بسم الله الرحمن الرحيم

بسم الله الرحمن بسم الله الرحمن الرحيمالرحيم

Faculty of Allied Medical Sciences

Clinical Immunology & Serology Practice

(MLIS 201)

Prof. Dr. Ezzat M HassanProf. of ImmunologyMed Res Inst, Alex UnivE-mail: [email protected]

Objectives

1. To define tumor markers2. To describe the characters of ideal TM

3. To know the clinical applications of TM4. To know the classification of TM

5. To know the clinical use of some example of TM

DefinitionDefinition

Tumor markers are Tumor markers are gene products gene products that are produced that are produced in in low levels low levels by normal tissues.by normal tissues.

They are They are produced by a tumor in large quantities produced by a tumor in large quantities that that can differentiate tumor from normal tissue or detect can differentiate tumor from normal tissue or detect the presence of a tumor with blood testing.the presence of a tumor with blood testing.

Some tumor markers are Some tumor markers are specificspecific for a particular type for a particular type of cancer, while others are seen in several cancer of cancer, while others are seen in several cancer types.types.

Most of the well-known markers may also be Most of the well-known markers may also be elevated in elevated in non-cancerous conditionsnon-cancerous conditions, so tumor , so tumor markers alone are not diagnostic for cancer.markers alone are not diagnostic for cancer.

Characteristics of Ideal tumor markersCharacteristics of Ideal tumor markers

1- Organ specific and tumor specific (specificity).1- Organ specific and tumor specific (specificity).

2- Correlate with tumor load and activity.2- Correlate with tumor load and activity.

3- Positive only when malignancy is present.3- Positive only when malignancy is present.

4- Positive early in development of malignancy.4- Positive early in development of malignancy.

5- Easy to measure in blood5- Easy to measure in blood

At this time there are no tumor markers that work like thisAt this time there are no tumor markers that work like this. .

Clinical application of tumor markersClinical application of tumor markers

1- Screening and early detection of cancer. 1- Screening and early detection of cancer.

2- Diagnosis of cancer.2- Diagnosis of cancer.

3- prognosis (outlook) for certain cancer .3- prognosis (outlook) for certain cancer .

4- Detecting the early recurrence of cancer .4- Detecting the early recurrence of cancer .

5- Assess in differentiation between stages of cancer.5- Assess in differentiation between stages of cancer.

6- Monitor the course of cancer during treatment. 6- Monitor the course of cancer during treatment.

Classification of tumor markersClassification of tumor markers

Classification of tumor markers is based on:Classification of tumor markers is based on:

1- Biochemical structure. 1- Biochemical structure. 2- Function.2- Function.

3- Combination of biochemical structure and function.3- Combination of biochemical structure and function.

4- Discovery of oncofetal markers.4- Discovery of oncofetal markers.

Classification of tumor markers according to Classification of tumor markers according to structurestructure

1- Oncofetal Proteins1- Oncofetal Proteins 2- Tumor Associated Antigens 2- Tumor Associated Antigens 3- Hormones3- Hormones 4- Hormonal Receptors4- Hormonal Receptors 5- Enzymes5- Enzymes 6- Cytokines6- Cytokines 7- Oncogenes 7- Oncogenes 8- Carbohydrate Related Antigens8- Carbohydrate Related Antigens 9- Amino Sugar Derivatives9- Amino Sugar Derivatives

I- Oncofetal proteinsI- Oncofetal proteins

Examples:Examples:

1-Alpha- fetoprotein (AFP)1-Alpha- fetoprotein (AFP)

2-Carcinoembryonic Antigen (CEA) 2-Carcinoembryonic Antigen (CEA)

blood levels of Alpha fetoproteinblood levels of Alpha fetoprotein 1- Normal levels 1- Normal levels of AFP are usually less than 10 ng/Ml of AFP are usually less than 10 ng/Ml

(nanograms per milliliter).(nanograms per milliliter).At birth, normal infants have AFP levels 4 or more times normal At birth, normal infants have AFP levels 4 or more times normal

range, decreasing during the first 1-2 years of life.range, decreasing during the first 1-2 years of life.

2- Pysiological increase2- Pysiological increase

The majority of pregnant women having a high concentration of The majority of pregnant women having a high concentration of serum alpha fetoprotein serum alpha fetoprotein

3- Pathological increase 3- Pathological increase

1- Liver diseases1- Liver diseases

2- Testicular cancer 2- Testicular cancer

3- Ovarian cancer 3- Ovarian cancer

1-Liver diseases1-Liver diseases

1-Hepatocellular carcinoma.1-Hepatocellular carcinoma. AFP can be helpful in the diagnosis and to monitor the AFP can be helpful in the diagnosis and to monitor the

treatment of hepatocellular carcinoma. treatment of hepatocellular carcinoma. AFP levels of over 4,000 ng/mL are a sign of liver cancer.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 AFP is also useful in following the response to treatment for

liver cancer. If the cancer is completely removed with surgery, liver cancer. If the cancer is completely removed with surgery, the AFP level should go down to normal range . If the level the AFP level should go down to normal range . If the level goes back up again, it often means that the cancer has come goes back up again, it often means that the cancer has come back.back.

2-Acute and chronic hepatitis2-Acute and chronic hepatitis AFP levels are elevated in acute and chronic hepatitis AFP levels are elevated in acute and chronic hepatitis

above100 ng/mL. above100 ng/mL. AFP cannot be considered diagnostic of HCC.AFP cannot be considered diagnostic of HCC.

2-testicular cancer 2-testicular cancer

AFP levels are higher in certain testicular cancers and is used for AFP levels are higher in certain testicular cancers and is used for follow-up of these cancers.follow-up of these cancers.

3- ovarian cancer 3- ovarian cancer

AFP levels are higher in certain rare types of ovarian AFP levels are higher in certain rare types of ovarian

cancer called yolk sac tumor or mixed germ cell cancer.cancer called yolk sac tumor or mixed germ cell cancer.

2- Carcinoembryonic Antigen ( CEA)2- Carcinoembryonic Antigen ( CEA)

The word "carcinoembryonic" reflects the fact that CEA The word "carcinoembryonic" reflects the fact that CEA is produced by some cancers ("carcino-") and by the is produced by some cancers ("carcino-") and by the

developing fetus ("-embryonic").developing fetus ("-embryonic").

Normal blood levels Normal blood levels The normal range for CEA in an adult non-The normal range for CEA in an adult non-

smoker is <2.5 ng/ml smoker is <2.5 ng/ml For a smoker is <5.0 ng/ml.For a smoker is <5.0 ng/ml.

Abnormal levelsAbnormal levels The most frequent cancer which causes an increased The most frequent cancer which causes an increased

CEA is cancer of the colon and rectum.CEA is cancer of the colon and rectum. Others include cancers of the pancreas, stomach, breast, Others include cancers of the pancreas, stomach, breast,

lung, and certain types of thyroid and ovarian cancer.lung, and certain types of thyroid and ovarian cancer. Benign conditions which can elevate CEA include Benign conditions which can elevate CEA include

smoking, inflammatory bowel disease, pancreatitis, smoking, inflammatory bowel disease, pancreatitis, cirrhosis of the livercirrhosis of the liver

II- Tumor antigens II- Tumor antigens

Tumor antigen is a substance produced in Tumor antigen is a substance produced in tumor cellscells. .

Classification of Tumor AntigensClassification of Tumor Antigens1- 1- Tumor-Specific AntigensTumor-Specific Antigens, which are present only on tumor , which are present only on tumor

cells and not on any other cell cells and not on any other cell

2- 2- Tumor-Associated AntigensTumor-Associated Antigens, which are present on some , which are present on some tumor cells and also some normal cellstumor cells and also some normal cells

Examples of tumor antigensExamples of tumor antigens

CA125CA125

CA 15.3CA 15.3

CA 19.9CA 19.9

Tissue polypeptide antigenTissue polypeptide antigen

Prostatic specific antigenProstatic specific antigen

1- Cancer Antigen 125 (CA 125) 1- Cancer Antigen 125 (CA 125)

It is a protein that can be made by ovary cells. It is a protein that can be made by ovary cells.

If it is present in high levels in the blood or in other If it is present in high levels in the blood or in other body fluids or tissues, it may be a sign of ovarian body fluids or tissues, it may be a sign of ovarian cancer.cancer.

Normal levelsNormal levels The normal range for CA 125 ranges from 0 to 35The normal range for CA 125 ranges from 0 to 35μμg/mLg/mL

Abnormal levelAbnormal level1-Physiological1-Physiological In pregnancyIn pregnancy andand normal menstruationnormal menstruation

2-Pathological2-Pathologicaliicalcal Pathological conditions include: ovarian cancer & other diseases of Pathological conditions include: ovarian cancer & other diseases of

the ovarythe ovary

In addition to any benign and malignant conditions originating in In addition to any benign and malignant conditions originating in the the endometriumendometrium, , lungslungs, , breastbreast and and gastro intestinal tractgastro intestinal tract..

Clinical valueClinical value

1- As tumor marker1- As tumor markerNot used to screen for ovarian cancer because it is non-specific.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 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 are its lack of sensitivity and its inability to detect early stage cancers.cancers.

2-2- Monitor therapy during treatment for Monitor therapy during treatment for ovarian cancerovarian cancerIt is especially useful for detecting the recurrence of ovarian It is especially useful for detecting the recurrence of ovarian

cancer cancer

2-Cancer Antigen 15.3 ( CA 15.3)2-Cancer Antigen 15.3 ( CA 15.3)

CA 15.3 is a protein that is a normal product of breast tissue, and CA 15.3 is a protein that is a normal product of breast tissue, and it does not cause breast cancer. it does not cause breast cancer.

Levels of CA 15-3 increase in breast cancerLevels of CA 15-3 increase in breast cancer

In patients with In patients with localized breast cancerlocalized breast cancer (cancer limited to the (cancer limited to the breast) only about 30% will have increased levels of CA 15-3.breast) only about 30% will have increased levels of CA 15-3.

In patients with In patients with metastatic breast cancermetastatic breast cancer , CA 15-3 can be found , CA 15-3 can be found in 50 to 90% of all cases.in 50 to 90% of all cases.

Normal levelsNormal levels

Normal range of CA 15.3 is less than 25 u/ml (units/milliliter)Normal range of CA 15.3 is less than 25 u/ml (units/milliliter)

Abnormal levelsAbnormal levelsBreast cancer ,Breast cancer ,

Ovarian, lung and prostate cancer produce CA 15-3Ovarian, lung and prostate cancer produce CA 15-3

In some non- cancerous conditions, such as benign breast In some non- cancerous conditions, such as benign breast conditions and hepatitis.conditions and hepatitis.

Clinical value of CA 15.3Clinical value of CA 15.3

1-As tumor marker1-As tumor markerCA 15.3 is a tumor marker specific for breast cancer. CA 15.3 is a tumor marker specific for breast cancer.

CA 15.3 is not very sensitive in detecting early 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 only 5 to 30% of patients with stage I and II cancer have elevated levels.elevated levels.

2- Monitor therapy during treatment for breast 2- Monitor therapy during treatment for breast cancercancer

The main use of CA 15.3 is in the follow up of patients with The main use of CA 15.3 is in the follow up of patients with diagnosed Breast cancerdiagnosed Breast cancer

CA 15.3 is used to monitor patients post-operatively for recurrent CA 15.3 is used to monitor patients post-operatively for recurrent breast cancer. breast cancer.

3- Cancer Antigen 19.9 ( CA 19.9) 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.

Normal levelNormal level

Reference range is 0-55 U/MlReference range is 0-55 U/Ml

Abnormal levelAbnormal level

Abnormal levels can be seen inAbnormal levels can be seen in : :

Pancreatic cancer, bile duct cancers ,gastric Pancreatic cancer, bile duct cancers ,gastric cancers, colon cancers, esophageal cancerscancers, colon cancers, esophageal cancers , ,

Hepatomas ,non-gastrointestinal tract cancers, Hepatomas ,non-gastrointestinal tract cancers, cirrhosis and acute cholangitiscirrhosis and acute cholangitis

Clinical value of CA 19.9Clinical value of CA 19.9

1-As tumor marker1-As tumor marker It is used in patients with pancreatic cancer. It is used in patients with pancreatic cancer.

Still, it is the best tumor marker for following patients with Still, it is the best tumor marker for following patients with pancreatic cancer.pancreatic cancer.

CA 19-9 can also be used to watch colorectal cancer, but the CA 19-9 can also be used to watch colorectal cancer, but the

CEA test is preferred for this type of cancer.CEA test is preferred for this type of cancer.

2- Monitor therapy during treatment for 2- Monitor therapy during treatment for pancreatic cancerpancreatic cancer

Serial measurements of CA 19-9 may be useful during and Serial measurements of CA 19-9 may be useful during and following cancer treatment.following cancer treatment.

3-Hormones3-Hormones

Hormones which are used as tumor markers include:Hormones which are used as tumor markers include:

1-B-HCG 1-B-HCG

2-ACTH 2-ACTH

3-Calcitonin3-Calcitonin

4-Insulin 4-Insulin

5-Estrogen 5-Estrogen

6-Prolactin 6-Prolactin

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

Normal ranges of Normal ranges of BHCGBHCG

1-For female :1-For female :The following is a list of serum hCG levels.The following is a list of serum hCG levels.3 weeks since LMP: 5-50 mIU/ml 3 weeks since LMP: 5-50 mIU/ml 4 weeks since LMP: 3-426 mIU/ml 4 weeks since LMP: 3-426 mIU/ml 5 weeks since LMP: 18-7340 mIU/ml 5 weeks since LMP: 18-7340 mIU/ml 6 weeks since LMP: 1080-56500 mIU/ml 6 weeks since LMP: 1080-56500 mIU/ml 7-8 weeks since LMP: 7650-229000 mIU/ml 7-8 weeks since LMP: 7650-229000 mIU/ml 9-12 weeks since LMP: 25700-228000 mIU/ml 9-12 weeks since LMP: 25700-228000 mIU/ml 13-16 weeks since LMP: 13300-254000 mIU/ml 13-16 weeks since LMP: 13300-254000 mIU/ml 17-24 weeks since LMP: 4060-165400 mIU/ml 17-24 weeks since LMP: 4060-165400 mIU/ml 25-40 weeks since LMP: 3640-117000mIU/ml 25-40 weeks since LMP: 3640-117000mIU/ml Non-pregnant females: <0.5 mIU/ml Non-pregnant females: <0.5 mIU/ml Postmenopausal females: <9.5 mIU/ml. Postmenopausal females: <9.5 mIU/ml.

2-For male :2-For male :The normal range for men is between 0-5 Iu/ml .The normal range for men is between 0-5 Iu/ml .

Clinical ValueClinical Value

1-As a tumor marker1-As a tumor markerB HCG is used as marker of cancers including B HCG is used as marker of cancers including

choriocarcinoma and germ cell tumors.choriocarcinoma and germ cell tumors.

A positive result in males can be a test for testicularA positive result in males can be a test for testicular

Cancer.Cancer.

2-ACTH ( adrenal corticotrophic hormone)2-ACTH ( adrenal corticotrophic hormone)

ACTH is secreted from the anterior pituitary gland in ACTH is secreted from the anterior pituitary gland in response to corticotropin-releasing hormone from the response to corticotropin-releasing hormone from the hypothalamus.hypothalamus.Normal levelNormal levelAmAm………………..20-80 pg/ml..20-80 pg/mlPmPm………………..10-30 pg/ml..10-30 pg/ml

Clinical valueClinical value

As a tumor markerAs a tumor marker

ACTH can be used as atumor marker for pitutary gland ACTH can be used as atumor marker for pitutary gland

tumors and adrenal gland tumors.tumors and adrenal gland tumors.

5- Enzymes5- Enzymes

Examples: Examples:

1- Prostatic acid phosphatase (PAP)1- Prostatic acid phosphatase (PAP)

2- Alkaline phosphatase2- Alkaline phosphatase

1-Prostatic acid phosphatase (PAP)1-Prostatic acid phosphatase (PAP)

prostatic acid phosphatase is an prostatic acid phosphatase is an enzymeenzyme found in men, found in men,

primarily in the prostate gland and semen to determine primarily in the prostate gland and semen to determine

the health of the prostate gland. the health of the prostate gland.

Prostate dysfunction results in the release of PAP into Prostate dysfunction results in the release of PAP into

the bloodthe blood

Normal levelNormal level Normal rangeNormal range of serum PAP is 0.2-3.0 ng/mlof serum PAP is 0.2-3.0 ng/ml

Abnormal levelAbnormal levelThe most common causes for abnormal PAP values include :The most common causes for abnormal PAP values include :1-Prostate cancer1-Prostate cancer2-Prostate cancer that has spread outside the prostate2-Prostate cancer that has spread outside the prostate (particularly to bone)(particularly to bone)3- Prostatitis 3- Prostatitis 4- Physical stimulation of the prostate4- Physical stimulation of the prostate (colonoscopy, prostate examination)(colonoscopy, prostate examination)

6-Cytokines6-Cytokines

ExamplesExamples::

1 - IL-6 1 - IL-6

2- IL-2 soluble receptor 2- IL-2 soluble receptor

1- Interleukin-6 (IL-6)1- Interleukin-6 (IL-6)

IL-6 is secreted by T cells and macrophages to stimulate IL-6 is secreted by T cells and macrophages to stimulate immune response to trauma , especially burns or immune response to trauma , especially burns or other tissue damage leading to inflammation. other tissue damage leading to inflammation.

It acts as both a pro-inflammatory and anti-It acts as both a pro-inflammatory and anti-inflammatory cytokine.inflammatory cytokine.

Normal levelNormal level Norma range of IL-6 is 3 pg/mlNorma range of IL-6 is 3 pg/ml

Abnormal levelAbnormal levelElevated level is seen in cases ofElevated level is seen in cases of

Chronic lymphocytic leukeamia ( CLL )Chronic lymphocytic leukeamia ( CLL ) Prostate cancerProstate cancer

Advanced/metastaticAdvanced/metastatic cancer cancer DiabetesDiabetes

AtherosclerosisAtherosclerosis Systemic lupus erythematosusSystemic lupus erythematosus

Rheumatoid arthritisRheumatoid arthritis

Clinical value of IL-6Clinical value of IL-6

1-As a tumor marker1-As a tumor markerIL-6 can be used as a tumor marker for chronic lymphocytic IL-6 can be used as a tumor marker for chronic lymphocytic leukemia (CLL)leukemia (CLL)

2- Monitoring treatment2- Monitoring treatmentIL-6 can be used in monitoring of treatment.IL-6 can be used in monitoring of treatment.

3- For treatment3- For treatmentThere is an interest in developing anti-IL-6 agents as therapy There is an interest in developing anti-IL-6 agents as therapy

against many of diseases associated with increase levels of IL-6against many of diseases associated with increase levels of IL-6

Mention :The Clinical Application Tumor Markers

Assignment:

Examples and clinical applications of oncofetal tumor markers

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