1. بسم الله الرحمن الرحيم

2. Faculty of Allied Medical Sciences
Clinical Immunology & Serology Practice
(MLIS 201)

3. Tumor Markers Prof. Dr. Ezzat M Hassan Prof. of Immunology
Med Res Inst, Alex Univ

4. Objectives To define tumor markers
To describe the characters of ideal TM
To know the clinical applications of TM
To know the classification of TM
To know the clinical use of some example of TM

5. Definition
Tumor markers are gene products that are produced in low levels by normal tissues.
They are produced by a tumor in large quantities that can differentiate tumor from normal tissue or detect the presence of a tumor with blood testing.
Some tumor markers are specific for a particular type of cancer, while others are seen in several cancer types.
Most of the well-known markers may also be elevated in non-cancerous conditions, so tumor markers alone are not diagnostic for cancer.

6. Characteristics of Ideal tumor markers
1- Organ specific and tumor specific (specificity).
2- Correlate with tumor load and activity.
3- Positive only when malignancy is present.
4- Positive early in development of malignancy.
5- Easy to measure in blood
At this time there are no tumor markers that work like this.

7. Clinical application of tumor markers
1- Screening and early detection of cancer.
2- Diagnosis of cancer.
3- prognosis (outlook) for certain cancer .
4- Detecting the early recurrence of cancer .
5- Assess in differentiation between stages of cancer.
6- Monitor the course of cancer during treatment.

8. Classification of tumor markers
Classification of tumor markers is based on:
1- Biochemical structure.
2- Function.
3- Combination of biochemical structure and function.
4- Discovery of oncofetal markers.

9. Classification of tumor markers according to structure
1- Oncofetal Proteins
2- Tumor Associated Antigens
3- Hormones
4- Hormonal Receptors
5- Enzymes
6- Cytokines
7- Oncogenes
8- Carbohydrate Related Antigens
9- Amino Sugar Derivatives

10. I- Oncofetal proteins
Examples:
1-Alpha- fetoprotein (AFP)
2-Carcinoembryonic Antigen (CEA)

11. blood levels of Alpha fetoprotein
1- Normal levels of AFP are usually less than 10 ng/Ml (nanograms per milliliter).
At birth, normal infants have AFP levels 4 or more times normal range, decreasing during the first 1-2 years of life.
2- Pysiological increase
The majority of pregnant women having a high concentration of serum alpha fetoprotein
3- Pathological increase
1- Liver diseases
2- Testicular cancer
3- Ovarian cancer

12. 1-Liver diseases 1-Hepatocellular carcinoma.
AFP can be helpful in the diagnosis and to monitor the treatment of hepatocellular carcinoma.
AFP levels of over 4,000 ng/mL are a sign of liver cancer.
AFP is also useful in following the response to treatment for liver cancer. If the cancer is completely removed with surgery, the AFP level should go down to normal range . If the level goes back up again, it often means that the cancer has come back.

13. 2-Acute and chronic hepatitis
AFP levels are elevated in acute and chronic hepatitis above100 ng/mL.
AFP cannot be considered diagnostic of HCC.
2-testicular cancer
AFP levels are higher in certain testicular cancers and is used for follow-up of these cancers.
3- ovarian cancer
AFP levels are higher in certain rare types of ovarian
cancer called yolk sac tumor or mixed germ cell cancer.

14. 2- Carcinoembryonic Antigen ( CEA)
The word "carcinoembryonic" reflects the fact that CEA is produced by some cancers ("carcino-") and by the developing fetus ("-embryonic").

15. Normal blood levels Abnormal levels
The normal range for CEA in an adult non- smoker is <2.5 ng/ml
For a smoker is <5.0 ng/ml.
Abnormal levels
The most frequent cancer which causes an increased CEA is cancer of the colon and rectum.
Others include cancers of the pancreas, stomach, breast, lung, and certain types of thyroid and ovarian cancer.
Benign conditions which can elevate CEA include smoking, inflammatory bowel disease, pancreatitis, cirrhosis of the liver

16. II- Tumor antigens
Tumor antigen is a substance produced in tumor cells.
Classification of Tumor Antigens
1- Tumor-Specific Antigens, which are present only on tumor cells and not on any other cell
2- Tumor-Associated Antigens, which are present on some tumor cells and also some normal cells

17. Examples of tumor antigens
CA125
CA 15.3
CA 19.9
Tissue polypeptide antigen
Prostatic specific antigen

18. 1- Cancer Antigen 125 (CA 125)
It is a protein that can be made by ovary cells.
If it is present in high levels in the blood or in other body fluids or tissues, it may be a sign of ovarian cancer.

19. Normal levels Abnormal level
The normal range for CA 125 ranges from 0 to 35μg/mL
Abnormal level
1-Physiological
In pregnancy and normal menstruation
2-Pathologicalical
Pathological conditions include: ovarian cancer & other diseases of the ovary
In addition to any benign and malignant conditions originating in the endometrium, lungs, breast and gastro intestinal tract.

20. Clinical value 1- As tumor marker
Not used to screen for ovarian cancer because it is non-specific.
The key problems in using the CA-125 test as a screening tool are its lack of sensitivity and its inability to detect early stage cancers.
2- Monitor therapy during treatment for ovarian cancer
It is especially useful for detecting the recurrence of ovarian cancer

21. 2-Cancer Antigen ( CA 15.3)
CA 15.3 is a protein that is a normal product of breast tissue, and it does not cause breast cancer.
Levels of CA 15-3 increase in breast cancer
In patients with localized breast cancer (cancer limited to the breast) only about 30% will have increased levels of CA 15-3.
In patients with metastatic breast cancer , CA 15-3 can be found in 50 to 90% of all cases.

22. Normal levels Abnormal levels
Normal range of CA 15.3 is less than 25 u/ml (units/milliliter)
Abnormal levels
Breast cancer ,
Ovarian, lung and prostate cancer produce CA 15-3
In some non- cancerous conditions, such as benign breast conditions and hepatitis.

23. Clinical value of CA 15.3 1-As tumor marker
CA 15.3 is a tumor marker specific for breast cancer.
CA 15.3 is not very sensitive in detecting early breast cancer ; only 5 to 30% of patients with stage I and II cancer have elevated levels.
2- Monitor therapy during treatment for breast cancer
The main use of CA 15.3 is in the follow up of patients with diagnosed Breast cancer
CA 15.3 is used to monitor patients post-operatively for recurrent breast cancer.

24. 3- Cancer Antigen 19.9 ( CA 19.9)
CA 19.9 is synthesized by normal cells in pancreatic and bile ducts, gastric and colonic mucosa, bronchial and salivary glands, endometrium, and prostate.

25. Normal level
Reference range is 0-55 U/Ml
Abnormal level
Abnormal levels can be seen in:
Pancreatic cancer, bile duct cancers ,gastric cancers, colon cancers, esophageal cancers,
Hepatomas ,non-gastrointestinal tract cancers, cirrhosis and acute cholangitis

26. Clinical value of CA 19.9
1-As tumor marker
It is used in patients with pancreatic cancer.
Still, it is the best tumor marker for following patients with pancreatic cancer.
CA 19-9 can also be used to watch colorectal cancer, but the CEA test is preferred for this type of cancer.
2- Monitor therapy during treatment for pancreatic cancer
Serial measurements of CA 19-9 may be useful during and following cancer treatment.

27. 3-Hormones 1-B-HCG 2-ACTH 3-Calcitonin 4-Insulin 5-Estrogen
Hormones which are used as tumor markers include:
1-B-HCG
2-ACTH
3-Calcitonin
4-Insulin
5-Estrogen
6-Prolactin

28. 1- BHCG ( Human chorionic gonadotropin hormone )
It is a hormone produced by the placenta

29. Normal ranges of BHCG 1-For female : 2-For male :
The following is a list of serum hCG levels.
3 weeks since LMP: 5-50 mIU/ml
4 weeks since LMP: mIU/ml
5 weeks since LMP: mIU/ml
6 weeks since LMP: mIU/ml
7-8 weeks since LMP: mIU/ml
9-12 weeks since LMP: mIU/ml
13-16 weeks since LMP: mIU/ml
17-24 weeks since LMP: mIU/ml
25-40 weeks since LMP: mIU/ml
Non-pregnant females: <0.5 mIU/ml
Postmenopausal females: <9.5 mIU/ml.
2-For male :
The normal range for men is between 0-5 Iu/ml .

30. Clinical Value 1-As a tumor marker
B HCG is used as marker of cancers including
choriocarcinoma and germ cell tumors.
A positive result in males can be a test for testicular
Cancer.

31. 2-ACTH ( adrenal corticotrophic hormone)
ACTH is secreted from the anterior pituitary gland in
response to corticotropin-releasing hormone from the
hypothalamus.
Normal level
Am……… pg/ml
Pm……… pg/ml
Clinical value
As a tumor marker
ACTH can be used as atumor marker for pitutary gland tumors and adrenal gland tumors.

32. 5- Enzymes Examples: 1- Prostatic acid phosphatase (PAP)
2- Alkaline phosphatase

33. 1-Prostatic acid phosphatase (PAP)
prostatic acid phosphatase is an enzyme found in men,
primarily in the prostate gland and semen to determine
the health of the prostate gland.
Prostate dysfunction results in the release of PAP into
the blood

34. Normal level Abnormal level Normal range of serum PAP is 0.2-3.0 ng/ml
The most common causes for abnormal PAP values include :
1-Prostate cancer
2-Prostate cancer that has spread outside the prostate
(particularly to bone)
3- Prostatitis
4- Physical stimulation of the prostate
(colonoscopy, prostate examination)

35. 6-Cytokines
Examples:
1 - IL-6
2- IL-2 soluble receptor

36. 1- Interleukin-6 (IL-6)
IL-6 is secreted by T cells and macrophages to stimulate immune response to trauma , especially burns or other tissue damage leading to inflammation.
It acts as both a pro-inflammatory and anti- inflammatory cytokine.

37. Normal level Abnormal level Norma range of IL-6 is 3 pg/ml
Elevated level is seen in cases of
Chronic lymphocytic leukeamia ( CLL )
Prostate cancer
Advanced/metastatic cancer
Diabetes
Atherosclerosis
Systemic lupus erythematosus
Rheumatoid arthritis

38. Clinical value of IL-6 1-As a tumor marker 2- Monitoring treatment
IL-6 can be used as a tumor marker for chronic lymphocytic
leukemia (CLL)
2- Monitoring treatment
IL-6 can be used in monitoring of treatment.
3- For treatment
There is an interest in developing anti-IL-6 agents as therapy against many of diseases associated with increase levels of IL-6

39. Study Questions:
Mention : The Clinical Application Tumor Markers

40. Examples and clinical applications of oncofetal tumor markers
Assignment:
Examples and clinical applications of oncofetal tumor markers
نورهان مصطفى محمد

41. Thank you