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TUMOR MARKERS
Prof. Adi Koesoema Aman .
Departement of Clinical Pathology Universityof Sumatera Utara / RSUP. H.Adam Malik
Medan .
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PENGERTIAN SECARA UMUM :
Penanda tumor serologik merupakan produkyang berasal dari tumor , yang kadarnyadalam darah merupakan pencerminan
masa tumor yang ada dalam tubuh .
Dulunya dianggap ada harapan produktersebut sensitip dan spesifik sehinga
dapat digunakan sebagai test kanker tipetumor tertentu .
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What are Tumor Markers
Biological substances synthesized andreleased by cancer cells or produced bythe host in response to the presence of
tumor
Detected in a solid tumor, in circulating
tumor cells in peripheral blood, in lymphnodes, in bone marrow, or in otherbody 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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PENGGUNAAN PENANDA TUMOR .
Skrening dan Deteksi Awal .
Differential Diagnosis .
Menentukan Prognosis . Meramal Residif .
Menganalisa Respons Terapi.
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Klasifikasi Penanda Tumor .
Protein Onkofetal .- Carcino Embrionik Antigen ( CEA ) .
- Alfa feto Protein ( AFP ) .
Hormon .- HCG ,HPL , ACTH , ADH , Parathormon .
Enzim .
- PAP , LDH , NSE . Immunoglobulin .
Antigen terassosiasi tumor
- CA 19-9 , CA 125 , PSA .
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Potential Uses of Tumor
Markers
Population Screening
Diagnosis
Establishing prognosis, staging
Postoperatory evaluationaccess the
radicality of the surgery
Monitor treatment response Surveillance for recurrence
Targets for therapeutic intervention
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Statistical Considerations
Sensitivitycancer (+), abnormal test
Specificitycancer (-), normal test
Positive predictive valueabnormal test,cancer (+)
Negative predictive valuenormal test,cancer (-)
Prevalenceaffect PPV, every marker has
failed as a screening test inASYMPTOMA -TIC persons, because the PREVALENCE ofcancer is low amongASYMPTOMATICpersons
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Tumor Specific Proteins
Expressed only in tumor cells Example: an oncogene is translocated and fused
to an active promoter of another gene fusionproteins constant active production
development of malignant clone
Philadelphia chromosome in CML, t(9;22)(q34;q11) bcr/abl translocation
T(8;21) acute non-lymphocytic leukemia,t(15;17) APL
Hematological malignancies
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Non-Specific Proteins or MarkersRelated to Malignant Cells
Oncofetal proteinsexpressed by cells
as they de-differentiate and take onembryonic characteristics
-FPHCC, testicular, ovarian cancer
CEAmany GI tumors
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Cell Specific Proteins Overexpressed inMalignant Cells
Proteins expressed normally bydifferentiated cells, but are expressed at
higher rates in the corresponding tumorcells
PSAprostate cancer
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CEA
fibrocystic breast disease Found also in 30~50%of breast cancer, small cell lung cancer,mucinous cystadenocarcinoma of ovary,
adenocarcinoma of cervix
Elevation (
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Alpha-Fetoprotein in HCC
Glycoprotein, found in fetal liver, yolk sac,GI tract, biochemically related to albuminin adults
half-life4~6 days Normal serum levels
12~15th gestational week 30~40 ng/ml
At birth 30 ng/ml
>1 years old (adult)
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Increased in 70% HCC, elevated in hepatoblastoma,20~70% germ cell tumors (yolk sac tumors,embryonal cell carcinoma) of testis and ovary, exceptdysgerminoma
For Hbs Ag (+) chronic hepatitis/cirrhosis screening,further improved by using US
The absolute AFP level correlates with tumor bulk
CSFplasma ratio of AFP > 1:40 suggest CNSinvolvement
Benignconditions that cause hepatic parenchymalinflammation, hepatic necrosis and hepaticregeneration, ex. hepatitis, pregnancy, primary biliary
cirrhosis, extrahepatic biliary obstruction
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Germ Cell Tumors
Human chorionic gonodotropin(HCG)Glycoprotein synthesized by syncythiotrophoblastic
cells of normal placenta, never in males!
Serum and urine HCG in early gestation and peakin the first trimester (60~90 days)
T : 1.25 days, ~30 hours
Elevated ingestational trophoblastic disease ( aprogressive rise in after 90 days of gestation
highly suggestive), choriocarcinoma
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Breast Cancer
CA 15-3monitor treatment and todetect recurrenceNormal< 31 U/ml
in 20% with localized breast cancer, ~80%with metastatic disease, esp. if with boneinvolvment
Specificity of 86%, sensitivity of 30%
Also increased in gastric, pancreatic, cervicallung cancer
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Cervical Sqamous Cell
Carcinoma
Squamous cell carcinoma antigen(SCC)
Normal value:
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Oncogenic versus & low-risk HPV types
>120 types identified2
~3040 anogenital types2,3
~1520 oncogenic types*,2,3
HPV 16 and HPV 18 typesaccount for the majority of
worldwide cervical cancers.4
~15-20 nononcogenic** types
HPV 6 and 11 types are
most often associated with
external anogenital warts
(90%).3
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-
stranded DNA virus1
*High risk; ** Low risk
ld id l f i
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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 inCervical Cancer*,1
58
57
12.6
69.7
14.6
67.6
1752.5
25.7
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Ovarian Cancer
CA-125 Cell surface glycoprotein, present during embryonic
development of coelomic epithelium and is present in adultstructures derived from it
Normal80% of epithelial ovarian cancer, cell typesserous >
endometriod, clear cell > mucinous
Correlate with tumor bulk
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Low specificity and poor sensitivity in detectingsmall-volume disease
Also found in carcinoma of pancreas, colon ,gallbladder, stomach, kidney, breast, and lung
Endometriosis is the most common alternativediagnosis, elevated levels also found in PID, 1st
trimester CA 19-9
A mucin, normal serous(27%)
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Pancreatic Cancer
CA 19-9
mucin, normal
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Prostate Cancer
PSA
Tissue specific antigen , produced byprostatic alveolar and ductal epithelial cells , aserine protease, t 1/22~3 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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Free PSAPSA that is not bound to the plasma
antiproteases 1-antichymotrypsin and 2-
macroglobulinAn in ratio of free/total PSA is associated with
increased probability of prostate cancer
97% specific for this disease, 96% sensitivity in
detecting disease
For population screeningand diagnosisan
increase of 0.75 ng/ml per year in any given
patient has high sensitivity and specificity forprostate cancer vs BPH, especially when combinedwith DRE and TRUS
M l
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Melanoma
Tyrosinase
Use RT-PCR to detect hematogenous spread ofmelanoma cells from a solid tumor in peripheralblood
S100B protein
For confirmation of amelanotic malignantmelanoma in immunohistology
in 70% with stage IV metastasized melanoma
MIA (melanoma inhibitory activity) Preoperation: 59% at stage III, 89% at stage IV
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Thyroid Cancer
Thyroglobulin Tissue-specific, glycoprotein produced by thyroid
follicular cells
normal:
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Multiple Myeloma
2-microglobulin
Normal: 0.7~2.0(serum), 20~600 (urine)
Correlates with tumor burden, prognosis,
response to therapy
Increase with poor renal function
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Lymphoma
Burkitts type lymphoma and leukemia T (8;14)due to juxtaposition and activation of the
c-myc gene
CD 25most sensitive serum marker for tumorburden
CD 44high concentration indicates poorprognosis
Lactate dehydrogenase (LDH)
normal: 100~250 IU/L
high-grade lymphomas, blood levels correlate closelywith disease activity and response to therapy
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Neuroendocrine Tumors
Neuron-specific enolase (NSE)A neuronal isoenzyme of the cytoplasmic enzyme
enolase, in neuroendocrine cells
As a prognostic factor in neuroblastoma
Occur in neuroendocrine tumors: medullary carcinomaof the thyroid, pheochromocytoma, carcinoid tumors;immature teratoma, 65~85% with small cell carcinomaof lung, ~38% with non-small-cell lung cancer, andmelanoma
Correlate with stage and bulk of disease N-myc oncogenein neuroblastomaN-myc copy
number is associated with stage and prognosis
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TRANSLOKASI
KROMOSOM PHILADELPHIA
9 22
bcr
22q
abl
9q
bcr abl
22q 9q
Chimeric bcr-abl gene
Chimeric bcr-abl protein
bcr ablTranslokasi
C l i
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Conclusion
Screeningmost tumor markers fail, because
1. Low prevalence of malignancy in asymptomaticpersons
2. Not elevated in patients with small-volume(early) cancer
Diagnosismost markers have low specificity, only
for high risk groups (FP,-HCG ,PSA, thyrocalcitonin)
Prognosismarkers correlate with tumor burden
Monitor treatment responsemost markers level
alone cannot be used to define CR (except: -HCG introphoblastic malignancy)
Early detection of recurrence
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