K8.Tumor Marker's.ppt

7/21/2019 K8.Tumor Marker's.ppt

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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

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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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K8.Tumor Marker's.ppt