on-k8 kuliah tumor marker's.ppt
TRANSCRIPT
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TUMOR MARKERSTUMOR MARKERS
Prof. Adi Koesoema Aman .Prof. Adi Koesoema Aman .
dr. Zulfikar Lubis SpPK(K) .dr. Zulfikar Lubis SpPK(K) .
Departement of Clinical PathologyDepartement of Clinical Pathology
University of Sumatera Utara / RSUP.University of Sumatera Utara / RSUP.
H.Adam Malik Medan .H.Adam Malik Medan .
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PENGERTIAN SECARA UMUM :PENGERTIAN SECARA UMUM :
Penanda tumor serologik merupakanPenanda tumor serologik merupakan
produk yang berasal dari tumor ,produk yang berasal dari tumor ,
yang kadarnya dalam darahyang kadarnya dalam darah
merupakan pencerminan masamerupakan pencerminan masa
tumor yang ada dalam tubuh .tumor yang ada dalam tubuh .
Dulunya dianggap ada harapan produkDulunya dianggap ada harapan produk
tersebut sensitip dan spesifiktersebut sensitip dan spesifiksehinga dapat digunakan sebagaisehinga dapat digunakan sebagai
test kanker tipe tumor tertentu .test kanker tipe tumor tertentu .
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What are Tumor MarkersWhat are Tumor Markers
Biological substances synthesizedBiological substances synthesizedand released by cancer cells orand released by cancer cells or
produced by the host in responseproduced by the host in response
to the presence of tumorto the presence of tumor
Detected in a solid tumor, inDetected in a solid tumor, in
circulating tumor cells incirculating tumor cells inperipheral blood, in lymph nodes,peripheral blood, in lymph nodes,
in bone marrow, or in other bodyin bone marrow, or in other body
fluid (urine, stool, ascites)fluid (urine, stool, ascites)
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PENGERTIAN PENANDA TUMOR
PENGERTIAN LAMA :
Berbagai substansi yang diekskresikan olehsel kanker kedalam cairan tubuh /
diproduksi oleh sel jinak sebagai respons
terhadap keganasan
Tumor marker
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PENGERTIAN BARU PENANDA TUMOR
PENGERTIAN LAMAPLUS
Berbagai molekul termasuk onkogen
& anti onkogen serta produknya yangdiekspresikan oleh sel kanker
BIOMARKER KEGANASAN
Dapat diukur kualitatif & kuantitatif
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P
EN
A
N
D
A
T
U
MO
R
SELULER :
perubahan yang tampak/diidentifikasi di tingkat
seluler
SEROLOGIK :
produk sel ganas
produk sel sebagai respons
terhadap keganasan
MOLEKULER
(Biomarker)
perubahan yang diidentifikasi
di tingkat molekuler
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ONKOGENESIS DAN PENANDA TUMOR
Growth promoting
oncogenes
Tumor suppressor
genesDNA repair
gene
Gangguan kontrol
genetik
Mutasi
Inaktivasi
Mutasi
Amplifikasi
Apoptosis Defek
Defek
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MULTISTEP CARCINOGENESISMULTISTEP CARCINOGENESIS
Environment CarcinogenCarcinogen
Electroph interm
metabolism Excretion
detoxification
detoxification
Binding to DNA
RNA, proteinNormal cell
DNA repair
Cell death
Permanent DNA lesion
DNA replication
Preneoplastic cells
Neoplastic cells
? ?
Initiation
Promotion
and
Progression
Multiple factors
Multiple stages
Multiple genetic
targets
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PENGGUNAAN PENANDA TUMOR .PENGGUNAAN PENANDA TUMOR .
Skrening dan Deteksi Awal .Skrening dan Deteksi Awal .
Differential Diagnosis .Differential Diagnosis .
Menentukan Prognosis .Menentukan Prognosis . Meramal Residif .Meramal Residif .
Menganalisa Respons TerapiMenganalisa Respons Terapi ..
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Klasifikasi Penanda Tumor .Klasifikasi Penanda Tumor .
Protein Onkofetal .Protein Onkofetal .- Carcino Embrionik Antigen ( CEA ) .- Carcino Embrionik Antigen ( CEA ) .
- Alfa feto Protein ( AFP ) .- Alfa feto Protein ( AFP ) .
Hormon .Hormon .- HCG ,HPL , ACTH , ADH , Parathormon .- HCG ,HPL , ACTH , ADH , Parathormon .
Enzim .Enzim .
- PAP , LDH , NSE .- PAP , LDH , NSE . Immunoglobulin .Immunoglobulin .
Antigen terassosiasi tumorAntigen terassosiasi tumor
- CA 19-9 , CA 125 , PSA .- CA 19-9 , CA 125 , PSA .
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Potential Uses of TumorPotential Uses of Tumor
MarkersMarkersPopulation ScreeningPopulation Screening
DiagnosisDiagnosis
Establishing prognosis, stagingEstablishing prognosis, staging
Postoperatory evaluationPostoperatory evaluation accessaccess
the radicality of the surgerythe radicality of the surgery
Monitor treatment responseMonitor treatment responseSurveillance for recurrenceSurveillance for recurrence
Targets for therapeuticTargets for therapeutic
interventionintervention
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Positive Predictive ValuePositive Predictive Value
of a Tumour Markerof a Tumour Marker
True positivesTrue positives
True positives + False positivesTrue positives + False positives
The probability with which a tumour exists within a controlgroup in the case of positive test results
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Negative Predictive ValueNegative Predictive Value
of a Tumour Markerof a Tumour Marker
True negativesTrue negatives
True negatives + False negativesTrue negatives + False negatives
The probability with which no tumour exists within a controlgroup in the case of negative test results
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SpecificitySpecificity
True negativesTrue negativesTrue negatives + False positivesTrue negatives + False positives
The percentage of normal persons or persons with benign conditions forwhom a negative result is obtained. The greater the specificity, thefewer the false-positives.
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SensitivitySensitivity
True positivesTrue positives
True positives + False negativesTrue positives + False negatives
The percentage of test results which are correctly positive in thepresence of a tumour. The greater the sensitivity, the fewer the false-negatives.
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Cut-off value
The concentration of a tumour markerThe concentration of a tumour markerwhich differentiates healthy subjectswhich differentiates healthy subjects
from diseased subjectsfrom diseased subjects
usually taken as the mean concentrationusually taken as the mean concentrationof a control group plus 2 standardof a control group plus 2 standard
deviations (or the 95th percentile)deviations (or the 95th percentile)
control group could be healthy subjectscontrol group could be healthy subjects
or persons with benign diseaseor persons with benign disease
target specificity should be 95% ( 5%target specificity should be 95% ( 5%
false positives)false positives)
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Dynamic follow upDynamic follow up
Conc. of TM
Time
cut off
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Dynamic follow upDynamic follow up
Conc. of TM
Time
cut off
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Statistical ConsiderationsStatistical ConsiderationsSensitivitySensitivity cancer (+), abnormal testcancer (+), abnormal testSpecificitySpecificity cancer (-), normal testcancer (-), normal testPositive predictive valuePositive predictive value abnormalabnormal
test, cancer (+)test, cancer (+)Negative predictive valueNegative predictive value normal test,normal test,
cancer (-)cancer (-)PrevalencePrevalence affect PPV, everyaffect PPV, every
marker has failed as a screening test inmarker has failed as a screening test inASYMPTOMA -TICASYMPTOMA -TIC persons, becausepersons, becausethe PREVALENCE of cancer is lowthe PREVALENCE of cancer is lowamongamong ASYMPTOMATICASYMPTOMATIC personspersons
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Tumor Specific ProteinsTumor Specific Proteins
Expressed only in tumor cellsExpressed only in tumor cells Example: an oncogene is translocated andExample: an oncogene is translocated and
fused to an active promoter of another genefused to an active promoter of another gene
fusion proteins constant active fusion proteins constant active
production development of malignantproduction development of malignantcloneclone
Philadelphia chromosome in CML, t(9;22)Philadelphia chromosome in CML, t(9;22)
(q34;q11) bcr/abl translocation(q34;q11) bcr/abl translocationT(8;21) acute non-lymphocytic leukemia,T(8;21) acute non-lymphocytic leukemia,
t(15;17) APLt(15;17) APL
HematologicalHematological malignanciesmalignancies
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Non-Specific Proteins or MarkersNon-Specific Proteins or Markers
Related to Malignant CellsRelated to Malignant Cells
Oncofetal proteinsOncofetal proteins expressed byexpressed by
cells as they de-differentiate andcells as they de-differentiate and
take on embryonic characteristicstake on embryonic characteristics-FP-FP HCC, testicular, ovarian cancerHCC, testicular, ovarian cancer
CEACEA many GI tumorsmany GI tumors
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Cell Specific ProteinsCell Specific Proteins
Overexpressed in Malignant CellsOverexpressed in Malignant Cells
Proteins expressed normally byProteins expressed normally by
differentiated cells, but are expresseddifferentiated cells, but are expressed
at higher rates in the correspondingat higher rates in the correspondingtumor cellstumor cells
PSAPSA prostate cancerprostate cancer
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Colorectal CancerColorectal Cancer
Carcinoembryonic antigen (CEA)Carcinoembryonic antigen (CEA)fetal glycoprotein found on cell surfaces,fetal glycoprotein found on cell surfaces,
produced by fetal GI tract, liver, andproduced by fetal GI tract, liver, andpancreaspancreas
Normal serum and tissue fluid valueNormal serum and tissue fluid value
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CEACEA
fibrocystic breast disease Found also infibrocystic breast disease Found also in
30~50% of30~50% ofbreast cancerbreast cancer, small cell lung, small cell lung
cancer, mucinous cystadenocarcinoma ofcancer, mucinous cystadenocarcinoma of
ovary, adenocarcinoma of cervixovary, adenocarcinoma of cervix
Elevation (
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Alpha-Fetoprotein in HCCAlpha-Fetoprotein in HCC
Glycoprotein, found in fetal liver, yolkGlycoprotein, found in fetal liver, yolksac, GI tract, biochemically related tosac, GI tract, biochemically related to
albumin in adultsalbumin in adults
half-lifehalf-life 4~6 days4~6 daysNormal serum levelsNormal serum levels
12~15th gestational week 30~40 ng/mlAt birth 30 ng/ml
>1 years old (adult)
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Increased in 70%Increased in 70% HCCHCC, elevated in, elevated inhepatoblastomahepatoblastoma, 20~70%, 20~70% germ cell tumorsgerm cell tumors(yolk sac tumors, embryonal cell carcinoma) of(yolk sac tumors, embryonal cell carcinoma) oftestis and ovary,testis and ovary, except dysgerminomaexcept dysgerminoma
For Hbs Ag (+) chronic hepatitis/cirrhosisFor Hbs Ag (+) chronic hepatitis/cirrhosisscreening, further improved by using USscreening, further improved by using US
The absolute AFP level correlates with tumorThe absolute AFP level correlates with tumorbulkbulk
CSFCSF plasma ratio of AFP > 1:40 suggestplasma ratio of AFP > 1:40 suggest
CNS involvementCNS involvementBenignBenign conditions that cause hepaticconditions that cause hepatic
parenchymal inflammation, hepatic necrosisparenchymal inflammation, hepatic necrosisand hepatic regeneration, ex.and hepatic regeneration, ex. hepatitishepatitis,,
pregnancy, primary biliary cirrhosis,pregnancy, primary biliary cirrhosis,
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Germ Cell TumorsGerm Cell Tumors
Human chorionic gonodotropinHuman chorionic gonodotropin((HCGHCG))Glycoprotein synthesized byGlycoprotein synthesized by
syncythiotrophoblastic cells of normalsyncythiotrophoblastic cells of normalplacenta,placenta, never in males!never in males!
Serum and urine HCG in early gestation andSerum and urine HCG in early gestation and
peak in the first trimester (60~90 days)peak in the first trimester (60~90 days)
T : 1.25 days, ~30 hoursT : 1.25 days, ~30 hours
Elevated inElevated in gestational trophoblasticgestational trophoblastic
diseasedisease ( a progressive rise in after 90 days( a progressive rise in after 90 days
of gestation highly suggestive),of gestation highly suggestive),
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Germ Cell TumorsGerm Cell Tumors
DetectionDetection
Monitor treatment response (ex. C/T)Monitor treatment response (ex. C/T)
production of BHCG ceases onproduction of BHCG ceases on
commencement of tx, rising or persistentlycommencement of tx, rising or persistentlyelevated levels are diagnostic of resistanceelevated levels are diagnostic of resistance
to C/Tto C/T
evaluate radicality of the surgery: ex. Inevaluate radicality of the surgery: ex. In
testicular cancer, the presence of -HCGtesticular cancer, the presence of -HCGafter orchiectomy residual cancer andafter orchiectomy residual cancer and
needs further treatmentneeds further treatment
Monitor relapse (reliable indicator of CR)Monitor relapse (reliable indicator of CR)
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Breast CancerBreast Cancer
CA 15-3CA 15-3 monitor treatment and tomonitor treatment and todetect recurrencedetect recurrenceNormalNormal < 31 U/ml< 31 U/ml
in 20% with localized breast cancer,in 20% with localized breast cancer,~80% with metastatic disease, esp. if~80% with metastatic disease, esp. ifwith bone involvmentwith bone involvment
Specificity of 86%, sensitivity of 30%Specificity of 86%, sensitivity of 30%
Also increased in gastric, pancreatic,Also increased in gastric, pancreatic,cervical lung cancercervical lung cancer
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Breast CancerBreast Cancer
Estrogen receptor (ER)Estrogen receptor (ER)
2 isoforms2 isoforms ERa + ERbERa + ERb
ERaERa better prognosis, predictor of relapse better prognosis, predictor of relapse
useful when deciding on adjuvant hormoneuseful when deciding on adjuvant hormonetreatmenttreatment
Not guarantee response, fails in 30~40% of patientsNot guarantee response, fails in 30~40% of patients
to endocrine treatmentto endocrine treatment
As diagnostic marker when it is a primary unknownAs diagnostic marker when it is a primary unknowntumortumor
ERbERb distinct biological roles and ligand binding distinct biological roles and ligand binding
specificity, good prognostic factor, correlate with lowspecificity, good prognostic factor, correlate with low
grade and (-) axillary LN statusgrade and (-) axillary LN status
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HER-2/neu oncogeneHER-2/neu oncogene (using monoclonal(using monoclonal
antibody)antibody) overexpression related to poor prognosisoverexpression related to poor prognosisin breast cancerin breast cancer
Oncogene c-erbB-2 geneOncogene c-erbB-2 gene overexpressed in 30%overexpressed in 30%of breast cancers, correlation between c-erbB-2 geneof breast cancers, correlation between c-erbB-2 genepositivity, positive axillary node status, reduced timepositivity, positive axillary node status, reduced timeto relapse and reduced overall survivalto relapse and reduced overall survival
BRCA1 gene on chromosome 17qBRCA1 gene on chromosome 17q familialfamilial
breast-ovarian cancer syndromebreast-ovarian cancer syndrome, and breast cancer, and breast cancerin early-onset breast cancer families in early-onset breast cancer families high riskhigh riskscreeningscreening
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Cervical Sqamous CellCervical Sqamous Cell
CarcinomaCarcinoma
Squamous cell carcinomaSquamous cell carcinoma
antigenantigen ((SCCSCC))Normal value:
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Oncogenic versus & low-risk HPVOncogenic versus & low-risk HPV
typestypes
>120 types identified>120 types identified22
~3040 anogenital types~3040 anogenital types2,32,3
~1520 oncogenic types*~1520 oncogenic types* ,2,3,2,3
HPV 16 and HPV 18 typesHPV 16 and HPV 18 types
account for the majority ofaccount for the majority of
worldwide cervicalworldwide cervicalcancers.cancers.44
~15-20 nononcogenic** types~15-20 nononcogenic** types
HPV 6 and 11 types areHPV 6 and 11 types are
most often associatedmost often associated
withwithexternal anogenital wartsexternal anogenital warts
(90%).(90%).33
1. Howley PM, Lowy DR. In: Knipe DM, Howley PM, eds. Philadelphia, Pa: Lippincott-Raven; 2001:21972229.
2. Schiffman M, Castle PE.Arch Pathol Lab Med. 2003;127:930934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210S224. 4. MuozN, Bosch FX, Castellsagu X, et al. Int J Cancer. 2004;111:278285.
Nonenveloped double-Nonenveloped double-
stranded DNA virusstranded DNA virus11
*High risk; ** Low risk
World ide Pre alence of HPV T pes inWorldwide Prevalence of HPV Types in
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Central/SouthAmerica
Northern Africa
North America/Europe
South Asia
16
18
45
3133
HPV Type
52
Others
A pooled analysis and multicenter case control study (N = 3607)
1. Muoz N, Bosch FX, Castellsagu X, et al. Int J Cancer. 2004;111:278285.
Worldwide Prevalence of HPV Types inWorldwide Prevalence of HPV Types in
Cervical CancerCervical Cancer*,1*,1
58
57
12.6
69.7
14.6
67.6
1752.5
25.7
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Ovarian CancerOvarian Cancer
CA-125CA-125 Cell surface glycoprotein, present during embryonicCell surface glycoprotein, present during embryonic
development of coelomic epithelium and is presentdevelopment of coelomic epithelium and is present
in adult structures derived from itin adult structures derived from it
NormalNormal 80% of epithelial ovarian cancer, cell types
serousserous> endometriod, clear cell > mucinous> endometriod, clear cell > mucinous
Correlate with tumor bulkCorrelate with tumor bulk
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Low specificity and poor sensitivity inLow specificity and poor sensitivity in
detecting small-volume diseasedetecting small-volume disease
Also found in carcinoma of pancreas, colon ,Also found in carcinoma of pancreas, colon ,
gallbladder, stomach, kidney, breast, andgallbladder, stomach, kidney, breast, and
lunglung
Endometriosis is the most commonEndometriosis is the most common
alternative diagnosis, elevated levels alsoalternative diagnosis, elevated levels alsofound in PID, 1found in PID, 1stst trimestertrimester
CA 19-9CA 19-9
A mucin, normalA mucin, normal serous (27%)
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Pancreatic CancerPancreatic Cancer
CA 19-9CA 19-9 mucin, normalmucin, normal
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Prostate CancerProstate Cancer
PSAPSA Tissue specific antigenTissue specific antigen , produced by, produced by
prostatic alveolar and ductal epithelialprostatic alveolar and ductal epithelial
cells , a serine protease, t 1/2cells , a serine protease, t 1/2 2~3 days2~3 days
Age Serum PSA (ng/ml)40~50 0~2.5
50~60 0~3.5
60~70 0~4.5
70~80 0~6.5
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RelapseRelapse
Reflect response to treatment and correspond toReflect response to treatment and correspond totumor volume and androgen leveltumor volume and androgen level
As a predictor of surgical failureAs a predictor of surgical failure by using RT-PCRby using RT-PCR
for PSA to detect circulating prostate cancer cellsfor PSA to detect circulating prostate cancer cellsin the bloodstreamin the bloodstream
PSA is expected to be undetectable >30 days afterPSA is expected to be undetectable >30 days after
the radical prostatectomy, persistent elevatedthe radical prostatectomy, persistent elevatedlevel indicate residual diseaselevel indicate residual disease
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Free PSAFree PSA PSA that is not bound to the plasmaPSA that is not bound to the plasmaantiproteases 1-antichymotrypsin and 2-antiproteases 1-antichymotrypsin and 2-macroglobulinmacroglobulin
An in ratio of free/total PSA is associatedAn in ratio of free/total PSA is associatedwith increased probability of prostate cancerwith increased probability of prostate cancer
97% specific for this disease, 96% sensitivity97% specific for this disease, 96% sensitivity
in detecting diseasein detecting diseaseForFor population screeningpopulation screening and diagnosisand diagnosis
an increase of 0.75 ng/ml per year in anyan increase of 0.75 ng/ml per year in anygiven patient has high sensitivity andgiven patient has high sensitivity and
specificity for prostate cancer vs BPH,specificity for prostate cancer vs BPH,especially when combined with DRE andespecially when combined with DRE and
TRUSTRUS
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FPSAFPSA
FPSA non complexed form of PSAFPSA non complexed form of PSA
If level of PSA is between 3- 20If level of PSA is between 3- 20 g/lg/l
Ratio FPSA/PSA discriminationRatio FPSA/PSA discriminationbetween cancer and benign prostaticbetween cancer and benign prostatic
hyperplasiahyperplasia
Cut off 0,25Cut off 0,25
As the ratio increases, probability ofAs the ratio increases, probability of
BPH increasesBPH increases
M lMelanoma
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MelanomaMelanoma
TyrosinaseTyrosinase
Use RT-PCR to detect hematogenousUse RT-PCR to detect hematogenousspread of melanoma cells from a solidspread of melanoma cells from a solidtumor in peripheral bloodtumor in peripheral blood
S100B proteinS100B proteinFor confirmation of amelanotic malignantFor confirmation of amelanotic malignant
melanoma in immunohistologymelanoma in immunohistologyin 70% with stage IV metastasizedin 70% with stage IV metastasized
melanomamelanomaMIA (melanoma inhibitory activity)MIA (melanoma inhibitory activity)Preoperation: 59% at stage III, 89% atPreoperation: 59% at stage III, 89% at
stage IVstage IV
Th id C
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Thyroid CancerThyroid Cancer
ThyroglobulinThyroglobulin Tissue-specificTissue-specific, glycoprotein produced by thyroid, glycoprotein produced by thyroid
follicular cellsfollicular cells
normal:
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Multiple MyelomaMultiple Myeloma
2-microglobulin2-microglobulin Normal:Normal: 0.7~2.00.7~2.0 (serum),(serum), 20~60020~600
(urine)(urine)
Correlates with tumor burden,Correlates with tumor burden,prognosis, response to therapyprognosis, response to therapy
Increase with poor renal functionIncrease with poor renal function
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LymphomaLymphoma
Burkitts type lymphoma and leukemiaBurkitts type lymphoma and leukemia T (8;14)T (8;14) due to juxtaposition and activationdue to juxtaposition and activation
of the c-myc geneof the c-myc gene
CD 25CD 25 most sensitive serum marker formost sensitive serum marker fortumor burdentumor burden
CD 44CD 44 high concentration indicates poorhigh concentration indicates poorprognosisprognosis
Lactate dehydrogenase (LDH)Lactate dehydrogenase (LDH)
normal: 100~250 IU/Lnormal: 100~250 IU/Lhigh-grade lymphomas, blood levels correlatehigh-grade lymphomas, blood levels correlate
closely with disease activity and response toclosely with disease activity and response totherapytherapy
N d i TN d i T
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Neuroendocrine TumorsNeuroendocrine Tumors
Neuron-specific enolase (NSE)Neuron-specific enolase (NSE)A neuronal isoenzyme of the cytoplasmicA neuronal isoenzyme of the cytoplasmicenzyme enolase, in neuroendocrine cellsenzyme enolase, in neuroendocrine cells
As a prognostic factor inAs a prognostic factor in neuroblastomaneuroblastoma
Occur inOccur in neuroendocrine tumorsneuroendocrine tumors: medullary: medullarycarcinoma of the thyroid, pheochromocytoma,carcinoma of the thyroid, pheochromocytoma,carcinoid tumors; immature teratoma, 65~85%carcinoid tumors; immature teratoma, 65~85%withwith small cell carcinoma of lungsmall cell carcinoma of lung, ~38% with, ~38% withnon-small-cell lung cancernon-small-cell lung cancer, and melanoma, and melanoma
Correlate with stage and bulk of diseaseCorrelate with stage and bulk of disease N-myc oncogeneN-myc oncogene in neuroblastomain neuroblastoma N-myc copyN-myc copy
number is associated with stage and prognosisnumber is associated with stage and prognosis
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TRANSLOKASITRANSLOKASI
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TRANSLOKASITRANSLOKASI
KROMOSOM PHILADELPHIAKROMOSOM PHILADELPHIA
9 22
bcr
22q
abl
9q
bcr abl
22q 9q
Chimeric bcr-abl gene
Chimeric bcr-abl protein
bcrablTranslokasi
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ConclusionConclusion
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ConclusionConclusion
ScreeningScreening most tumor markers fail, becausemost tumor markers fail, because
1. Low prevalence of malignancy in1. Low prevalence of malignancy inasymptomatic personsasymptomatic persons
2. Not elevated in patients with small-2. Not elevated in patients with small-
volume (early) cancervolume (early) cancer
DiagnosisDiagnosis most markers have lowmost markers have lowspecificity, only for high risk groups (FP,-specificity, only for high risk groups (FP,-
HCG ,PSA, thyrocalcitonin)HCG ,PSA, thyrocalcitonin)
PrognosisPrognosis markers correlate with tumormarkers correlate with tumor
burdenburden Monitor treatment responseMonitor treatment response mostmost
markers level alone cannot be used to definemarkers level alone cannot be used to define
CR (except: -HCG in trophoblasticCR (except: -HCG in trophoblastic
malignancy)malignancy)
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