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TUMOR MARKERS TUMOR MARKERS / TUMOR ANTIGEN

o Many cancers are associated with the
abnormal production of some molecules
which can be measured in plasma. These
molecules are known as tumor markers.
SPECIFIC TUMOR MARKERS
o AFP alpha-feto protein
o B2M beta -2- microglobulin
o Beta HCG
o BTA Bladder tumor antigen
o CA 15-3
o CA 27.29
o CA 125
o CA 72 -4
o Produced directly by the tumor or by non-
tumor cells
o Consist of hierarchy of clinical laboratory
test from the least to the most informative &
used in oncology
Benefits
o Screening for common cancers
o Monitoring of cancer survivors after
treatment
o Diagnosis of specific tumor types
particularly in brain tumors and instances
where biopsy is not feasible
o Determining the effectiveness of cancer
treatment

o CA 19-9 o Determining recurrent cancer

o Calcitonin Useful markers used to determine recurrent

o CEA Carcinoembryonic antigen cancer
o Cga chromagnin A o Prostate specific antigen (PSA) prostate
cancer
o S100
o Human Chorionic gonadotrophin (HCG) for
o TA 90
gestational trophoblastic tumors and some
o Thyroglobulin germ cell cancers
o TPA tissue polypeptide antigen o Alpha-feto protein germ cell cancers
o CA 125 for epithelial ovarian cancer
HORMONE RECEPTORS o Carcinoembryonic antigen (CEA) for colon
o HER 2 & rectal cancers
o Hcg (beta HCG) o CA 15 3 for breast cancer
o LASA-p (lipid associated sialic acid in
plasma TWO GROUPS
o NSE (neuron specific enolase) Cancer specific markers
o NM22 Tissue specific markers
o PSA
o PAP prostatic acid phosphatase Cancer specific markers
o PSMA prostate specific membrane o Related to the presence of cancerous tissues
antigen o Useful in follow-up of treated patients &
progress of the disease
o Examples are: CEA, CA 19-9, CA 125

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Tissue specific markers
o Related to tissues which have developed
cancers
o May not be related to tumors & maybe
elevated when no cancer is present
o Examples are: PSA, beta-HCG, AFP, AFP-
L3, thyroglobulin
A good tumor marker should have those
properties:
1. A tumor marker should be present in or
produced by tumor itself
2. A tumor marker should not be present in
healthy tissues
3. Plasma level of a tumor marker should be at
a minimum level in healthy subjects and in
benign conditions.
4. A tumor marker should be specific for a
tissue, it should have different
immunological properties when it is
synthesized in other tissues.
5. Plasma level of the tumor marker should be
in proportion to the both size of tumor and
activity of tumor.
6. Half- life of a tumor should not be very
long.
7. A tumor marker should be present in plasma
at a detectable level, even though tumor size
is very small.
TUMOR MARKERS CAN BE CLASSIFIED AS
RESPECT WITH THE TYPE OF
MOLECULE
1. Enzymes or isoenzymes (ALP, PAP)
2. Hormones (calcitonin)
3. Oncofetal antigens (AFP, CEA)
4. Carbonhydrate epitopes recognized by
monoclonal antibodies (CA 15-3, CA 19-9,
CA- 125)
5. Receptors (Estrogen, Progesterone)
6. Genetic changes (mutations in some
oncogenes and tumor suppressor genes.
Some mutations in BRCA1 and 2 have been
linked to hereditary breast ovarian cancer)
POTENTIAL USES OF TUMOR MARKERS
o Screening in general population
o Differential diagnosis of symptomatic
patients
o Clinical staging of cancer
o Estimating tumor volume
o As a prognostic indicator for disease
progression
o Evaluating the success of treatment
o Detecting the recurrence of cancer
o Monitoring response to therapy
o Radioimmunolocalization of tumor masses.
o In order to use tumor marker for screening
in the presence of cancer in asymptomatic
individuals in general population, the marker
should be produced by tumor cells and not
be present in healthy people.
o However, most tumor markers are
present in normal, benign and cancer
tissues and are not specific enough to be
used for screening cancer.
o Few markers are specific for a single
individual tumor, most are found with
different tumors of the same tissue type.
o They are present in higher quantities in
blood from cancer patients than in blood
from both healthy subjects and patients with
benign diseases.
o Some tumor markers have a plasma level in
proportion to the size of tumor while some
tumor markers have a plasma level in
proportion to the activity of tumor.
o The clinical staging of cancer is aided by
quantitation of the marker.
o Serum level of marker reflects tumor
burden.
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o The level of the marker at the time of
diagnosing may be used as a prognostic
indicator for disease progression and patient
survival. After successful initial treatment,
such as surgery, the marker value should
decrease. The rate of the decrease can be
predicted by using the half-life of the
marker.
o The magnitude of marker reduction may
reflect the degree of success of the
treatment.
o In the case of recurrence of the cancer,
marker increases again.
o Most tumor marker values correlate with the
effectiveness of treatment.
ENZYMES
ALKALINE PHOSPHATASE (ALP)
o Increased alkaline phosphatase activities
are seen primary or secondary liver cancer.
Its level may be helpful in evaluating
metastatic cancer with bone or liver
involvement, Placental ALP, regan
isoenzyme, elevates in a variety of
malignancies, including ovarian, lung,
gastrointestinal cancers and Hodgkins
disease.
PROSTATIC ACID PHOSPHATASE
(PAP)
o It is used for staging prostate cancer and for
monitoring therapy. 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)
o The clinical use of PAP has been replaced
by PSA. PSA is much more specific for
screening or for detection early cancer. It is
found in mainly prostatic tissue.
o PSA exists in two major forms in blood
circulation. The majority of PSA is
complexed with some proteins. A minor
component of PSA is free.
o PSA testing itself is not effective in
detecting early prostate cancer. Other
prostatic diseases, urinary bladder
catheterization and digital rectal
examination may lead an increased PSA
level in serum.
o The ratio between free and total PSA is a
reliable marker for differentiation of
prostatic cancer from benign prostatic
hyperplasia.
o The use of PSA should be together with
digital rectal examination and followed by
transrectal ultrasonography for an accurate
diagnosis of cancer.
o Serum level of PSA was found to be
correlated with clinical stage, grade and
metastasis.
o The greatest clinical use of PSA is in the
monitoring of treatment.
o This treatment includes radical
prostatectomy, radiation therapy and
antiandrogen therapy
o The PSA level should fall below the
detection limit.
o This may require 2-3 weeks. If it is still at a
high level after 2-3 weeks, it must be
assumed that a residual tumor is present.
o Androgen deprivation therapy may have
direct effect on the PSA level that is
independent of the antitumor effect. This
subject must be considered always.
HORMONES
CALCITONIN
o Calcitonin is a hormone which decreases
blood calcium concentration
o Its elevated level is usually associated with
medullary thyroid cancer
o Calcitonin levels appear to correlate with
tumor volume and metastasis
o Calcitonin is also useful for monitoring
treatment and detecting the recurrence of
cancer.
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o However, calcitonin levels are also at a high
level in some patients with cancer of lung,
breast, kidney, liver and in nonmalignant
conditions such as pulmonary diseases,
pancreatitis, Pagets disease,
hyperparathyroidism, myeloproliferative
disorder and pregnancy.
HUMAN CHORIONIC
GONADOTROPIN (hCG)
o It is a glycoprotein appears in pregnancy. Its
high level is a useful marker for tumors of
placenta and some tumors of testes.
o hCG is also at a high level in patients with
primary testes insufficiency.
o hCG does not cross the blood brain barrier.
Higher levels in BOS may indicate
metastase to brain
ONCOFETAL ANTIGENS
o most reliable markers in this group are a-
fetoprotein and carcinoembryonic antigen
(CEA)
a Fetoprotein (AFP)
o a fetoprotein is a marker for hepatocellular
and germ cell carcinoma
o it is also increased in pregnancy and chronic
liver diseases
o AFP is useful for screening (AFP levels
greater than 1000 g/L are indicative for
cancer except pregnancy), determining
prognosis and monitoring therapy of liver
cancers.
o AFP is also a prognostic indicator of
survival.
o Serum AFP levels are less than 10 g/L in
healthy adults. Elevated AFP levels are
associated with shorter survival time.
o AFP and hCG combined are useful in
classifying and staging germ cell tumors.
One or both markers are increased in those
tumors.
CARCINOEMBRYONIC ANTIGEN
(CEA)
o It is a cell surface protein and a well-defined
tumor marker.
o CEA is a marker for colorectal,
gastrointestinal, lung and breast carcinoma.
o CEA levels are also elevated in smokers and
some patients having benign conditions such
as cirrhosis, rectal polyps, ulcerative colitis
and benign breast disease.
o CEA testing should not be used for
screening. Some tumors dont produce
CEA. It is useful for staging and
monitoring therapy.
CARBONHYDRATE MARKERS
o These markers either are antigens on the
tumor cell surface or are secreted by tumor
cells.
o They are high molecular weight mucins or
blood group antigens. Monoclonal
antibodies have been developed against
these antigens.
o Most reliable markers in this group are CA
15-3, CA 125 and CA 19-9.
CA 15 3
o CA 15-3 is a marker for breast carcinoma.
o Elevated CA 15-3 levels are also found in
patients with pancreatic, lung, ovarian,
colorectal and liver cancer and in some
benign breast and liver diseases.
o It is not useful in diagnosis. It is most
useful for monitoring therapy.
CA 125
o Although CA 125 is a marker for ovarian
and endometrial carcinomas, it is not
specific.
o CA 125 elevates in pancreatic, lung, breast,
colorectal, gastrointestinal cancer, and in
benign conditions such as cirrhosis,
hepatitis, endometriosis, pericarditis, and
early pregnancy.
o It is useful in detecting residual disease in
cancer patients following initial therapy.
o A preoperative CA 125 level of less than
65 kU/L is associated with a greater 5-year
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survival rate than is a level of greater 65
kU/L
o It is also useful in differentiating benign
from malignant disease in patients with
ovarian masses.
o In the detection of recurrence, use of CA
125 level as an indicator is about 75%
accurate.
CA 19-9
o CA 19-9 is a marker for both colorectal and
pancreatic carcinoma.
o However elevated levels were seen in
patients with hepatobiliary, gastric,
hepatocellular and breast cancer and in
benign conditions such as pancreatitis and
benign gastrointestinal diseases.
o CA 19-9 levels correlate with pancreatic
cancer staging.
o It is useful in monitoring pancreatic and
colorectal cancer.
o Elevated levels of CA 19-9 can indicate
recurrence before detected by radiography or
clinical findings in pancreatic and colorectal
cancer.
PROTEIN MARKERS
o Most reliable markers in this group are 2
microglobulin, ferritin, thyroglobulin and
immunoglobulin.
2 MICROGLOBULIN
o 2 microglobulin is a marker for multiple
myeloma, Hodgkin lymphoma.
o It also increases in chronic inflammation
and viral hepatitis.
FERRITIN
o Ferritin is a marker for Hodgkin lymphoma,
leukemia, liver and lung and breast cancer.
THYROGLOBULIN
o it is a useful marker for detection of
differentiated thyroid cancer.
IMMUNOGLOBULIN
o Monoclonal immunoglobulin has been used
as marker for multiple myeloma for more
than 100 years.
o Monoclonal paraproteins appear as sharp
bands in the globulin area of the serum
protein electrophoresis.
o Bence Jones protein is a free monoclonal
immunoglobulin light chain in the urine and
it is a reliable marker for multiple myeloma.
RECEPTOR MARKERS
o Estrogen and progesterone receptors are
used in breast cancer as indicators for
hormonal therapy.
o Patients with positive estrogen and
progesterone receptors tend to respond to
hormonal treatment.
o Those with negative receptors will be treated
by other therapies.
o Hormone receptors also serve as a
prognostic factor in breast cancer. Patients
with positive receptor levels tend to survive
longer.
o Cytoplasmic estrogen receptors are now
routinely measured in samples of breast
tissue after surgical removal of a tumor of
patients with breast cancer, 60% have
tumors with estrogen receptor.
o Approximately two thirds of patients with
estrogen receptor (+) tumors respond to
the hormonal therapy. 5% of patients with
estrogen receptor (-) tumors respond to
hormonal therapy.
C-erbB2 (HER 2 Neu)
o It is a receptor for epidermal growth factor
(EGF) but it doesnt contain EGF binding
domain. It serves as a co - receptor in EGF
action.
o In the case of increased expression of C-
erbB2 leads the oto activation and
increased signal transduction.
o Increased expression of C erbB2 was
determined in some cancers. It was
suggested as an important factor for
carcinogenesis and metastasis.
o Routine measurement of C-erbB2 was
started in our hospital.
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GENETIC CHANGES
o Four classes of genes are implicated in
development of cancer:
1) Protooncogenes which are
responsible for normal cell growth
and differentiation
2) Tumor suppressor genes which
are involved in recognition and
repair of damaged DNA.
3) Apoptosis related genes are
responsible for regulation of
apoptosis.
4) DNA repair genes alterations on
these genes may lead to tumor
development.

SUSCEPTIBLE PROTOONCOGENES:
o K- ras, N- ras mutations are found to be
correlated with acute myeloid leukemia,
neuroblastoma.

SUSCEPTIBLE DNA REPAIR GENES: ADDITIONAL INFORMATION

o BRCA 1 and BRCA2 are specific genes
inherited predisposition for developing
breast and ovarian cancer, and mutations on
these genes are newly measured in some
laboratories.
o Mismatch repair genes are mutated in
some colon cancers
SUSCEPTIBLE TUMOR SUPPRESSOR
GENES:
o Retinoblastoma gene
o P 53 gene
o P 21 gene
o Those genetic markers are very new and not
routinely measured in laboratories
CHROMOSOMAL TRANSLOCATION
o c-myc gene has been found to be
translocated from 8. chromosome to 14.
chromosome and then become activated in
Burkitts lymphoma.
o myc gene encodes a DNA-binding protein
which stimulates cell dividing.
o In a chronic myeloid leukemia, there is a
translocation between chromosomes 9 and
22.
SPECIMEN FOR DETECTION
o Blood
o Urine
o Fluids
o Biopsy
o Reporting: ng/mL, U /mL (units / milliliter)
ALPHA - FETOPROTEIN (AFP)
o Helpful in the diagnosis of liver cancer
(hepatocellular carcinoma)
o Usually less than 10 ng/ml
o Increased in acute & chronic hepatitis
o Used in response of the patient to treatment
with liver cancer
BETA - 2 MICROGLOBULIN
o Elevated in multiple myeloma, chronic
lymphocytic leukemia & lymphomas
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o Seen higher in non-cancerous disease
(kidney disorder)
o Follow-up treatment for multiple myeloma
BLADDER TUMOR ANTIGEN
o Found in bladder cancer
o Non-cancerous kidney stones & UTI
o Used together with NMp 22 as a tool for
recurrent bladder cancer
o Reported as BTA+ or BTA
o Helpful in cytoscopy standard diagnosis
and follow-up for bladder cancer
CA 15 - 3
o Useful in diagnosing breast cancer
o Elevated levels are found in less than 10%
of patients with early disease and 70% of
patients with advance disease
o Can also seen in benign breast cancer and
hepatitis
o NV = less than 30 U /ml
CA 27.29 (BR 27.29)
o Best marker for prognosis in breast cancer
o Used to diagnose cancer during and after
treatment
o Protein product of the breast cancer-
associated MUC 1 gene, elevated in breast
cancer
o Present in 30% of low stage disease and 60
70% advance stage disease
o May also seen in benign ovarian breast and
liver disease, in colon, stomach, pancreas
and lung malignancies
o NV = less than 40 U /ml
CA 125
o Standard tumor marker used for women
during or after treatment for epithelial
ovarian cancer
(non-mucinous epithelial ovarian neoplasms)
o NV = less than 35 U/ml, decrease in post-
menopausal women slightly increase in
follicular phase of menstrual cycle
o Elevated in only 50% of patients with stage I
disease & has poor positive predictive value
in unselected women
o Increase in uterine fibroids or endomitriosis,
lung, pancreatic, breast & colon cancer &
patients with cancer in the past
CA 125 in non-neoplastic abdominopelvic
disorders
o Pregnancy
o Fibroids
o Benign ovarian cyst
o Pelvic inflammation
o Ascites
o endometriosis
o Utilize in differentiating pelvic masses
o A fall in CA 125 during initial treatment
suggest treatment efficacy (disease free
survival, fall in 3 cycles treatment improved
survival), increase suggest treatment failure
and disease recurrence
o Rising values suggest relapse seen in an
interval of 3- 6 months poor prognosis)
CA 72 -4
o New test available for ovarian and
pancreatic cancers
o Also detects digestive tract especially
stomach cancers
CA 19-9
o First developed to detect colorectal cancer
o Useful in patients with pancreatic cancer /
colorectal cancer & biliary carcinoma
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o Increased also in patients with stomach, o Pancreatitis

esophagus & bile cancers, pancreatitis &
thyroid disease
o Useful in detecting patients response to
treatment
CEA (Affected by)
o NV = less than 37 U /ml
CALCITONIN
o Hormone produced by cells called
parafollicular C cells in the thyroid gland
o Normally regulates blood Calcium levels
o NV= less than 12 pg /ml
o Increased in medullary thyroid carcinoma
(MTC) a rare cancer that starts in the
parafollicular C- cells (greater than 100 pg/ml)
CARCINOEMBRYONIC ANTIGEN
(CEA
o Elevated in 25% of tumors confined in colon
50% with positive nodes, 75% distant
metastases
o Liver is the primary site for its metabolism
(most sensitive in liver metastases 94%,
poorly sensitive to locoregional recurrences
60%
o It occurs in other malignancies, gastric
adenocarcinoma, pancreatic
adenocarcinoma, thyroid carcinoma, cervical
adenocarcinoma, urothelial carcinoma
o Not used to diagnose or screen for colorectal
cancers but it is preferred tumor marker to
help predict outlook in patients with
colorectal cancers
o Used to follow-up treatment with lung &
breast cancer
Non-neoplastic conditions
o Smoking
o Peptic ulcer
o Inflammatory bowel disease
o Hypothyroidism
o Biliary obstruction
o cirrhosis
o Tumor stage
o Tumor grade
o Tumor ploidy
o Tumor site obstruction
o Liver function
o Smoking
Chromagnin A
o Made by neuroendocrine tumors which
include carcinoid tumors, neuroblastoma,
small cell lung cancer
o Most sensitive marker for carcinoid tumor
HER 2
o Is a protein that tells breast cancer cells to
grow
o Patients positive with HER 2 would most
likely respond to certain treatment such as
trantuzumab (herceptin) & lapatinib (tykerb)
o Detected by immunohistochemistry, based
on the grade according to proportion of cells
expressing intense nuclear staining
HUMAN CHORIONIC
GONADOTROPIN
o Elevated in patients with testicular and
ovarian cancers (germ cell tumors) and
gestational trophoblastic disease)
o Normally elevated in pregnant women, and
marijuana has been associated with low-
level elevation of HCG
o Also, seen in patients with mediastinal germ
cell tumors (cancer at the middle of the
chest)
o HCG value of more than 50,000 mIU/ml
suggest poor prognosis
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LIPID ASSOCIATED SIALIC ACID IN
PLASMA
o Used for detection of ovarian cancer
o Highly non-specific marker
o Elevated LASA-P has been demonstrated in
hematolymphoid neoplasms and tumors of
the breast, GI tract, lung and ovary
o Useful in monitoring the response to therapy
and detecting disease recurrence in certain
patients
PSA PROSTATE SPECIFIC
ANTIGEN
o Should be combined with digital rectal
examination (age 50 up)
o High specificity, sensitivity & low cost
o Organ specific but not cancer specific
o Increased in benign prostatic hyperplasia
(BPH), prostatitis, prostatic infarct and following
needle biopsy
o PSA value greater than 10 ng/ml rarely
associated with benign disease
o Increase normally with age
Specimen Handling
o Free PSA (is a protease appears to minimize
the viscosity of ejaculate) less stable than
bound PSA, specimen should be processes
immediately to prevent this effect
o Specimen that cannot be examined in 2
hours should be separated and frozen
o % free PSA has proven to be more sensitive
& specific than total PSA and has greatly
aided decision-making in men with PSA less
than 10
o The advantage of % free PSA is only seen
when prostatic volume is less than 60 cc.
PSA Isoforms
o PSA is released from glandular cells as pro-
PSA (to make mature PSA 7 amino acids
is clipped from pro PSA)
o Clipping give rise to several additional
(truncated) forms of pro-PSA having 2, 4 or
5 amino acids
o In prostate cancer, increase in pro-PSA and
truncated forms
o Detection of prostate cancer has improved in
men whose total PSA is in 2.5 4.0 range.
Benign PSA (bPSA)
o Refers to a form of PSA that was first
isolated in the transition zone of benign
prostatic hyperplasia (BPH)
o It discriminates BPH from non- BPH
prostatic enlargement
THYROGLOBULIN
o Mainstay for detection of tumor recurrence
in differentiated (follicular and papillary)
thyroid carcinoma
o It has a half-life of 65 hours, 6 months to
become undetectable following total
thyroidectomy
o In normal circumstances, it is cleared in
circulation by the catabolism in the liver and
recycling in the thyroid
TUMOR ASSOCIATED TRYPSIN
INHIBITOR (TATI)
o Used a marker for mucinous ovarian
carcinoma, urothelial carcinoma (20% low
stage to 80% high stage tumor) and 70%
sensitive in renal carcinoma. It was first
discovered in the urine of patients with
ovarian carcinoma
o Cleared by kidneys, elevated in renal failure
o In pancreatitis, increased is associated in
severity of condition
o Complimentary with CA-125
o Elevated in 60% of gastric carcinoma
particularly diffuse (infiltrative, signet ring)
types
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ALPHA FETOPROTEIN (AFP)
o Major component of fetal serum, having
physiologic effects same with albumin
o Synthesized in the fetal liver, yolk sac
and fetal gastrointestinal tract & after
birth recedes to undetectable level
ALKALINE PHOSPHATASE
o Highly non-specific tumor marker
o Increased maybe an indication of
osteoblastic activity (osteogenic sarcoma
or bone metastases)
o Elevated in active Paget disease of the
bone
o Most sensitive liver function test in liver
metastases (hepatic metastases)
LDH
o Lymphoma, melanoma, acute leukemia,
seminoma (germ cell tumors)
o Non-cancerous cause: hepatitis, MI
(heart attack), stroke, anemia (pernicious
& thalassemia), muscular dystrophy,
certain medications (narcotics, aspirin,
anesthetics, alcohol), muscle injury
o Reference range: 100-333 u/l
NSE - Neuron-Specific Enolase
o Small cell lung cancer, neuroblastoma
o NC: Proton pump inhibitor treatment,
hemolytic anemia, hepatic failure, end
stage renal failure, brain injury, seizure,
stroke
o Normal < 9 ug/L
NMP 22 (urine test)
o Bladder cancer
o NC: BPH (benign prostatic
hypertrophy), prostatitis
o Normal <10 U/ml
PAP - PROSTATIC ACID
PHOSPHATASE
o Metastatic prostate cancer, myeloma,
lung cancer, osteogenic sarcoma
o NC: prostatitis, Gauchers disease,
osteoporosis, cirrhosis,
hyperparathyroidism, prostatic
hypertrophy
o Normal: 0.5 to 1.9 u/l
VMA (Vanillylmandelic acid)
o Neuroblastoma** Pheochromocytoma,
ganglioneuroma, rhabdomyosarcoma
o NC: Dietary intake (bananas, vanilla,
tea, coffee, ice cream, chocolate),
medications (tetracyclines, methyldopa,
MAOIs)
o 8-35 mmols over 24 hours
HVA (Homovanillic acid)
o Neuroblastoma
o NC: same as VMA, in addition:
psychosis, major depression, dopamine
(a medication)
o Up to 40 mmols over 24 hours
5-HIAA (5-Hydroxy-Indol Acetic Acid)
o Carcinoid tumors
o NC: Celiac & tropical sprue, Whipples
disease, dietary: walnuts, pecans,
bananas, avocados, eggplants,
pineapples, plums & tomatoes;
medications: acetaminophen, aspirin and
guaifenesin
o Normal 6-10 mg over 24 hours.
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