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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 tract
2. hypercalcemia
3. Bence-Jones proteinuria
4. hyperuricemia
5. 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 growthregulatory 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 angiogenesisdependent
• 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
AFP
Germ cell
AFP
Hepatoma
HCG
Germ cell
HCG
Choriocarcino
ma
Ovarian
CA 125
Screeni
ng
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Diagnos
is
Prognos
is
Monitori
ng
Follo
w-up
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Acid
phosphat
PSA
Prostate
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Prostate
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CEA
Colorectal
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Calcitoni
n
Medullary
carcinoma of
thyroid
Endocrine
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Hormone
s
Paraprot
eins
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 firsttrimester pregnancy, endometriosis, ovarian cysts, benign breast disease, kidney
disease and liver disease.