Fakeeh College for Medical Sciences
MBBS program
Diagnostic module
MED
Tumor markers
Dr. Ahmed Faheem Dr. Noha Hazem
Assistant Professor of Associate Professor of
Clinical Biochemistry Clinical Biochemistry
FCMS
FCMS
Students Learning outcomes SG HM
At the end of this lecture students will be able to:
1. Define tumour marker
2. Identify historical background of tumour markers
3. List Properties of ideal tumour marker
4. Classify tumour markers
5. Explain Clinical applications and methods of detection of tumour markers
6. Discuss Common cancers and their associated tumour markers
CONTENTS
1- Introduction
2- Definition
3- Historical background
4- Properties of ideal TM
5- Classifications
6- Clinical applications
7- Methods of detection
8- Common cancers and associated TM
Introduction:
• A major challenge in the management of patients with cancer is the
lack of specific tools for
• The early detection
• Accurate prediction of biological behavior
• Accurate assessment of prognosis
• Role of tumour markers:
• Tumour markers can play a crucial role in detecting disease and
assessing response to therapy
Definition:
• A substance present in or produced by a tumour
(benign or malignant)
• Or a substance produced by the host in response to the
tumour's presence
Historical background
• 1846 – Bence jones first identified BJ protein in urine of patients of
Multiple myeloma (cancer of plasma cells).
• 1930- 1990- Acid phosphatase served as marker for prostate cancer
• 1963- AFP discovered as tumour marker for HCC
• 1965- CEA discovered as tumour marker for colon cancer
• 1975- monoclonal antibodies tech. was developed which facilitates the
discovery of new tumour markers including CA125, CA15.3, CA19.9
Properties of ideal TM
Or Criteria
• Highly sensitive
• Highly specific.
• 100% accurate in differentiating between healthy individuals and tumor
patients
• Show positive correlation with tumor volume and extent
• Predict early recurrence and have prognostic value
• Detectable at early stage of tumor
• Short half life to rapidly mirror treatment schedules
• Measured easily.
Soluble markers – classical tumour
markers , various chemical substances
Tumour Circulating cellular elements –
circulating tumour cells, circulating
markers endothelial cells and their precursors
Genetic abnormalities – detection of
mutations in oncogenes and tumour
supressor genes, protein products of
oncogenes, further changes
What are the chemical classes/classi es/nature of the marker?
Chemical characteristics of TU markers
• Enzymes – PSA (prostate specific antigen), NSE (neuron specific enolase),TK, LDH
• Immunoglobulins – IgG, IgM, IgA, B2-microglobulin, free light chains
• Hormones – growth hormon, ACTH, TG, PRL, calcitonin, PTH, hCG
• Cytokeratines (soluble derivatives) – tissue polypeptide antigen (TPA), tissue
F
polypeptide specific antigen (TPS), fragment of cytokeratine 19 (CYFRA 21-1)
• Glycoproteins, glycolipids and saccharides – AFP, hCG, CEA, squamous cell
carcinoma antigen (SCC), CA 19-9, CA 125, CA 15-3, CA 549, CA 72-4
• Receptors – estrogen and progesteron receptors, HER2/neu, EGF
Tumour markers –
Clinical-chemical Classification:
Origin classi cation of
tumor markers
• Oncofetal antigens
• Tissue and organ specific antigens
• Non-specific antigens
Oncofetal antigens
• Substances produced during the fetal period or by placenta, postnatally low
e
concentration and increase in connection with some disease, mainly tumours.
• Antigens that appear soon in the ontogenesis and postnatally characteristic for
less differentiated (i.e. more malignant) tumours.
• alpha-fetoprotein (AFP)
• human chorionic gonadotrophin (hCG) carcinoembryonic antigen
(CEA) placental alkaline phosphatase (PLAP)
Tissue and organ specific antigens
• Physiologically present in healthy tissue or organ, outside released only
in minimal amounts
• Pathological states (tumours, inflammation, injury) – increased release
as
• prostatic specific antigen (PSA), neuron specific enolase (NSE), protein S-100,
soluble fragments of cytokeratins (TPA, TPS, CYFRA 21-1), CA(cancer) antigen
defined by monoclonal antibodies, squamous cells carcinoma antigen (SCC),
thyreoglobulin (TG), hormones and their precursors in tumours from glands
which produce them physiologically (e.g. C-peptid in insulinoma)
Non-specific antigens
• enzymes and hormones produced by tumours from organs which do not
as
produce them physiologically – paraneoplastic production), as a reaction
I
to the presence of tumour
• ferritin, lactate dehydrogenase (LDH), thymidinkinase (TK), B2-
microglobulin, some acute phase reactants,lipid associated
sialic acid (LASA)
• EX. lung tumours – ACTH, ADH, parathormon etc.
Roles for tumor markers
Clinical applications:
• 1- Role in screening:
• Tumor markers play a limited role for tumor screening, just because
if
• Relatively low sensitivity
• Lack of specificity
• Not elevated in early stage
• Inappropriate for the detection of small in situ cancer
• Examples used as screening tool:
• AFP for liver cancer
• PSA for prostate cancer
2- Role in Diagnosis:
q Most tumor markers levels alone are often insufficient to diagnose cancer
for the following reasons: L
DLE
Ø TM levels can be elevated in people with benign conditions
Ø TM levels are not elevated in every person with cancer (especially in
the early stages of the disease).
Ø Many TM are not specific to a particular type of cancer
___
q So, TM is not the key diagnostic tool but can be a complementary sign to
clinical finding & medical imaging.
q Several approaches have been suggested recently to improve the
diagnostic yield of many tumor markers by:
Ø The use of multiple markers
Ø Improving both the specificity and sensetivity of the TM.
3- Role in staging/ prognosis:
qThe pre therapeutic level of certain TM can contributes a
0
It
prognostic factor because of links with:
Ø Metabolic activity
Ø Tumor size
Ø Invasion
qAllow doctors to refine therapeutic strategy by selecting
groups with risk of failure response to treatment.
Which results in bad
prognosis and result
4- Role in monitoring & recurrence:
qOne of the most useful applications
qThe serum level of TM reflect the success of surgery or
the efficacy of chemotherapy.
qIf the marker level in the blood goes down, that is almost
always a sign that the treatment is effective.
qIf TM level after surgery remain elevated would indicate
either incomplete removal of the tumor, recurrence, or the
presence of metastases
Methods of detection:
• Immunoassay by using monoclonal Abs
I Soluble material
• RIA
Soluble e material
• ELISA
• IHC (immunohistochemistry): ER, PR, Her-2 neu
Cellular level
• FISH: Her-2 neu
• RT-PCR
• HPLC
Common cancers and associated TM
Alpha Fetoprotein
• Hepatocellular carcinoma mainly
• Germ Cell Tumors
E
• Classifying and staging with hCG
o
• Nonseminomas: both AFP & hCG elevated (90%)
• Seminomas: AFP not elevated, hCG elevated 30%
o
• AFP level not directly related to tumor size f
Disadvantage
• Elevated in pregnancy, liver disease (hepatitis, cirrhosis, GI tumors)
Normally
y
• AFP Tumor-specific glycoforms may improve specificity of AFP for HCC
Elevated in
CEA pregnancy
normally
• Elevated in smokers and elderly
• Elevated in colorectal cancer (CRC), breast, pancreatic, GI, and lung
Has highest level
cancer
• – Breast cancer: used for detecting and monitoring metastatic
• CEA 150-300 kDa glycoprotein
disease
• Elevated in benign diseases: cirrhosis, emphysema & rectal polyps
• CEA – Not useful for CRC Screening Combined with
s CEA
D
• New more specific marker for CRC: TIMP-1 (Tissue inhibitor of
CA 15-3/CA27.29
• High molecular weight glycoprotein (Polymorphic Epithelial Mucin)
• Breast cancer marker
Characteristics of this
• Correlate with stage and tumor size marker
• Prognosis & predict response to chemotherapy
• Detect residual disease following initial therapy
• Detect recurrence, correlates with disease progression or regression
• NOT sensitive enough for early detection
• Elevated in benign diseases of liver & breast
• Elevated in other cancers: pancreatic, lung, ovarian, colorectal, & liver
CA 125
High molecular weight
t
• >200-2000 kDa glycoprotein
• Increased in benign diseases: pregnancy, endometriosis, ovarian
cysts, PID, cirrhosis, hepatitis, pericarditis
• Increased in other cancers: Ovarian cancer, lung, breast, GI,
endometrial, & pancreatic y Most common
• Synthesis modified by Taxol
Beta-2-microglobulin (B2M)
• Cancer types: Multiple myeloma, chronic lymphocytic
leukemia, and some lymphomas
• Tissue analyzed: Blood, urine, or cerebrospinal fluid
• How used: To determine prognosis and follow response to
treatment
Beta-human chorionic gonadotropin (Beta-hCG)
• Cancer types: Choriocarcinoma and germ cell tumors
• Tissue analyzed: Urine or blood
• How used: To assess stage, prognosis, and response to
treatment
BRCA1 and BRCA2 gene mutations
CA-25 is the
primary tumor
marker for
• Cancer type: Ovarian cancer ovarian cancer
• Tissue analyzed: Blood
• How used: To determine whether treatment with a
particular type of targeted therapy is appropriate
BCR-ABL fusion gene (Philadelphia chromosome)
• Cancer type: Chronic myeloid leukemia, acute lymphoblastic
leukemia, and acute myelogenous leukemia
• Tissue analyzed: Blood and/or bone marrow
• How used: To confirm diagnosis, predict response to targeted
therapy, and monitor disease status
CA19-9
b GIT cancer
• Cancer types: Pancreatic cancer, gallbladder cancer, bile
duct cancer, and gastric cancer
b most common
• Tissue analyzed: Blood
• How used: To assess whether treatment is working
Calcitonin
• Cancer type: Medullary thyroid cancer
• Tissue analyzed: Blood
• How used: To aid in diagnosis, check whether treatment is
working, and assess recurrence
CD20
• Cancer type: Non-Hodgkin lymphoma
• Tissue analyzed: Blood
• How used: To determine whether treatment with a
targeted therapy is appropriate
Fibrin/fibrinogen
• Cancer type: Bladder cancer
• Tissue analyzed: Urine
• How used: To monitor progression and response to
treatment
Lactate dehydrogenase
• Cancer types: Germ cell tumors, lymphoma, leukemia,
melanoma, and neuroblastoma
• Tissue analyzed: Blood
• How used: To assess stage, prognosis, and response to
treatment
Nuclear matrix protein 22
• Cancer type: Bladder cancer
• Tissue analyzed: Urine
• How used: To monitor response to treatment
