TUMOR MARKERS

Prof. Dr.Adi koesoema Aman Sp. PK(KH)

Dr. Zulfikar Lubis SpPK ( K )
Departement Patologi Klinik
FK USU/RSUP.H.A.MALIK
 Difinisi :
Berbagai jenis kanker berhubungan dengan produksi
abnormal dari beberapa molekul yang dapat diukur
di dalam plasma. Molekul –molekul ini dikenal
sebagai tumor marker.
 Idealnya Tumor marker :

1. Terdapat pada atau dihasilkan oleh tumor itu sendiri.

2. Tidak dijumpai pada jaringan yang sehat.
3. Kadar di dalam plasma pada subjek yang sehat dan
tumor jinak harus berada pada kadar minimum.
4. Spesifik untuk jaringan tertentu dan memiliki
molekul imunologi yang berbeda apabila disintesis
oleh jaringan lain.
5. Kadar di dalam plasma harus sesuai, dalam
hal ukuran dan aktivitas tumor.
6. Waktu paruh yang tidak terlalu lama.
7. Mampu dideteksi di dalam plasma walaupun
ukuran tumor sangat kecil.
 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 .
 Tumor Specific Proteins
• Expressed only in tumor cells
• Example: an oncogene is translocated and fused
to an active promoter of another gene → fusion
proteins → 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
 Arti Klinis Tumor Marker
• Screening pada populasi umum
• Diagnosis banding pada pasien yang
memiliki gejala
• Staging klinis kanker
• Perkiraan volume tumor
• Indikasi prognosis untuk perkembangan
penyakit
• Evaluasi keberhasilan pengobatan
• Deteksi kekambuhan dari kanker
• Monitor respon terapi
• Radioimmunolocalization massa tumor
• Besarnya penurunan = kesuksesan
pengobatan
• Pada kekambuhan kanker, marker
meningkat kembali
• Kebanyakan nilai tumor marker berkorelasi
dengan efektivitas pengobatan.
 COMMON TUMOR MARKERS
Analyte Cancer Use
CEA Monitor colorectal, breast, lung cancer
CA-125 Ovarian cancer monitoring
CA15-3, 27. 29 Monitor recurrences of breast cancer
AFP Germ cell tumors, liver cancer
Total PSA Screen and monitor prostate cancer
Free PSA Distinguish prostate cancer from BPH
HCG Germ cell and trophoblastic tumors
Hormone
receptors Breast cancer therapy
NMP 22, BTA
FDP Monitor recurrences of bladder cancer
 SCREENING TESTS

• Cancer must be common

• The natural history of the cancer should be

understood

• Effective treatments must be available

• The test must be acceptable to both patients and

physicians

• The test must be safe and relatively inexpensive

 CEA

• Described by Gold and Freedman in1965 as a

marker for Colorectal Cancer

• Molecular mass of approximately 200,000 kA

• Glycoprotein with a carbohydrate composition

ranging from 50 - 85% of molecular mass

• CEA levels 5 - 10 times upper limit of normal

suggests colon cancer

• CEA is not used to screen for colon cancer

 CEA Distribution In Healthy Individuals and
Patients with Non-Malignant Conditions
% Distribution of CEA
ng/mL ng/mL ng/mL
Healthy Subjects 0-3.0 3.1-10 >10.0
Non Smokers 96 4 0
Smokers 80 19 1
Non-Malignant Diseases
Cirrhosis 53 42 5
Ulcerative Colitis 65 26 9
Rectal polyps 78 19 3
Pulmonary 52 39 9
Gastrointestinal 76 21 3
 CEA Distribution In Patients
With Malignant Disease

% Distribution of CEA
0-3 3.1-10 >10
ng/mL ng/mL ng/mL
Colorectal 28 20 52
Breast 50 27 23
Ovarian 80 16 4
Pulmonary 39 29 32
 CA-125
• CA-125 glycoprotein molecular weight 200-1,000 kda
• Introduced in 1983 by Bast for ovarian cancer
• In the US, in 1998 25,400 new cases will be diagnosed
and 14,500 women will die as a result of this disease
• 70% of the women with ovarian cancer are over the age
of 50
• One half of patients with stage 1 ovarian cancer have
elevated CA-125 levels and a five year survival rate of
90%. In late stage disease, the five year survival rate is
from 4-30%
• Worldwide incidence is highest in industrialized
countries and lowest in Japan and India
SYMPTONS OF OVARIAN CANCER

• ASCITES
• ABDOMINAL and PELVIC PAIN
• ABNORMAL UTERINE BLEEDING
• GASTROINTESTINAL DISCOMFORT
• WEIGHT LOSS
• URINARY FREQUENCY
 RISK FACTORS

INCREASED RISK DECREASED RISK

Family History Oral Contraceptive

Advanced Age Breast Feeding

Infertility
Tubal Ligation
Nulliparity
CA-125 Distribution In Healthy Subjects and Patients with
Non-Malignant Conditions
% Distribution of CA-125
<35 35-65 >65
u/mL u/mL u/mL
Healthy Individuals 98 1.7 1.3
Non-Malignant Conditions
Pregnancy 73 22 5
Cirrhosis 30 13 57
Pulmonary Disease 94 0 6
Pelvic Inflammatory Disease 76 3 21
Endometriosis 86 11 3
Ovarian Cysts 90 7 3
Uterine Fibroids 77 13 10
Breast Fibroids 100 0 0
 CA-125 Distribution In Patients With
Malignant Disease

% Distribution of CA-125
Cancers <35 35-65 >65
u/mL u/mL u/mL
Ovarian 14 9 77
Lung 56 19 25
Breast 82 8 10
Endometrial 70 8 22
Cervical 66 15 19
Colorectal 76 11 12
 Ovarian Cancer
• CA-125：
– Cell surface glycoprotein, present during embryonic
development of coelomic epithelium and is present in adult
structures derived from it
– Normal：<35 U/ml, t ½：4~5 days
– For followup, an increase may predict recurrent disease,
may precede clinical recurrence by months
– >80% of epithelial ovarian cancer, cell types： serous >
endometriod, clear cell > mucinous
– Correlate with tumor bulk
 Low specificity and poor sensitivity in detecting small-
volume disease
Also found in carcinoma of pancreas, colon , gallbladder,
stomach, kidney, breast, and lung
Endometriosis is the most common alternative diagnosis,
elevated levels also found in PID, 1st trimester
CA 19-9
A mucin, normal：<37 U/ml, does not increase during
pregnancy
Monitor of a subpopulation of patients that did not
express CA 125, ex. Mucinous (76%) > serous (27%)
 Pancreatic Cancer
• CA 19-9：
– mucin, normal：<37
– infrequently elevated in patients with other
mucin-secreting cancer (colorectal, gastric cancer)
– Diagnosis, monitor, detect relapse, 70% specificity
and 90% sensitivity
– Mild ↑in pancreatitis and early stage of pancreatic
cancer, ∴not for diagnosing early-stage pancreatic
caner
 Prostate Cancer
• PSA：
– Tissue specific antigen , produced by
prostatic alveolar and ductal epithelial cells , a
serine protease, t 1/2：2~3 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
 Relapse

 Reflect response to treatment and correspond to tumor volume

and androgen level

 As a predictor of surgical failure：by using RT-PCR for PSA to

detect circulating prostate cancer cells in the bloodstream

 PSA is expected to be undetectable >30 days after the radical

prostatectomy, persistent elevated level indicate residual disease
• Free PSA：PSA that is not bound to the plasma
antiproteases α1-antichymotrypsin and α2-
macroglobulin
– An ↑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 screening and diagnosis：an
increase of 0.75 ng/ml per year in any given
patient has high sensitivity and specificity for
prostate cancer vs BPH, especially when combined
with DRE and TRUS
 MULTIPLE MYELOMA

Multiple Myeloma - proliferation of a single clone of

plasma cells that produces a monoclonal protein

Annual Incidence - 4 in 100,000

Number of cases per year - 13,000

Represents 1% of all malignant diseases

Median age at diagnosis - 65 years
Median survival - 3 years
 ETIOLOGY OF MULTIPLE MYELOMA

Radiation Exposure

Agriculture - Farming & Pesticide Use

Chemicals - Benzene

Not Related to Smoking or Alcohol Consumption

 Monoclonal Gammopathy of
Undetermined Significance

Defined as the presence of a serum monoclonal protein at

low levels
Number of cases per year - 750,000-1,000,000
54% Men 46% Women

Occurs in 2% of persons over 50 years, 3% over 70 years

Median age at diagnosis - 72 years

Median survival - 12 years

M
Y
E 12
L
O
M 10
A

P
8
E
R 6

1
0
4
0
,
2
0
0
0 0 M,White M, Black F, White F, Black
SYMPTOMS OF MULTIPLE MYELOMA

Bone Pain - Back, Ribs

Osteoporosis
Bone Fracture
Fatigue
Anemia
Renal Failure
Infections
 Clinical Laboratory in Multiple Myeloma

-Biochemical -
Serum monoclonal proteins >3.0 g/dL
Polyclonal Immunoglobulin Decreased
Proteinuria, Bence-Jones Protein present in urine
BUN, Creatinine
Calcium ,N

- Hematological -
Hemoglobin Decreased
Anemia - Normochromatic, Normocyte
ESR Increased
 Major Laboratory Features of MM

% of MM
Findings patients affected
Hemoglobin <12 g/dL 65
Serum calcium >11.0 mg/dL 14
Serum creatinine > 1.7 mg/dL 23
Serum M-protein present 92
Urine M-protein present 75
M-protein in serum or urine (or both) 99
Bone lesions 75
Bone marrow plasma cells >10% 90
Monoclonal Gammopathy of Undetermined Significance
( MGUS )

Serum monoclonal protein <3.0 g/dL

Stability of monoclonal protein during long term follow-up
<10% Plasma cells in bone marrow
None or a small amount of Bence-Jones protein in urine
Absence of lytic bone lesions
Serum calcium, BUN, creatinine - Normal
Hemoglobin - Normal
 Laboratory Data at Diagnosis for MGUS

Serum concentration of the uninvolved

immunoglobulin is decreased in 38% of patients

Urine - Kappa Bence-Jones Protein 21%

Lambda Bence-Jones Protein 10%

For most of the patients, the concentration of the

Bence-Jones protein was <150 mg/24 hr

No light chain was detected in 69% of the patients

Distribution Frequency of Monoclonal Proteins In MGUS

Biclonal 2%

IgM 14%

IgG 73% IgA 11%

 Clinical Course of 241 Patients with MGUS

M Protein >3.0 g/dL No Increase in M

No Myeloma (23) Protein (46)
10%
19%

47%
24%
Died of Unrelated Developed Myeloma &
Causes (173) Unrelated Diseases (59)
 Normal SPE

Albumin 1 2  
 Monoclonal
Albumin decreased
gammopathy
Sharp peak in gamma region

Albumin 1 2  
 Translokasi Kromosom
• Gen c-myc dijumpai translokasi dari
kromosom 8 ke kromosom 14 dan menjadi
aktif pada Burkitt’s lymphoma.
• Gen myc encode protein pengikat DNA
yang menstimulasi pembelahan sel.
 TRANSLOKASI
KROMOSOM PHILADELPHIA
bcr
22q
abl
9q

bcr abl

22q 9q
Chimeric bcr-abl gene
9 22

Translokasi abl
bcr

Chimeric bcr-abl protein

• Pada chronic myeloid leukemia terjadi
translokasi kromosom 9 dan 22.
TERIMA
KASIH