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Dr. Anshuman Aashu
1st year PGT, General Surgery
IPGMER &SSKM Hospital
TUMOUR MARKER
WHAT ARE TUMOUR
MARKERS
 Biological substances synthesized and
released by the tumour cells or by the host
body in response to a tumour.
 Detected in higher than normal levels in
blood, serum, urine or other body fluids.
 Indicators of
cellular, biochemical, molecular, or genetic
alterations whereby neoplasia can be
recognised.
 Found to be raised in certain benign
conditions also and hence, elevated levels
need to be interpreted with caution.
HISTORICAL BACKGROUND
1863 Bence Jones Protein
1940 Acid Phosphatase
1960 Immunoassay
1963 -Fetoprotein
1965 Carcinoembryonic Antigen
1975 Monoclonal Antigens
1980 CA 125, PSA, Carbohydrate
Antigens
1970 Oncogenes
1980 Tumour Suppressor Genes
2001 Microarrays, Mass Spectrometry,
Neural Network, Multiparametric
Analysis
CLINICAL APPLICATION
 Screening.
 Diagnosis.
 Staging.
 Prognosis.
 Therapy.
 Surveillance and monitoring.
Screening
 Best example is the screening of prostate cancer
with serum PSA.
 Apart from PSA, no other tumour markers have
shown reliability for the purpose of screening.
 Major disadvantage being the overdiagnosis and
overtreatment of a certain tumour based on
screening with tumour markers.
 Some recent studies, like ERSPC and PLCO
trials didn’t show any significant mortality benefit
even in prostate cancer screened with PSA level.
Only one in eight screen-detected cancers is
likely to kill the patient.
Diagnosis and Staging
 Tumour markers doesn’t help in establishing the
diagnosis per se in most of the cases but
corroborates it.
 Helps in distinguishing benign from malignant
cases in some tumours.
 Correlates with amount of tumour present and
hence, identifies the tumour burden.
 Sometimes, allow subtype classification and
hence helps in staging of the disease.
Prognosis, Therapy and
Monitoring
 The mere presence or absence of a tumor marker
or its quantification helps in determining the
prognosis.
 Predicts the response to therapy and hence
guides the choice of therapy in many cases.
 The newer modality of targeted therapy is based
on the presence or absence of such markers.
 Identifies the response to therapy with change in
levels.
 Helps in the monitoring for recurrences in follow-
up.
THE IDEAL TUMOUR MARKER
 High sensitivity and specificity.
 Level should correlate with the tumour burden.
 Levels in healthy patient should be much lower
than that in a cancer patient.
 Predict recurrences before they are clinically
detectable.
 The tumour marker assay should be reducible,
rapid, and inexpensive.
AN IDEAL TUMOUR
MARKER IS STILL AN
ENIGMA
CATEGORIES OF TUMOUR
MARKER
 Protein:
o Oncofetal antigens – CEA, AFP.
o Hormones – HCG, Calcitonin, Catecholamine and
its metabolites, Ectopic hormones.
o Isoenzymes – Neuron specific enolase, Acid
phosphatase.
o Mucin and other glycoprotiens – CA-19-9, CA-
125, CA-15-3.
o Specific proteins – Immunoglobulins, PSA.
 RNA based markers:
o Overexpressed or underexpressed transcripts.
o Regulatory RNAs (e.g., micro-RNAs)
 DNA-based markers:
o Single nucleotide polymorphisms (SNPs).
o Chromosomal translocation – bcr-abl (Philadelphia).
o Microsatellite instability.
o Changes in DNA copy number.
o Epigenetic changes(e.g., differential promoter-
region methylation)
DETECTION OF TUMOUR
MARKER
 Serological: Enzyme assays.
 Immunological:
 Immunosorbent assay.
ELISA.
Radioimmuno assay.
 Cytogenetic analysis:
FISH.
Spectral karyotyping.
Comparative genomic hybridization.
 Genetic analysis:
Sequencing.
Reverse transcription.
Gel electrophoresis.
DNA micro-array analysis.
 Proteomics:
Surface-enhanced laser desorption/ionization
Recommendations for ordering
test
 Never rely on result of a single test.
 Repeat tests while following up should be ordered
from the same lab using same kit.
 The half-life of the marker should be taken into
account before interpreting the result.
 Multiple markers should be considered to improve
the outcome of the test.
 Ectopic tumour markers should always be kept in
mind.
CARCINOEMBRYONIC
ANTIGEN
 Complex glycoprotein that is associated with the
plasma membrane of tumor cells, from which it
may be released in to the blood.
 Mainly used for colorectal cancer but may be
elevated in:
 Smokers
 Some benign conditions – IBD, pancreatitis,
cirrhosis, COPD etc
 Other malignant lesions – ovarian, breast,
pulmonary.
 Normal <2.5 ng/ml, Borderline 2.5-5.0 ng/ml,
Elevated >5 ng/ml.
 Upper limit of normal level in smokers considered
to be 5 ng/ml.
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
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
CEA (contd)
 Not useful for screening purposes as higher rate
of false positive results seen and low sensitivity in
early cases.
 Elevated level reflects tumour burden.
 More the concentration:
Worse the prognosis.
Higher the chances of recurrence.
 More sensitive for hepatic and retroperitoneal
metastases. Relatively insensitive for local
recurrences and pulmonary or peritoneal
metastases.
 Monitors response to chemotherapy in metastatic
-Fetoprotein
 Used for Hepatocellular carcinoma and non-
seminomatous testicular tumour.
 Elevated in benign conditions like cirrhosis, acute
and chronic hepatitis, 2nd and 3rd semester of
pregnancy, IBD etc.
 Other malignant conditions show elevation and
include pancreatic, gastric, colorectal or lung
cancer.
 Upper limit of normal value in non-pregnant adult
is <25ng/ml.
 No detectable level in upto 20% of HCC cases.
 Level correlates with tumour burden, staging and
AFP (contd)
 Prognosis not only depend on the initial
concentration but also the rate of its rise called
the AFP doubling time.
 Level decreases with resection or ablation and
hence marks response to the therapy. Level
should decrease and remain below 10 ng/ml.
 Maintenance of a higher level after treatment
predicts early recurrence.
Carbohydrate Antigen 19-9
 Serum marker for pancreatic cancer.
 Lewis a negative blood group patients don’t
produce this antigen and hence can’t be used in
this group that consists of 10% of population.
 Also elevated in benign biliary tract diseases,
acute and chronic pancreatitis.
 Elevated in malignant lesions of biliary tract
(95%), stomach, liver, colon and lung.
 For above reasons, use is limited to monitoring of
response to therapy, not as a diagnostic marker.
 Level correlates with tumour burden and hence
marks prognosis.
Prostate Specific Antigen
 Formed in prostatic epithelium and secreted in
prostatic ducts.
 Highly specific tissue marker for prostate but not
a specific cancer marker as level is elevated in
benign prostatic diseases.
 Not only the level but the rate of increase of the
level (PSA velocity) and its concentration per unit
volume of prostatic tissue (PSA density) is also
imoportant.
 Normal upper limit varies with the age of the
patient.
 Only tumour marker widely used for screening
Carbohydrate Antigen 125
 Normally present in the fetus as a derivative of
coelomic epithelium.
 In healthy adults, detected in epithelium of
fallopian tubes, endometrium and endocervix.
 Upper limit of normal 35 U/ml
 Elevated in benign conditions like PID,
endometriosis, adenomyosis, fibroids, cirrhosis
and ascites.
 Elevated in ovarian carcinoma and cancer of
fallopian tube, endometrium and cervix. Non
gynaec malignancies including pancreas, colon,
lung and liver also have elevated level.
CA-125 (contd)
 Not useful for screening due to low specificity.
 Marks worse prognosis with elevated levels.
 Monitors disease course with decreasing levels
following therapy and increasing level predicting
recurrence.
 Peritoneal fluid level of CA 125 found to be more
sensitive than serum level.
-HCG
 Glycoprotein synthesized from the
syncytiotrophoblastic cells of normal placenta.
 Level is elevated in early pregnancy with peak in
the first trimester.
 Elevated in gestational trophoblastic neoplasia-
choriocarcinoma.
 Elevated in non-seminomatous testicular germ
cell tumours and constitute an important tumour
marker for testicular malignancies alongwith AFP,
LDH and PLAP.
Estrogen Receptor (ER)
 2 isoforms:ERa and ERb
 ERa → better prognosis, predictor of relapse
 useful when deciding on adjuvant hormone treatment
 As diagnostic marker when it is a primary unknown
tumor
 ERb → Good prognostic factor, correlates with low
grade and negative axillary LN status tumours.
 HER-2/neu oncogene (using monoclonal
antibody) - over expression related to poor
prognosis in breast cancer
 Oncogene c-erbB-2 gene:over expressed in
30% of breast cancers, correlation between c-
erbB-2 gene positivity, positive axillary node
status, reduced time to relapse and reduced
overall survival.
 BRCA1 gene on chromosome 17q:familial
breast-ovarian cancer syndrome, and breast
cancer in early-onset breast cancer families
→ high risk screening
- To monitor Rx. & to detect recurrence BR Ca
 ↑ in 20% with localized breast cancer, ~80% with
metastatic disease, esp. if with bone involvement
 Specificity of 86%, sensitivity of 30%
 Also ↑ in gastric, pancreatic, cervical & lung cancer.
Other common tumour markers
 Neuron specific enolase – neuroendocrine
tumours like small cell carcinoma of lung,
neuroblastoma, pheochromocytoma etc.
 Calcitonin – medullary carcinoma of thyroid.
 Thyroglobulin – follicular carcinoma of thyroid.
 S-100, Tyrosinase – Malignant melanoma.
 Other DNA and RNA based markers.
Tumour marker

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Tumour marker

  • 1. Dr. Anshuman Aashu 1st year PGT, General Surgery IPGMER &SSKM Hospital TUMOUR MARKER
  • 2. WHAT ARE TUMOUR MARKERS  Biological substances synthesized and released by the tumour cells or by the host body in response to a tumour.  Detected in higher than normal levels in blood, serum, urine or other body fluids.  Indicators of cellular, biochemical, molecular, or genetic alterations whereby neoplasia can be recognised.  Found to be raised in certain benign conditions also and hence, elevated levels need to be interpreted with caution.
  • 3. HISTORICAL BACKGROUND 1863 Bence Jones Protein 1940 Acid Phosphatase 1960 Immunoassay 1963 -Fetoprotein 1965 Carcinoembryonic Antigen 1975 Monoclonal Antigens 1980 CA 125, PSA, Carbohydrate Antigens 1970 Oncogenes 1980 Tumour Suppressor Genes 2001 Microarrays, Mass Spectrometry, Neural Network, Multiparametric Analysis
  • 4. CLINICAL APPLICATION  Screening.  Diagnosis.  Staging.  Prognosis.  Therapy.  Surveillance and monitoring.
  • 5. Screening  Best example is the screening of prostate cancer with serum PSA.  Apart from PSA, no other tumour markers have shown reliability for the purpose of screening.  Major disadvantage being the overdiagnosis and overtreatment of a certain tumour based on screening with tumour markers.  Some recent studies, like ERSPC and PLCO trials didn’t show any significant mortality benefit even in prostate cancer screened with PSA level. Only one in eight screen-detected cancers is likely to kill the patient.
  • 6. Diagnosis and Staging  Tumour markers doesn’t help in establishing the diagnosis per se in most of the cases but corroborates it.  Helps in distinguishing benign from malignant cases in some tumours.  Correlates with amount of tumour present and hence, identifies the tumour burden.  Sometimes, allow subtype classification and hence helps in staging of the disease.
  • 7. Prognosis, Therapy and Monitoring  The mere presence or absence of a tumor marker or its quantification helps in determining the prognosis.  Predicts the response to therapy and hence guides the choice of therapy in many cases.  The newer modality of targeted therapy is based on the presence or absence of such markers.  Identifies the response to therapy with change in levels.  Helps in the monitoring for recurrences in follow- up.
  • 8. THE IDEAL TUMOUR MARKER  High sensitivity and specificity.  Level should correlate with the tumour burden.  Levels in healthy patient should be much lower than that in a cancer patient.  Predict recurrences before they are clinically detectable.  The tumour marker assay should be reducible, rapid, and inexpensive.
  • 9. AN IDEAL TUMOUR MARKER IS STILL AN ENIGMA
  • 10. CATEGORIES OF TUMOUR MARKER  Protein: o Oncofetal antigens – CEA, AFP. o Hormones – HCG, Calcitonin, Catecholamine and its metabolites, Ectopic hormones. o Isoenzymes – Neuron specific enolase, Acid phosphatase. o Mucin and other glycoprotiens – CA-19-9, CA- 125, CA-15-3. o Specific proteins – Immunoglobulins, PSA.  RNA based markers: o Overexpressed or underexpressed transcripts. o Regulatory RNAs (e.g., micro-RNAs)
  • 11.  DNA-based markers: o Single nucleotide polymorphisms (SNPs). o Chromosomal translocation – bcr-abl (Philadelphia). o Microsatellite instability. o Changes in DNA copy number. o Epigenetic changes(e.g., differential promoter- region methylation)
  • 12. DETECTION OF TUMOUR MARKER  Serological: Enzyme assays.  Immunological:  Immunosorbent assay. ELISA. Radioimmuno assay.  Cytogenetic analysis: FISH. Spectral karyotyping. Comparative genomic hybridization.
  • 13.  Genetic analysis: Sequencing. Reverse transcription. Gel electrophoresis. DNA micro-array analysis.  Proteomics: Surface-enhanced laser desorption/ionization
  • 14. Recommendations for ordering test  Never rely on result of a single test.  Repeat tests while following up should be ordered from the same lab using same kit.  The half-life of the marker should be taken into account before interpreting the result.  Multiple markers should be considered to improve the outcome of the test.  Ectopic tumour markers should always be kept in mind.
  • 15. CARCINOEMBRYONIC ANTIGEN  Complex glycoprotein that is associated with the plasma membrane of tumor cells, from which it may be released in to the blood.  Mainly used for colorectal cancer but may be elevated in:  Smokers  Some benign conditions – IBD, pancreatitis, cirrhosis, COPD etc  Other malignant lesions – ovarian, breast, pulmonary.  Normal <2.5 ng/ml, Borderline 2.5-5.0 ng/ml, Elevated >5 ng/ml.  Upper limit of normal level in smokers considered to be 5 ng/ml.
  • 16. 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
  • 17. 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
  • 18. CEA (contd)  Not useful for screening purposes as higher rate of false positive results seen and low sensitivity in early cases.  Elevated level reflects tumour burden.  More the concentration: Worse the prognosis. Higher the chances of recurrence.  More sensitive for hepatic and retroperitoneal metastases. Relatively insensitive for local recurrences and pulmonary or peritoneal metastases.  Monitors response to chemotherapy in metastatic
  • 19. -Fetoprotein  Used for Hepatocellular carcinoma and non- seminomatous testicular tumour.  Elevated in benign conditions like cirrhosis, acute and chronic hepatitis, 2nd and 3rd semester of pregnancy, IBD etc.  Other malignant conditions show elevation and include pancreatic, gastric, colorectal or lung cancer.  Upper limit of normal value in non-pregnant adult is <25ng/ml.  No detectable level in upto 20% of HCC cases.  Level correlates with tumour burden, staging and
  • 20. AFP (contd)  Prognosis not only depend on the initial concentration but also the rate of its rise called the AFP doubling time.  Level decreases with resection or ablation and hence marks response to the therapy. Level should decrease and remain below 10 ng/ml.  Maintenance of a higher level after treatment predicts early recurrence.
  • 21. Carbohydrate Antigen 19-9  Serum marker for pancreatic cancer.  Lewis a negative blood group patients don’t produce this antigen and hence can’t be used in this group that consists of 10% of population.  Also elevated in benign biliary tract diseases, acute and chronic pancreatitis.  Elevated in malignant lesions of biliary tract (95%), stomach, liver, colon and lung.  For above reasons, use is limited to monitoring of response to therapy, not as a diagnostic marker.  Level correlates with tumour burden and hence marks prognosis.
  • 22. Prostate Specific Antigen  Formed in prostatic epithelium and secreted in prostatic ducts.  Highly specific tissue marker for prostate but not a specific cancer marker as level is elevated in benign prostatic diseases.  Not only the level but the rate of increase of the level (PSA velocity) and its concentration per unit volume of prostatic tissue (PSA density) is also imoportant.  Normal upper limit varies with the age of the patient.  Only tumour marker widely used for screening
  • 23. Carbohydrate Antigen 125  Normally present in the fetus as a derivative of coelomic epithelium.  In healthy adults, detected in epithelium of fallopian tubes, endometrium and endocervix.  Upper limit of normal 35 U/ml  Elevated in benign conditions like PID, endometriosis, adenomyosis, fibroids, cirrhosis and ascites.  Elevated in ovarian carcinoma and cancer of fallopian tube, endometrium and cervix. Non gynaec malignancies including pancreas, colon, lung and liver also have elevated level.
  • 24. CA-125 (contd)  Not useful for screening due to low specificity.  Marks worse prognosis with elevated levels.  Monitors disease course with decreasing levels following therapy and increasing level predicting recurrence.  Peritoneal fluid level of CA 125 found to be more sensitive than serum level.
  • 25. -HCG  Glycoprotein synthesized from the syncytiotrophoblastic cells of normal placenta.  Level is elevated in early pregnancy with peak in the first trimester.  Elevated in gestational trophoblastic neoplasia- choriocarcinoma.  Elevated in non-seminomatous testicular germ cell tumours and constitute an important tumour marker for testicular malignancies alongwith AFP, LDH and PLAP.
  • 26. Estrogen Receptor (ER)  2 isoforms:ERa and ERb  ERa → better prognosis, predictor of relapse  useful when deciding on adjuvant hormone treatment  As diagnostic marker when it is a primary unknown tumor  ERb → Good prognostic factor, correlates with low grade and negative axillary LN status tumours.
  • 27.  HER-2/neu oncogene (using monoclonal antibody) - over expression related to poor prognosis in breast cancer  Oncogene c-erbB-2 gene:over expressed in 30% of breast cancers, correlation between c- erbB-2 gene positivity, positive axillary node status, reduced time to relapse and reduced overall survival.  BRCA1 gene on chromosome 17q:familial breast-ovarian cancer syndrome, and breast cancer in early-onset breast cancer families → high risk screening
  • 28. - To monitor Rx. & to detect recurrence BR Ca  ↑ in 20% with localized breast cancer, ~80% with metastatic disease, esp. if with bone involvement  Specificity of 86%, sensitivity of 30%  Also ↑ in gastric, pancreatic, cervical & lung cancer.
  • 29. Other common tumour markers  Neuron specific enolase – neuroendocrine tumours like small cell carcinoma of lung, neuroblastoma, pheochromocytoma etc.  Calcitonin – medullary carcinoma of thyroid.  Thyroglobulin – follicular carcinoma of thyroid.  S-100, Tyrosinase – Malignant melanoma.  Other DNA and RNA based markers.