TUMOR MARKER’S

Prof. Adi Koesoema Aman .

Prof. Ratna Akbari Ganie .

Departement of Clinical Pathology University

of Sumatera Utara / RSUP. H.Adam Malik
Medan .
 PENGERTIAN SECARA UMUM :

Penanda tumor serologik merupakan produk

yang berasal dari tumor , yang kadarnya
dalam darah merupakan pencerminan
masa tumor yang ada dalam tubuh .
Dulunya dianggap ada harapan produk
tersebut sensitip dan spesifik sehinga
dapat digunakan sebagai test kanker tipe
tumor tertentu .
PENGERTIAN PENANDA TUMOR

PENGERTIAN LAMA :
Berbagai substansi yang diekskresikan oleh
sel kanker kedalam cairan tubuh /
diproduksi oleh sel jinak sebagai respons
terhadap keganasan

“Tumor marker”
PENGERTIAN BARU PENANDA TUMOR

PENGERTIAN LAMA
PLUS

Berbagai molekul termasuk onkogen

& anti onkogen serta produknya yang
diekspresikan oleh sel kanker

BIOMARKER KEGANASAN
Dapat diukur kualitatif & kuantitatif
 SEROLOGIK :
P produk sel ganas
E produk sel sebagai respons
N terhadap keganasan
A
N
D SELULER :
A perubahan yang tampak/
diidentifikasi di tingkat
T seluler
U
M
MOLEKULER
O
(Biomarker)
R
perubahan yang diidentifikasi
di tingkat molekuler
 ONKOGENESIS DAN PENANDA TUMOR

Growth promoting DNA repair Tumor suppressor

oncogenes gene genes
Defek

Mutasi Mutasi
Amplifikasi Inaktivasi

Apoptosis Defek

Gangguan kontrol
genetik
 Markers？
What are Tumor Markers？

Biological substances synthesized and
released by cancer cells or produced by
the host in response to the presence of
tumor

Detected in a solid tumor, in circulating

tumor cells in peripheral blood, in lymph
nodes, in bone marrow, or in other
body fluid (urine, stool, ascites)
PENGGUNAAN PENANDA TUMOR .

Skrening dan Deteksi Awal .

Differential Diagnosis .

Menentukan Prognosis .

Meramal Residif .

Menganalisa Respons Terapi .
 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
19--9 , CA 125 , PSA .
 Potential Uses of Tumor
Markers

Population Screening

Diagnosis

Establishing prognosis, staging
evaluation：access the

Postoperatory evaluation：
radicality of the surgery

Monitor treatment response

Surveillance for recurrence

Targets for therapeutic intervention
 Statistical Considerations

Sensitivity：cancer (+), abnormal test
Sensitivity：

Specificity
Specificity：：cancer (-
(-), normal test
value：abnormal test,

Positive predictive value：
cancer (+)
value：normal test,

Negative predictive value：
cancer (-
(-)

Prevalence
Prevalence： ：affect PPV, ∴every marker has
failed as a screening test in
ASYMPTOMATIC persons, because the
PREVALENCE of cancer is low among
ASYMPTOMATIC persons
 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-
non-lymphocytic leukemia,
t(15;17) APL

Hematological malignancies
 Non-Specific Proteins or Markers
Non-
Related to Malignant Cells

proteins：expressed by cells
Oncofetal proteins：
as they de-
de-differentiate and take on
embryonic characteristics
FP：HCC,

α-FP： testicular, ovarian cancer

CEA：many GI tumors
CEA：
Cell Specific Proteins Overexpressed in
Malignant Cells

Proteins expressed normally by

differentiated cells, but are expressed at
higher rates in the corresponding tumor
cells

PSA
PSA： ：prostate cancer
 Colorectal Cancer

Carcinoembryonic antigen (CEA)

fetalglycoprotein found on cell surfaces, produced
by fetal GI tract, liver, and pancreas
value：<3.0 ng/ml

Normal serum and tissue fluid value：

Circulating half-
half-life ：weeks
life：

Detect early relapse of colorectal cancer and
prognostic indicator

Normal CEA：lower metastasis incidence
pretherapy CEA：
CEA：higher metastasis incidence

High initial CEA：

In 2/3 of patients an elevated CEA may be the 1st
indication of relapse
 CEA

fibrocystic breast disease Found also in 30~50%
of breast cancer,
cancer, small cell lung cancer,
mucinous cystadenocarcinoma of ovary,
adenocarcinoma of cervix

Elevation (<10 ng/ml) in smokers,

smokers, COPD,
COPD,
inflammatory or peptic bowel disease, liver
inflammation or cirrhosis, renal failure,
 Alpha--Fetoprotein in HCC
Alpha

Glycoprotein, found in fetal liver, yolk sac,
GI tract, biochemically related to albumin
in adults

half
half--life
life：：4~6 days
levels：

Normal serum levels：

12~15th gestational week 30~40 ng/ml

At birth 30 ng/ml
>1 years old (adult) <20 ng

Increased in 70% HCC,
HCC, elevated in hepatoblastoma,
hepatoblastoma,
20~70% germ cell tumors (yolk sac tumors,
embryonal cell carcinoma) of testis and ovary, except
dysgerminoma

For Hbs Ag (+) chronic hepatitis/cirrhosis screening,

further improved by using US

The absolute AFP level correlates with tumor bulk

CSF：plasma ratio of AFP > 1:40 → suggest CNS

CSF：
involvement

Benign：conditions that cause hepatic parenchymal

Benign：
inflammation, hepatic necrosis and hepatic
regeneration, ex. hepatitis,
hepatitis, pregnancy, primary biliary
cirrhosis, extrahepatic biliary obstruction
 Germ Cell Tumors

Human chorionic gonodotropin (βHCG
βHCG))

Glycoprotein synthesized by syncythiotrophoblastic
cells of normal placenta, never in males!

Serum and urine HCG ↑in early gestation and peak
in the first trimester (60~90 days)

T ½: 1.25 days, ~30 hours
in：gestational trophoblastic disease ( a

Elevated in：
progressive rise in after 90 days of gestation →
highly suggestive), choriocarcinoma
 Germ Cell Tumors

Detection

Monitor C/T)：
treatment response (ex. C/T)：
production of BHCG ceases on commencement of
tx, rising or persistently elevated levels are
diagnostic of resistance to C/T

evaluate radicality of the surgery: ex. In
testicular cancer, the presence of β-β-HCG after
orchiectomy → residual cancer and needs further
treatment

Monitor relapse (reliable indicator of CR)
 Breast Cancer

CA15-3：monitor treatment and to
CA15-
detect recurrence

Normal：<
Normal： 31 U/ml

↑in 20% with localized breast cancer, ~80%
with metastatic disease, esp. if with bone
involvment

Specificity of 86%, sensitivity of 30%

Also increased in gastric, pancreatic, cervical
lung cancer
 Breast Cancer
Estrogen receptor (ER)：

2 isoforms：
isoforms ：ERa + ERb

ERa → better prognosis, predictor of relapse

useful when deciding on adjuvant hormone
treatment

Not guarantee response, fails in 30~40% of
patients to endocrine treatment

As diagnostic marker when it is a primary unknown
tumor

ERb → distinct biological roles and ligand binding
specificity, good prognostic factor, correlate with
low grade and (-(-) axillary LN status

HER-2/neu oncogene (using monoclonal
HER-
：overexpression related to poor
antibody)：
antibody)
prognosis in breast cancer

Oncogene c- c-erbB gene：overexpressed in

erbB--2 gene：
30% of breast cancers, correlation between c- c-erbB
erbB--
2 gene positivity, positive axillary node status,
reduced time to relapse and reduced overall
survival

BRCA1 gene on chromosome 17q： 17q：familial

breast--ovarian cancer syndrome
breast syndrome,, and breast cancer
in early-
early-onset breast cancer families → high risk
screening
 Cervical Sqamous Cell
Carcinoma

Squamous cell carcinoma antigen

(SCC
SCC))

Normal value: <2 ng/ml

Not sensitive enough for screening early –
stage carcinoma

Prognosis, monitor
 Ovarian Cancer

CA-
CA-125：
125：

Cell surface glycoprotein, present during embryonic
development of coelomic epithelium and is present in adult
structures derived from it

Normal：
Normal ：<35 U/ml, t ½：
½：4~5 days

For followup, an increase may predict recurrent disease,
may precede clinical recurrence by months

types： serous >
>80% of epithelial ovarian cancer, cell types：
endometriod, clear cell > mucinous

Correlate with tumor bulk

Low specificity and poor sensitivity in detecting
small--volume disease
small

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-
19-9

A normal：<37 U/ml, does not increase
mucin, normal：
during pregnancy

Monitor of a subpopulation of patients that did not
express CA 125, ex. Mucinous (76%) > serous
(27%)
 Pancreatic Cancer

19-9：
CA 19-

mucin, normal：
normal ：<37

infrequently elevated in patients with other
mucin--secreting cancer (colorectal, gastric cancer)
mucin

Diagnosis, monitor, detect relapse, 70% specificity
and 90% sensitivity

Mild ↑in pancreatitis and early stage of pancreatic
cancer, ∴not for diagnosing early-
early-stage pancreatic
caner
 Prostate Cancer

PSA：
PSA ：

Tissue specific antigen , produced by
prostatic alveolar and ductal epithelial cells , a
1/2：2~3 days
serine protease, t 1/2：
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 failure：by using RT-

a predictor of surgical failure： 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

PSA：PSA that is not bound to the
Free PSA：
plasma antiproteases α1-
α1-antichymotrypsin and
α2
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
diagnosis：an

For population screening and diagnosis：
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
 Melanoma

Tyrosinase

Use RT-
RT-PCR to detect hematogenous spread of
melanoma cells from a solid tumor in peripheral
blood

S100B protein

For confirmation of amelanotic malignant
melanoma in immunohistology

↑in 70% with stage IV metastasized melanoma

MIA (melanoma inhibitory activity)

Preoperation: 59% at stage III, 89% at stage IV
 Thyroid Cancer

Thyroglobulin：
Thyroglobulin：

Tissue-specific,
Tissue- specific, glycoprotein produced by thyroid
follicular cells

normal: <60 ug/L

Also increased in breast or lung cancer

Thyrocalcitonin：
Thyrocalcitonin：

Produced by thyroid C cells and medullary thyroid cancer

normal: <100 ng/L or <29 p mole/L

Effective in screen patients with 1st degree relatives
affected by medullary thyroid cancer and multiple
endocrine neoplasia type 2
 Multiple Myeloma

Β2 microglobulin：
Β2--microglobulin：

Normal: 0.7~2.0 (serum), 20~600 (urine)

Correlates with tumor burden, prognosis,
response to therapy

Increase with poor renal function
 Lymphoma

leukemia：
Burkitt’s type lymphoma and leukemia：

(8;14)： due to juxtaposition and activation of the
T (8;14)：
c-myc gene

25：most sensitive serum marker for tumor
CD 25：
burden
44：high concentration indicates poor

CD 44：
prognosis
(LDH)：

Lactate dehydrogenase (LDH)：

normal: 100~250 IU/L

high--grade lymphomas, blood levels correlate closely
high
with disease activity and response to therapy
 Neuroendocrine Tumors

Neuron--specific enolase (NSE)
Neuron

A neuronal isoenzyme of the cytoplasmic enzyme
enolase, in neuroendocrine cells

As a prognostic factor in neuroblastoma

Occur in neuroendocrine tumors:
tumors: medullary carcinoma
of the thyroid, pheochromocytoma, carcinoid tumors;
immature teratoma, 65~85% with small cell carcinoma
of lung,
lung, ~38% with non-
non-small-
small-cell lung cancer,
cancer, and
melanoma

Correlate with stage and bulk of disease

neuroblastoma：N-myc copy
N-myc oncogene in neuroblastoma：
number is associated with stage and prognosis
 Conclusion

Screening：most tumor markers fail, because
Screening：

1. Low prevalence of malignancy in asymptomatic
persons

2. Not elevated in patients with small-
small-volume
(early) cancer

Diagnosis：
Diagnosis ：most markers have low specificity, only
for high risk groups (αFP, β-
β-HCG , PSA,
thyrocalcitonin)

Prognosis：
Prognosis ：markers correlate with tumor burden

response：most markers’ level
Monitor treatment response：
alone cannot be used to define CR (except: β-β-HCG in
trophoblastic malignancy)

Early detection of recurrence