Tumor Markers

• Basic concepts and terminology• Cancer

– Benign versus malignant– Metastasis – Staging.

• Clinical utilities of tumor markers• Examples of tumor markers and their

uses

Basic concepts and terminology

• Two major processes involved in cell growth:

– Proliferation: the growth or production of cells by

multiplication

– Differentiation: cellular differentiation is the process

by which a less specialized cell becomes a more

specialized cell type.

• Cancer is a disease of abnormal growth.

• When the growth and development of normal cell loses

control, tumor cells begin to appear, which is called

tumorigenesis.

Definition of cancer• According to the American Cancer Society, cancer is a

group of diseases characterized by uncontrolled growth

and spread of abnormal cells

• It consists of more than 100 different diseases

• Cancer can arise in many sites and behave differently

depending on its organ of origin

• Cancer is an abnormal, continuous multiplying of cells.

The cells divide uncontrollably and may grow into

adjacent tissue or spread to distant parts of the body.

• The mass of cancer cells eventually become large

enough to produce lumps, masses, or tumors that can

be detected

Neoplasia and hyperplasia• Neoplasia and hyperplasia are two similar biologic processes

• Hyperplasia involves the multiplication of cells in an organ or

tissue, which may consequently have increased in volume.

• Neoplasia involves the possibility of normal cells undergoing

cancerous proliferation as hyperplasia taking place under less

controlled conditions; it is, therefore, a form of pathologic

hyperplasia.

• The major difference between them is how growth is controlled.

• Hyperplasia serves a useful purpose and is controlled by stimuli,

whereas neoplasia is unregulated and serves no purpose.

• The elevation of tumor marker in the case of the hyperplasia will be

transient, whereas neoplasia will be long lasting phenomena

Characteristics of Cancer

1. Abnormality

• Cells are the structural units of all living things.

• trillions of cells are found in human,

• Cells carry out all kinds of functions of life: the beating

of the heart, breathing, digesting food, thinking,

walking, and so on.

• However, all of these functions can only be carried out

by normal healthy cells.

• Some cells stop functioning or behaving as they should

serving no useful purpose in the body at all, and

become cancerous cells.

Characteristics of Cancer

2. Uncontrollability

• The most fundamental characteristic of cells is their ability to

reproduce themselves.

• They do this simply by dividing.

• The division of normal and healthy cells occurs in a

regulated and systematic fashion. In most parts of the body,

the cells continually divide and form new cells to supply the

material for growth or to replace injured cells. For example,

when you cut your finger, certain cells divide rapidly until the

tissue is healed and the skin is repaired. They will then go

back to their normal rate of division.

• In contrast, cancer cells divide in a random manner. The

result is that they typically go into a non-structured mass or

tumor.

Characteristics of Cancer

3. Invasiveness

• Tumors destroy the part of the body in which they originate

and then spread to other parts where they start new growth

and cause more destruction invasive cancer.

• This characteristic distinguishes cancer from benign growths,

which remain in the part of the body in which they start.

• Although benign tumors may grow quite large and press on

neighboring structures, they do not spread to other parts of

the body.

• Frequently, they are completely enclosed in a protective

capsule of tissue and they typically do not pose danger to

human life like malignant tumors

Characteristics of Cancer

• Although cancer is often referred to as a single condition, it

actually consists of more than 100 different diseases.

• Cancer can arise in many sites and behave differently

depending on its organ of origin.

• Breast cancer, for example, has different characteristics

than lung cancer.

• Cancer originating in one body organ takes its

characteristics with it even if it spreads to another part of

the body. For example, metastatic breast cancer in the

lungs continues to behave like breast cancer when viewed

under a microscope, and it continues to look like a cancer

that originated in the breast.

Cancer and its consequences• In western societies one death in five is caused by

cancer

• The effects of tumor growth may be local or systemic

– E.g. obstruction of blood vessels, lymphatics or ducts, damage to nerves, effusions, bleeding, infection, necrosis of surrounding tissues and eventually death of the patient.

• The cancer cells may secrete toxins locally or into the general circulation

– Both endocrine and non-endocrine tumors may secrete hormones or other regulatory molecules

Local effects of tumors• The local growth of a tumor can cause a wide range of

abnormalities in commonly requested biochemical tests

• This may be a consequence of obstruction of blood vessels

or ducts

– e.g. the blockage of bile ducts by carcinoma of head of

pancreas causes elevated serum alkaline phosphatase

and sometimes jaundice

• The liver is often the site of metastatic spread of a tumor

• Metastatic spread of a tumor to an important site may

precipitate complete system failure

– For example, destruction of the adrenal cortex by tumor

causes impaired aldosterone and cortisol secretion

Local effects of tumors• Rapid tumor growth gives rise to abnormal

biochemistry– Leukemia and lymphoma are often associated

with elevated serum urate concentrations – Serum lactate dehydrogenase is often elevated – Large tumor may cause lactic acidosis

• Renal failure may occur in patients with malignancy for the following reasons:1. obstruction of the urinary tract2. hypercalcemia3. Bence-Jones proteinuria4. hyperuricemia5. nephrotoxicity of cytotoxic drugs

Cancer cachexia• Cancer cachexia: bad condition describes the wasting characteristics

that are usually seen in cancer patients like weight loss, wasting of muscle,

loss of appetite, and general debility that can occur during a chronic

disease)

• The features include anorexia, lethargy, weight loss, muscle weakness,

anemia and pyrexia.

• The development of cancer cachexia is due to many factors and is

incompletely understood

1. inadequate food intake.

2. impaired digestion and absorption.

3. competition between the host and tumor for nutrients. The growing

tumor has a high metabolic rate and may deprive the body of nutrients.

One consequence of this is a fall in the plasma cholesterol level in

cancer patients.

4. increased energy requirement of the cancer patients. The host reaction

to the tumor is similar to the metabolic response to injury, with

increased metabolic rate and altered tissue metabolism.

• Certainly, there is an imbalance between dietary calories intake and body

requirements

Cancer cachexia• Tumor spread may cause infection, dysphagia

(difficulty in swallowing), persistent vomiting and diarrhea

• The observation that small tumors can have profound effect on host metabolism suggests that cancer cells secrete or cause the release of humoral agents that mediate the metabolic changes of cancer cachexia

• Some of these, such as tumor necrosis factor, have been identified

Differences between normal and cancer cells

• When either differentiation or proliferation becomes unregulated, there is a risk for normal cells to be converted into cancer cells

• This process is usually associated with changes of the genetic components of the cell

• Changes include:

1. Mutation of cellular oncogenes (oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a tumor cell)

2. abnormal regulation of their expression

3. rearrangements of oncogenic DNA sequences (oncogenic: describing a substance, organism, or environment that is known to be a casual factor in the production of a tumor. Some animal viruses are known to be oncogenic; others are suspected of being so in man, including some papovaviruses, adneviruses, and herpesviruses

Benign and malignant tumors

• Most tumor cells undergo a benign stage, gradually progress to

malignancy, and eventually become metastasized if not treated.

• The genetic instability associated with tumor cells can make

tumor cells more susceptible to additional mutations, which may

ultimately lead to malignant disease.

• During the benign stage, tumors remain at the primary site

and present a smaller risk to the host. At this stage, the patient

stands a good chance of being treated, such as by complete

removal of tumor the early detection of a benign tumor is

critical to cancer prevention in general and to high-risk families

in particular.

• All benign tumors are well differentiated and composed of cells

resembling the mature normal cells from the tissue of origin of

the neoplasm.

Benign and malignant tumors

• Benign tumors:

– are not cancerous

– can usually be removed

– do not come back in most cases

– do not spread to other parts of the body, and the cells do

not invade other tissues

• Malignant tumors:

– are cancerous

– can invade and damage nearby tissues and organs

– metastasize (cancer cells break away from a malignant

tumor and enter the bloodstream or lymphatic system to

form secondary tumors in other parts of the body)

Metastasis

• Most cancer deaths are associated with metstatic disease.

• Metastasis is a multistep processes involving numerous tumor

cell-host cell and cell-matrix interactions.

• For tumor cells to metastasize:

– the tumor cells at the primary site have to first penetrate

their adjacent surroundings, including the epithelial basement

membrane and the stroma.

– they then invade blood or lymphatic vessels and are carried

to distant sites, until they are finally arrested in the

venous/capillary beds or solid tissue of a distant organ.

– in this new environment, these tumor cells must again

penetrate the vascular walls to proliferate at the new distant

site.

Metastasis

• In general, the larger, more aggressive, or more rapidly

growing the primary neoplasm, the greater the likelihood

that the tumor cells will metastasize.

• Metastasis is highly selective process.

• Cells isolated from individual tumors may differ in many

ways:

– with respect to capacity for invasion and metastasis.

– growth rate.

– cell surface receptors.

– immunogenicity

– response to cytotoxic drugs.

Signal transduction pathway

• The pathway of signal transduction controls both cell cycle

and apoptosis

• The pathway is an orderly and specific transmission of

growth-regulatory messages from outside the cell to the

machinery controlling replication inside the cell nucleus.

• On binding of the stimulus to the receptor, the transmission

of signal is carried out by protein phosphorylation involving

activation of the enzymatic function of many kinases

• These stimuli include hormones, insulin, cytokines,

epidermal growth factor and others

Cell cycle• The cell cycle is one of the most important

determining factors controlling cell proliferation.

• Cell cycle is tightly regulated and controlled

with different factors( Cyclin A, Cyclin-

dependent kinases: CDK2, Cyclin D1 , CDK4 and

others• Tumors results from the absence of certain cell

cycle controls.• Defects in the cell cycle machinery may,

therefore, help cause cancer

Apoptosis

• The balance between cell proliferation and cell death is

affected by apoptosis.

• Apoptosis, a programmed cell or physiologic death, is a

natural self-destruct system present in all cells.

• Failure of cells to undergo apoptotic cell death may lead to

cancer.

• It is a natural process the body employs for the replacement

of cells and the deletion of damaged cells.

• Apoptosis is a control mechanism for tissue remodeling

during growth and development apoptosis provides a way

for the body to eliminate cells that have developed

improperly, or that have sustained genetic damage.

Angiogenesis

• Is a fundamental process by which new blood

vessels are formed

• Tumor growth and metastasis are angiogenesis-

dependent

• A tumor must continuously stimulate the growth

of new capillary blood vessels for the tumor to

grow

• Angiogenesis is critical, not only for growth of

cancer mass but also for the shedding of primary

cells from the primary tumor and development of

metastases

General categories of cancers• Carcinomas are cancers that occur in epithelial surfaces;

the cells that form the outer surface of the body to line or cover the body's cavities, tubes and passageways.

• Adenocarcinomas are cancers that form on a glandular surface, such as the lung, breast, prostate, ovary, or kidney

• Sarcomas are cancers that occur in supporting structures, such as bone, muscle, cartilage, fat, or fibrous tissue

• Leukemias and lymphomas are cancers that occur in blood cell elements

• Brain cancers, nerve cancers, melanomas, and certain testicular and ovarian cancers do not fall into this general categories

Ectopic hormones

• Some cancers secrete hormones, even though the tumor has not arisen

from an endocrine organ Referred as ectopic hormone production,

• Small cell carcinomas (Common malignant neoplasm of bronchus) are the

most aggressive of the lung cancers and are associated with ectopic

hormone production Ectopic ACTH secretion (Adrenocorticotropic

hormone secreted by the anterior pituitary gland and stimulate androgens

and cortisol release from the adrenal cortex causing Cushing’s

syndrome

• Patients with malignancy develop SIAD (syndrome of inappropriate

antidiuretic hormone). High levels of ADH water is retained and

patients present with hyponatremia. This is probably the commonest

biochemical abnormality seen in patients with cancer and is almost

invariably due to pituitary ADH secretion in response to non-osmotic

stimuli

• Some cancers may cause hypercalcemia. In many cases this is due to the

secretion of parathyroid hormone related protein (PTHrP), so-called

because of its relationship with PTH in its structure and function.

Grading• Cancer can be described by tow ways grading and staging

• A biopsy is examined microscopically

– Low grade: slow growing, well differentiated, less

aggressive, and less likely to spread quickly

– Intermediate grade

– High grade: fast growing, poorly differentiated, tend to be

more 'aggressive', and are more likely to spread quickly

• Grading systems differ depending on the type of cancer

– For example, breast cancers are graded 1, 2 or 3 which is

much the same as low, intermediate and high grade

– Another example is prostate cancer which is graded by a

Gleason Score

Staging

• Staging: to determine the presence and site of metastases

from a primary tumor in order to plan therapy.

• In addition to clinical examination, a variety of imaging and

surgical techniques may be employed to provide a more

accurate assessment.

– Stage 0 or carcinoma in situ: Carcinoma in situ is very early

cancer. The abnormal cells are found only in the first layer

of cells of the primary site and do not invade the deeper

tissues.

– Stage I: Cancer involves the primary site, but has not

spread to close tissues.

– Stage IA: a very small amount of cancer: visible under a

microscope and is found deeper in the tissues.

– Stage IB: a larger amount of cancer is found in the tissues.

Staging

• Stage II: Cancer has spread to nearby areas but is still inside

the primary site.

• Stage IIA: cancer has spread beyond the primary site.

• Stage IIB: cancer has spread to other tissue around the primary

site.

• Stage III : Cancer has spread throughout the nearby area.

• Stage IV: Cancer has spread to other parts of the body.

• stage IVA: cancer has spread to organs close to the pelvic area

• stage IVB: cancer has spread to distant organs, such as the

lungs

• Recurrent: Recurrent disease means that the cancer has come

back (recurred) after it has been treated.

Tumor markers

Tumor markers are substances that can be detected in higher-than-

normal amounts in the blood, urine, or body tissues of some patients

with certain types of cancer.

Tumor markers are produced either by the body in response to the

presence of cancer or certain benign (non-cancerous) conditions or by

the tumor itself. Their measurement or identification is useful in

patient diagnosis or clinical management.

A tumor marker has been secreted or released by the tumor cells.

Such markers are not necessarily unique products of the malignant

cells, but may simply be expressed by the tumor in a greater amount

than normal cells.

The ideal marker would be

a “blood test” for cancer

a positive result would occur only in patients with malignancy,

one that would correlate with stage and response to treatment

that was easily and reproducibly measured.

No tumor marker now available has met this ideal.

Tumor Markers

• Tumor markers are molecules occurring in blood or

tissue that are associated with cancer and whose

measurement or identification is useful in patient

diagnosis or clinical management.

• The ideal marker would be:

• a "blood test" for cancer in which a positive result

would occur only in patients with malignancy

• would correlate with stage and response to treatment

• easily and reproducibly measured.

• No tumor marker now available has met this ideal.

Clinical utilities of tumor markers

Tumor markers can be used for one of the following purposes:

1. Screening a healthy population or a high risk population for

the presence of cancer even that most tumor markers, lack

specificity and sensitivity.

2. Monitoring the course in a patient in remission or while

receiving surgery, radiation, or chemotherapy gives an

indication of the effectiveness of antitumor drug used.

3. Detection of recurrence following surgical removal of the

tumor Because patients being monitored have already had

their cancer identified, the specificity of the tumor marker is

less important than sensitivity. The sensitivity is important to

detect recurrence as early as possible.

Clinical utilities of tumor markers

4. Determining the prognosis in a patient is usually based on tumor aggressiveness:

– a. determine how a patient should be treated

– b. indicate risk and predict the length of a relapse-free

– c. survival period at the time of primary therapy.

5. early detection and making an early diagnosis of cancer or of a specific type of cancer allows the detection of early neoplasms at the curable stage.

• No test meets all of those requirements.

Tumor Antigens

Include markers defined by both monoclonal antibodies and polyclonal antisera, called oncofetal antigens. The oncofetal substances, present in embryo or fetus, diminish to low levels in the adult but reappear in the tumor.

Carcinoembryonic Antigen (CEA)

• The CEA was one of the first oncofetal antigens to be described and exploited clinically.

• It is a complex glycoprotein that is associated with the plasma membrane of tumor cells.

• CEA is a normal cell product that is over-expressed by adenocarcinomas, primarily of the colon, rectum, breast and lung.

• CEA is the most widely used tumor marker for gastrointestenal cancer (colon)

• Elevated CEA levels are found in a variety of cancers colon, pancreatic, gastric, lung, and breast cancer.

• It is normally found in small amounts in the blood of most healthy people but may become elevated in people who have cancer or certain benign conditions.

Carcinoembryonic Antigen (CEA)

• Elevated CEA levels can also occur in patients with non-cancerous

conditions, including inflammatory bowel disease,

pancreatitis and liver disease, chronic lung disease,

cirrhosis.

• The CEA was found to be elevated in up to 19 percent of smokers

and in 3 percent of a healthy control population.

• The test for CEA cannot substitute for a pathological diagnosis.

• As a screening test, the CEA is also inadequate.

• The CEA has been suggested as having prognostic value for

patients with colon cancer.

• CEA values have been positively correlated with stage and

negatively correlated with disease free survival.

• The CEA is of some use as a monitor in treatment. Usually the CEA

returns to normal within 1 to 2 months of surgery,

α1-Fetoprotein

• α -Fetoprotein is a normal fetal serum protein synthesized by

the liver, yolk sac, and gastrointestinal tract

• It is a major component of fetal plasma, reaching a peak

concentration of 3 mg/ml at 12 weeks of gestation. Following

birth, it clears rapidly from the circulation, having a half life

of 3.5 days, and its concentration in adult serum is less than

20 ng/ml.

• AFP is of importance in diagnosing hepatocellular carcinoma

and may be useful in screening procedures.

• An elevated AFP has been termed “the single most

discriminating laboratory test indicative of malignant disease

now available” it could be valuable in screening for

hepatocellular carcinoma in high risk populations.

Alpha-Fetoprotein

• The AFP is less frequently elevated in other malignancies

such as pancreatic cancers, gastric cancers, colonic cancers,

and bronchogenic cancers. This elevation was not

necessarily associated with liver metastases

• The AFP is rarely elevated in healthy persons, and a rise is

seen in only a few disease states like liver diseases, viral or

drug induced hepatitis.

• Thus, AFP is a useful marker in hepatocellular carcinoma and

germ cell tumors

• The AFP is high in the first trimester of gestation and in the

case of the presence of neural tube defect

• Newborn have much higher serum AFP than adults

CA 125

• CA125 is an antigen present on most of ovarian carcinomas.

• It is defined by a monoclonal antibody (OC125) that was generated

by immunizing laboratory mice with a cell line established from

human ovarian carcinoma.

• It circulates in the serum of patients with ovarian carcinoma

and investigated for possible use as a marker.

• The level CA125 correlates with patient response to treatment of

ovarian cancer

• The CA125 is elevated in other cancers including uterus, cervix,

pancreatic, lung, breast, and colon cancer, and in menstruation,

pregnancy, and other gynecologic and non gynecologic conditions.

• Changes in CA 125 levels can be used effectively in the

management of treatment for ovarian cancer.

• CA 125 levels can also be used to monitor patients for recurrence

of ovarian cancer.

CA19-9

• CA19-9 is defined by monoclonal antibody generated against a

colon carcinoma cell line to detect a mono sialo-ganglioside

found in patients with gastrointestinal adenocarcinoma.

• It is found it to be elevated in 21 to 42 percent of cases of

gastric cancer, 20 to 40 percent of colon cancer, and 71 to 93

percent of pancreatic cancer, and has been proposed to

differentiate benign from malignant pancreatic disease

• CA 19-9 has also been identified in patients with hepatocellular

cancer and bile-duct cancer.

• Non-cancerous conditions that may elevate CA 19-9 levels

include gallstones, pancreatitis, cirrhosis of the liver, and

cholecystitis.

• CA 19-9 can be used in monitoring of the patients and recurrent

cancer

Prostate-Specific Antigen (PSA)

• PSA is tissue specific tumor marker; it is found in normal prostatic

epithelium and secretions but not in other tissues.

• It is a glycoprotein, whose function may be to lyse the seminal clot.

• PSA is highly sensitive for the presence of prostatic cancer. The elevation

correlated with stage and tumor volume.

• It is predictive of recurrence and response to treatment.

• PSA is the first tumor marker recommended for screening of prostate

cancer in men older than age 50

• It found in two major forms: free form and PSA-α-antichymotrypsin (PSA-

ACT) complex.

• Measuring the ratio between the free and complexes of PSA helps to

differentiate benign prostate hyperplasia from prostate cancer

Age Range (Years)Caucasians [ng/ml]

40 - 49 0.0 - 2.5

50 - 59 0.0 - 3.5

60 - 69 0.0 - 4.5

70 - 79 0.0 - 6.5

Hormones

• Hormones are produced by many tumors. The

hormone may be:

– a natural product of affected cells by cancer:• Insulin production by islet cell tumor,

• Calcitonin by medullary thyroid carcinoma,

• Catecholamines by pheochromocytoma.

– The hormone is not a natural product of its

associated organ, in which case is designated

“ectopic”. Examples include the production of

ACTH and ADH by lung cancers.

Calcitonin• Calcitonin is a hormone produced by parafollicular C cells in the

thyroid gland.

• It helps to regulate blood-calcium levels.

• In cancers of the parafollicular C cells, called medullary carcinomas

of the thyroid, levels of this hormone are elevated.

• Calcitonin is one of the rare tumor markers that can be used to

help diagnose early cancer.

• Because medullary carcinoma of the thyroid is often inherited,

blood calcitonin can be measured to detect the cancer in its

earliest stages in family members who are at risk.

• Other cancers, particularly lung cancers, can produce calcitonin,

but measurement of its level in the blood is not usually used to

follow these cancers.

Human Chorionic Gonadotropin (hCG)

• HCG is a glycoprotein consisting of subunits α and β, which

are nonconvalently linked.

• The hormone is normally produced by the trophoblastic cells

of the placenta and is elevated in pregnancy.

• hCG is elevated in the urine and serum during the pregnancy

• Its most important uses as a tumor marker are in

gestational trophoblastic disease (a group of rare

pregnancy-related tumours) and germ cell tumors of

ovary and testis.

• Gestational trophoblastic disease is proliferation of

trophoblastic tissue in pregnant causing excessive uterine

enlargement, vomiting, vaginal bleeding, diagnosis includes

measurement of the β hCG.

Human Chorionic Gonadotropin (hCG)

• All gestational trophoblastic tumors produce HCG, and

it is a valuable marker in these tumors,

• HCG is extremely sensitive, being elevated in women

with minute amounts of tumor.

• Free β- HCG is occasionally elevated in ovarian cancer

and lung cancers breast, lung, and gastrointestinal

tract, but in these diseases it has found little clinical

application.

• Free β- HCG is sensitive and specific for aggressive

neoplasmas

Thyroglobulin • Produced by the thyroid gland

• Thyroglobulin is elevated in many thyroid diseases

• When a thyroid cancer is surgically removed, the whole thyroid gland is usually also removed

• Therefore, any elevation of the thyroglobulin level above 10ng/ml suggests that the cancer has returned

• Metastatic thyroid cancer

• It is used to evaluate the effectiveness of treatment for thyroid cancer and to monitor for recurrence

Enzymes

Enzymes that can be used as markers are either native to normal tissue or associated with changes in metabolism that are unique to cancer tissue.

Neuron Specific Enolase

• Neuron specific enolase is an isozyme of the glycolytic pathway that is found only in brain and neuroendocrine tissue.

• It is an immunohistochemical marker for tumors of the central nervous system, neuroblastomas.

• NSE has been detected in patients with neuroblastoma, small-cell lung cancer, Wilms' tumor (nephroblastoma; tumor of kidney), melanoma, and cancers of the thyroid, testicle and pancreas.

• NSE as a tumor marker has concentrated primarily on patients with neuroblastoma and small-cell lung cancer.

Galactosyl Transferase II

• Galactosyl Transferase II, an isozyme of galactosyl

transferase, has been shown to be elevated in a variety of

malignancies, predominantly gastrointestinal.

• In colon cancer its level correlated with the extent of

disease and disease progression;

• In pancreatic cancer it was more sensitive and specific in

distinguishing benign from malignant disease than CEA and

other tests

Prostatic acid phosphatase

• It is capable of monitoring prostate malignancy

• It is rarely used now, because the PSA test is much more

sensitive

Alkaline phosphatase (ALP)

• ALP has been used to detect mainly malignancies in bone and liver

and to detect metastases to these organs.

• Osteoblastic lesions in the bone produced by prostate cancer

metastases give rise to enormous elevations in ALP,

• Whereas lesions produced by metastatic breast cancer cause only

mild or no elevation.

• Other causes of elevated ALP include extrahepatic obstruction of

the bilialy tract, which usually results in a twofold increase in ALP

levels.

• Diseases such as leukemia that infiltrate the liver can cause

marked elevations in ALP levels

• The source of the elevated ALP (bone or liver) can be identified by

measuring other liver enzymes, such as gamma-glutamyl-

transferase and or by measuring ALP activity

Creatine kinase (CK)

• Creatine kinase (CK) levels are helpful in establishing a diagnosis of

myocardial infarction.

• CK-BB (CKl) is found in the brain, gastrointestinal tract, uterus, and

prostate. Elevations of CK-BB (and total CK) can be found in prostatic

carcinoma and metastatic cancer of the stomach.

Immunoglobulins

• Production of a monoclonal immunoglobulin molecule is

characteristic of multiple myeloma.

• Bence Jones protein (paraproteins) are usually complete antibody

molecules but may be isolated light chains or, rarely, heavy chains.

• They may be lambda or kappa light chains and of any

immunoglobulin subtype.

• Bence Jones protein found in high concentration in serum and in urine

• Immunoglobulins are valuable in the staging and treatment of

myeloma, the amount of paraprotein serving as an index of tumor

volume.

Estrogen and progesterone receptors:

• These intracellular receptors are measured directly in

tumor tissue.

• Most oncologists have used the estrogen and

progesterone receptors not only to predict the probability

of response to hormonal therapy at the time of metastatic

disease, but also to predict the likelihood of recurrent

disease.

• These receptors are also used to predict the need for

adjuvant hormonal therapy or chemotherapy.

• The measurement of estrogen and progesterone receptors

in biopsy material has been used to determine which

breast cancer patients will respond to endocrine therapy,

e.g. with the antiestrogen tamoxifen

Immunocytochemical identification of estrogen receptors in 8 μm frozen sections of human breast cancers using monoclonal antibody. Cancers show low (left), moderate (center), or high (right) proportions of receptor-containing cells. × 100.

Susceptibility genes

• Several familial cancers are associated with germ line mutations in various genes

• The most prominent of these are the genes for susceptibility to breast and ovarian cancer, such as BRCA1 and BRCA2

• BRCA1 & BRCA2 (breast cancer 1 & 2):

– Are human genes belong to a class of genes known as tumor suppressors,

– some mutations of which are associated with a significant increase in the risk of breast cancer, as well as other cancers.

• Screening tests for BRCA1 and BRCA2 are now available to screen these families for the identification of carriers

Limitations of tumor markers

• Tumor-marker levels can be elevated in

people with benign conditions

• Tumor-marker levels are not elevated in

every person with cancer, especially in the

early stages of the disease

• Many tumor markers are not specific to a

particular type of cancer.

• The level of a tumor marker can be

elevated by more than one type of cancer

Marker Tumor Screening

Diagnosis

Prognosis

Monitoring

Follow-up

AFP Germ cell  

AFP Hepatoma  

HCG Germ cell  

HCG Choriocarcinoma

CA 125 Ovarian    

Acid phosphatPSA

Prostate    

Prostate    

CEA Colorectal      

Calcitonin

Medullary carcinoma of thyroid

 

Hormones

Endocrine    

Paraproteins

Myeloma    

Tumor markers that are used in University hospital:

1. Liver carcinoma: -fetoprotein

2. Ovarian carcinoma: CA 125

3. Colorectal cancer: CA 19.9

4. Pancreatic carcinoma: amylase, CEA (in case of liver metastasis)

5. Breast cancer: BRACA1, BRAC2

6. Prostate cancer: PSA (total and free). Most PSA in the blood is bound to serum proteins. A small amount is not protein bound and is called free PSA. In men with prostate cancer the ratio of free (unbound) PSA to total PSA is decreased. The risk of cancer increases if the free to total ratio is less than 25%.

7. Non specific marker: hCG

Case study

The End

Tumor Markers • Tumor markers can be used for one of four purposes:

– (1) Screening a healthy population or a high risk population for the

presence of cancer

– (2) Making a diagnosis of cancer or of a specific type of cancer

– (3) Determining the prognosis in a patient;

– (4) Monitoring the course in a patient in remission or while receiving

surgery, radiation, or chemotherapy.

• No test meets all of those requirements.

• The reason for this is the relative lack of sensitivity and specificity of the

available tests.

• Tumor markers include many substances that are not readily

systematically organized.

• These are not unique to cancer cells; but they represent unusual tumor

production of a normal element.

• Some markers are produced by the organism in response to the cancer's

presence.

Tumor markers

The primary use of tumor markers is to

assess a cancer's response to treatment

to check for recurrence.

tumor-marker levels may reflect the extent or stage of the

disease

can be useful in predicting how well the disease will respond to

treatment.

A decrease or return to normal in the level of a tumor marker may

indicate that the cancer has responded favorably to therapy.

A rise in the tumor-marker level may indicate that the cancer is

spreading.

Additionally, measurements of tumor-marker levels may be used

after treatment has ended as a part of follow-up care to check for

recurrence.

CA 15-3 and CA 27-29

• CA 15-3 is used in the management of patients with breast cancer,

especially advanced breast cancer.

• CA 15-3 cannot be used to screen or diagnose patients with breast cancer

because of low detection rate in early stages

• It has been widely used to monitor the effectiveness of treatment for

metastatic cancer.

• CA 15-3 levels may iraised by cancers of the ovary, lung, and prostate

• Elevated levels of CA 15-3 may be associated with non-cancerous

conditions, such as benign breast or ovarian disease, endometriosis, pelvic

inflammatory disease, and hepatitis.

• Similar to the CA 15-3 antigen, CA 27-29 is found in the blood of most

breast cancer patients.

• CA 27-29 levels can also be elevated by cancers of the colon, stomach,

kidney, lung, ovary, pancreas, uterus and liver.

• Non-cancerous conditions that can also elevate CA 27-29 levels include

first-trimester pregnancy, endometriosis, ovarian cysts, benign breast

disease, kidney disease and liver disease.