SEM 1: Tumor Markers production in addition to aerobic respiration in the
Introduction mitochondria, even under oxygen-sufficient
• TUMOR MARKERS are any cell product , enzyme,
serum proteins, metabolites, receptors, oncofetal
proteins present in or produced by a tumor, or
produced by the body in response to the tumor.
• Can be used as a marker to diagnose the
presence of a malignancy related to the following
events:
✓ Tumor formation
✓ Proliferation
✓ Differentiation
• Detected in
✓ Solid Tumor
✓ Circulating tumor cells in peripheral blood
✓ Lymph nodes, in bone marrow
✓ Other body fluids (urine, stool, ascites)
IDEAL CHARACTERISTICS FOR TUMOR MARKERS
a. Measured easily
b. High analytical sensitivity of assay method
c. High analytical specificity of assay method
d. Cost-effective
e. Test results contribute to patient care and
Outcome
Useful in the differentiation of neoplastic from non-
neoplastic disease and show positive correlation
with tumor volume and extent
Should be useful for screening of early cancer or
predict early recurrence and have prognostic
value
USES
✓ Screening in general population
✓ Differential diagnosis of symptomatic patients
✓ Clinical staging of cancer
✓ Estimating tumor volume
✓ Prognostic indicator for disease progression
✓ Evaluating the success of treatment
✓ Detecting the recurrence of cancer
✓ Monitoring response to therapy
✓ Post-operative evaluation
✓ Surveillance for recurrence
CLASSIFICATION ACCORDING TO FUNCTION AND
BIOCHEMICAL CHARACTERISTICS
1. Enzymes or isoenzymes (ALP, PAP)
2. Hormones (calcitonin, HCG)
3. Oncofetal antigens (AFP, CEA)
4. Carbohydrate epitopes recognized by
monoclonal antibodies (CA 15-3, CA 19-9, CA
125)
5. Receptors (estrogen, progesterone)
6. Serum and tissue proteins (B2-macroglobulin,
monoclonal IG, glial fibrillary acidic protein
(GFAP), Protein S-100)
7. Other biomolecules (polyamines)
ENZYMES
• ALKALINE PHOSPHATASE (ALP) – primary or
secondary liver cancer, metastatic cancer with
bone or liver involvement
• LACTATE DEHYDROGENASE (LD) – involved in tumor
initiation and metabolism. Cancer cells rely on
increased glycolysis resulting in increased lactate
conditions. elevated levels are found in
dysgerminoma.
• PROSTATIC ACID PHOSPHATASE (PAP) – prostate
cancer. Increased pap activity may be seen in
osteogenic sarcoma, multiple myeloma, and
bone metastasis of other cancers and in some
benign conditions such as osteoporosis and
hyperparathyroidism.
• PROSTATE SPECIFIC ANTIGEN (PSA) – is a serine
protease of 33-kd glycoprotein produced only in
epithelial cells of acini & in prostatic ducts
o It is a glycoprotein protease that functions
in liquefaction of seminal coagulum,
dissolves cervical mucous cap, allowing
sperm to enter. It also regulates seminal
fluid viscosity
o Forms of PSA found in the blood
1. Enveloped by protease inhibitor, A2-
macroglobulin; lacks
immunoreactivity
2. Complexed to another protease
inhibitor, A1-antichymotrypsin PSA-
ACT; immunologically detectable
3. Free PSA, not complexed to protease
inhibitor; immunologically detectable
4. Total PSA assays measure complexed
and free PSA forms, as they are
immunologically detectable
o PSA is detectable in the plasma of normal
men, its concentration increases both
with increasing age and in benign
prostatic hypertrophy (BPH) (common
problem of elderly men). Digital rectal
examination may increase plasma PSA
concentration slightly and transiently, but
significant increase can occur in both
acute urinary retention and prostatitis.
o Much more specific for screening or for
detection of early prostate cancer and is
very useful for monitoring patients
following prostatectomy.
HORMONES
• CALCITONIN – produced by C cells of thyroid
gland o control serum calcium level.
o Elevated in medullary cell carcinoma of
the thyroid (eutopic secretion)
• HUMAN CHORIONIC GONADOTROPIN (HCG) – a
heterodimer composed of 2 glycosylated sub-
units (alpha and beta chains) non-covalently
bonded.
o Physiological functions: produced by
syncytiotrophoblast of placenta.
▪ Maintain progesterone
production by the corpus luteum
during early pregnancy and can
be detected as early as one
week after conception.
o Tumors of placenta, gestational
trophoblastic disease and Some tumors of
testes and ovary
• INHIBIN – a peptide hormone normally produced
by ovarian granulosa cells.
 o It inhibits the secretion of fsh by the
anterior pituitary gland. Certain ovarian
tumors, mostly mucinous epithelial
ovarian carcinomas and granulosa cell
tumors also produce inhibin, and its serum
levels reflect the tumor burden.
o Elevated levels in postmenopausal
woman or premenopausal woman
presenting with amenorrhea and infertility
is suggestive of, but not specific for the
presence of a granulosa cell tumor.
o Levels may be used for tumor surveillance
after treatment to assess for residual or
recurrent disease.
ONCOFETAL ANTIGENS
• ONCOFETAL (ONCO-DEVELOPMENT) ANTIGENS,
are proteins normally produced during fetal
development.
o But can be expressed by certain types of
tumors.
o They represent the most specific tumor
markers available for clinical diagnosis &
disease management.
• ALPHA-FETOPROTEINS (AFP) – A 70kda
glycoprotein homologous to albumin synthesized
by the liver, yolk sac, and GIT.
o PHYSIOLOGICAL FUNCTION: appears to
perform some of the functions of albumin
in the fetal circulation.
o Malignancies with elevated levels
✓ Non-seminomatous germ cell
tumors (NSGCT) of testis, ovary,
and other sites
✓ Hepatocellular carcinoma (HCC)
✓ Hepatoblastoma in children, rarely
in adults
✓ Patients with other types of
advanced adenocarcinoma
✓ Benign conditions – hepatitis,
cirrhosis, biliary tract obstruction,
alcoholic liver disease, ataxia
telangiectasia, and hereditary
tyrosinemia
o Physiological conditions with elevated
levels
✓ Pregnancy
✓ First year of life (infants)
• MAIN CLINICAL APPLICATIONS
a. In combination with HCG, for monitoring
of patients with NSGCT (mandatory)
b. Independent prognostic marker for
NSGCT
c. Diagnostic aid for hepatocellular
carcinoma and hepatoblastoma
d. Screening for hepatocellular carcinoma
in high risk populations (e.g. patients with
cirrhosis due to hepatitis B or C)
• CARCINOEMBRYONIC ANTIGEN (CEA) – most
vulvar tumors of sweat gland origin, including
malignant tumors, stain positively for CEA.
o CEA is demonstrable in paget cells at
metastatic sites such as the lymph nodes.
o Present in most urothelial
adenocarcinomas of the female urethra.
o Elevated in up 30% of patients with
endometrial cancer but even with IHC,
benign and malignant glandular
proliferations of the uterine cervix is
cannot be distinguished
o Frequently present patients with cancer
that has metastasized to the ovary; that is
because the primary cancer is generally
mammary or GI in origin
o Colorectal, gastrointestinal, lung and
breast carcinoma
• SQUAMOUS CELL CARCINOMA ANTIGEN may be
increased in patients with epidermoid carcinoma
of the cervix, benign tumors of epithelial origin,
and benign skin disorders. SCC antigen may be
helpful in assessing response to chemotherapy
and in determining relapse when monitoring
patients with complete remission but not sensitive
enough for screening early –stage carcinoma.
• MÜLLERIAN INHIBITING SUBSTANCE (MIS) is
produced by granulosa cells in developing
follicles.
o It has emerged as a potential tumor
marker for granulosa cell tumors. As with
inhibin, MIS is typically undetectable in
postmenopausal women. An elevated
mis value is highly specific for ovarian
granulosa cell tumors; however, this test is
not commercially available for clinical
use.
CARBOHYDRATE MARKERS
• CA ANTIGENS are high molecular weight mucin
like glycoprotein expressed by various types of
cancer cells
• CA 15-3 – breast carcinoma may also be present
in pancreatic, lung, ovarian, colorectal and liver
cancer and in some benign breast and liver
diseases
• CA 125 – ovarian and endometrial carcinomas,
elevates in pancreatic, lung, breast, colorectal
and gastrointestinal cancer, and in benign
conditions such as cirrhosis, hepatitis,
endometriosis, pericarditis, and early pregnancy
• CA 19-9 – a mucin-like TM related to the lewis
blood group antigen. O glycolipid blood group
antigen-related marker; sialylated derivative of
the lewis blood group system, known as lexa.
Colorectal and pancreatic carcinoma, elevated
levels seen in hepatobiliary, gastric,
hepatocellular and breast cancer and in benign
conditions sch as pancreatitis and benign
gastrointestinal diseases
RECEPTOR MARKERS
• ESTROGEN AND PROGESTERONE RECEPTORS – used
in breast cancer as indicators for hormonal
therapy and commonly tested by IHC
o Patients with positive estrogen and
progesterone receptors tend to respond
to hormonal treatment
 PROTEIN MARKERS
• B2-MACROGLOBULIN – multiple myeloma,
Hodgkin lymphoma, also increases in chronic
inflammation and viral hepatitis
• FERRITIN – marker for Hodgkin lymphoma,
leukemia, liver, lung, and breast cancer
• THYROGLOBULIN – it is a useful marker for
detection of differentiated thyroid cancer
• IMMUNOGLOBULIN – Bence-Jones protein is a free
monoclonal immunoglobulin light chain in the
urine and is a reliable marker for multiple myeloma
COMMON CANCERS AND ASSOCIATED TUMOR MARKERS
BLADDER CANCER
• At present, no urinary tumor markers are
recommended for bladder cancer screening
• BLADDER TUMOR ANTIGEN (BTA) and NUCLEAR
MATRIX PROTEIN (NMP)-22 can be used along with
cystoscopy for diagnosis and follow-up although
cystoscopy and urine cytology (gold standard)
are still considered the current standard
Sensitivity % Specificity Method of
% Detection
BTA 55-70% 70-75% EIA
NM-22 80-85% 75-80% ELISA
Cytology 30-40% >90%
BREAST CANCER
• At present, no tumor marker has been found to be
useful for screening or for diagnosis of early stage
breast cancer
• At the time of diagnosis, breast cancer tissue
should be tested for ER and PR, as well as HER2
ANTIGEN. These markers provide Information on
how aggressive the cancer can be and how likely
it will respond to certain treatments.
• Methods- - IHC, FISH, CISH, RT-PCR
• CA 15-3 and CA 27.29 are used to monitor therapy
in patient with advanced breast cancer. CA 27.29
has better sensitivity and specificity than CA 15-3.
• Methods – ELISA using monoclonal antibodies, RIA
COLORECTAL CANCER
• At present, neither CEA nor CA 19-9 is useful as a
screening test for colorectal cancer
• An elevated CEA level before surgery may
indicate worse prognosis. If all the cancer has
been removed, CEA should return to normal levels
in about 4-6 weeks after treatment
• CEA measurement every 3-6 months should be
considered to help early diagnosis of recurrence
• CEA is also used to monitor patients being treated
for advanced or recurrent disease
• If CEA is not elevated in patients with advanced
or recurrent disease, CA 19-9 may be used to
follow the disease
LIVER CANCER
• Periodic screening by serum AFP measurements
and ultrasound for chronic hepatitis carriers are
useful to detect liver cancer at early stage
• AFP can also be used to follow up patients after
treatment
LUNG CANCER
• At present, no tumor marker has been proven to
be useful as screening tests
• Tumor markers that can be raised in lung cancer
include CEA in non-small cell cancer and NSE in
small cell lung cancer
• Because lung cancer is usually visible on CXR or
other imaging studies, tumor markers play a less
important role in follow-up
THYROID CANCER
• THYROGLOBULIN is a tissue specific marker, a
glycoprotein produced by thyroid follicular cells.
Levels are also increased in breast or lung cancer
(>60 UG/L)
• THYROCALCITONIN is produced by the Thyroid C
cells and medullary thyroid cancer. It is effective
 in screen patients with 1st degree relatives
affected by medullary thyroid cancer and
multiple endocrine neoplasia type 2.
PROSTATE CANCER
• PROSTATE SPECIFIC ANTIGEN (PSA) is commonly
used to detect prostate cancer at early stage
o Levels above 4 ng/ml suggest cancer
whereas levels above 10 ng/ml strongly
suggest cancer
o PSA is very useful in follow-up. After
curative surgery, PSA level should be zero
or very close to zero. Those treated with
radiotherapy should also have a
significant drop in PSA after treatment
o A subsequent rise in PSA after treatment
could indicate relapse
o PSA can also be used to assess response
to treatment for advanced disease
• In rare cases, prostate cancers that do not have
raised PSA levels and do not respond well to
hormonal therapy may turn out to have
neuroendocrine features. Patients with theses
cancers may have higher levels of
CHROMOGRANIN A
TESTICULAR SKIN
• Tumor markers commonly elevated in patients
with testicular cancer are HCG and AFP
• SEMINOMA: about 10% of men with seminoma will
have raised HCG. None will have elevated AFP
• NON-SEMINOMA: more than half of mean with
early stage disease have raised HCG or AFP or
both. The markers will be elevated in most men
with advanced disease
• HCG is almost always raised and AFP is never
elevated on choriocarcinoma
• In contrast, AFP but not HCG is raised in yolk sac
tumor or endodermal sinus tumor
LYMPHOMA
• Burkitt’s Type Lymphoma and Leukemia
o CD 25：most sensitive serum marker for
tumor burden
o CD 44：high concentration indicates
poor prognosis
o LACTATE DEHYDROGENASE (LDH)：normal
levels are 100~250 IU/L. High-grade
lymphomas, blood levels correlate closely
with disease activity and response to
therapy
CONCLUSION
• Screening: most tumor markers fail, because
1. Low prevalence of malignancy in
asymptomatic persons
2. Not elevated in patients with small-volume
(early) cancer
• Diagnosis: most markers have low specificity, only
for high risk groups (AFP, β-HCG , PSA,
thyrocalcitonin)
• Prognosis: markers correlate with tumor burden
• Monitor treatment response: most markers’ level
alone cannot be used to define cancer (except:
β-HCG in trophoblastic malignancy)
• Early detection of recurrence

OVARIAN CANCER
• CA 125 is very effective to assess response of
epithelial ovarian cancer to treatment or to
detect recurrence
• CA 125 can be used to screen for ovarian cancer
in women with strong family history of ovarian
cancer. Such women usually receive regular
ultrasounds together with CA 125 measurements
• Patients with ovarian germ cell tumors often have
raised levels of HCG and/or AFP, which are useful
in diagnosis and follow-up

MELANOMA SKIN
• At present, no tumor marker is of value in early
detection of melanoma
• Tumor markers TA-90 and S-100 can be used to
test tissue samples to help diagnose melanoma
• Serum level of S-100 is elevated when disease is
widespread this it can be used to look for
progression of melanoma
• Blood levels of TA-90 have been used to assess the
chance of metastasis of melanoma
• TYROSINASE – use rt-PCR to detect hematogenous
spread of Melanoma cells from a solid tumor in
peripheral blood