ON-K8 KULIAH TUMOR MARKER'S.ppt

7/27/2019 ON-K8 KULIAH TUMOR MARKER'S.ppt

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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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ON-K8 KULIAH TUMOR MARKER'S.ppt

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Transcript of ON-K8 KULIAH TUMOR MARKER'S.ppt