need for trained person
45

IMMUNOCYT
46

IMMUNOCYT(40-92%;62-84%)
variables sensitivity specificity
Immunocyt+ctyo
logy –LG
TUMOURS
79%
Cytology –LG
TUMOURS
8%
Immunocyt+ctyo
logy –HG
TUMOURS
99%
Cytology –HG
TUMOURS
75%
47

UROVYSION
 Detects increased copy numbers of chromosomes
3,7,17 and homozygous deletions of loci 9p21 using
FISH
 Test positive- 5 or more cells have two or more
chromosomal gains(3,7,17) or
 if more than 12 cells gain a single chromosome
 homozygous deletion 9p21 in >12cells
48

UroVysion test
49

UROVYSION
 Sensitivity-81%;specificity-96% for high grade
tumours & ca in situ , but low sensitivity 36-57% for
low grade/stage tumours
 Positive test can predict disease ahead upto 6-20
months in 60% of patients
 Complex aneuploidy of chromosome 7&17-high risk of
recurrence
 Isolated 9p21/chromosopme3 aberration-low risk
50

UROVYSION
 Better adjunct to cystoscopy than cytology but more
expensive
 Urovysion FISH useful in predicting recurrence after
intravesical theraphy
 Also very effective in arbitrating equivocal urine
cytology results
 Cytology scores over urovysion for detecting 2nd
primary who had cystectomy &urine diversion
51

CYTOKERATINS
 Intracellular cytoskeletal proteins (8,18,19,20)
 For cytokeratin 8 & 18 –threshold is 12ng/ml
 Cytokeratin 19 measured with CYFRA 21-1
test,sensitivity-75-96%;specificity 67-74%
 False positive cytokeratin19 –BPH,nephrolithiasis ,UTI
,previous BCG treatments
52

53

RCC associated antigen
G250/MN/CAIX
 Present in >85% of all RCC, 99% of the clear-cell
subtype
 No expression in normal kidney
 High CA-9 expression correlated with improved
survival
54

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Tumour markers in urology

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