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 wich a positive result would occur only in
patients with malignancy, one that would correlate with stage and
response to treatment and that was easily and reproducibly measured. No
tumor marker now available has met this ideal.
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
test meets all of those requirements. Specifically, no marker has been
established as a pratical cancer screening tool either in a general
healthy population or in most high risk poulations. The reason for this
is the relative lack of sensitivity and specificity of the available
tests, given the low prevalence of cancers in most population groups.
Given the low prevalence of cancer in general, even tests that are
highly sensitive and specific may have low predictive values.
markers include many substances that are not readily systematically
organized.Those discussed here are generally products or the cancer
cell, although none is unique to cancer cells; they represent aberrant
tumor production of a normal element. Some markers are produced by the
organism in response to the cancer's presence.
markers defined by both monoclonal antibodies and polyclonal antisera,
often the so called oncofetal antigens. The oncofetal substances,
present in embryo or fetus, diminish to low levels in the adult but
reappear in the tumor.
marker, CEA: Carcinoembryonic antigen (CEA) is a protein found in many
types of cells but associated with tumors and the developing fetus. CEA
is tested in blood. The normal range is <2.5
ng/ml in an adult non-smoker and <5.0
ng/ml in a smoker. The CEA was one of the first oncofetal
antigens to be described and exploited clinically. It is a complex
glycoprotein of molecular weight 20,000, that is associated with the
plasma membrane of tumor cells, from wich it may be released into the
CEA was first indentified in colon cancer, an abnormal CEA blood level
is specific neither for colon cancer nor for malignancy in general.
Elevated CEA levels are found in a variety of cancers other than
colonic, including pancreatic, gastric, lung, and breast. It is also
detected in benign conditions including cirrhosis, inflamatory bowel
disease, chronic lung disease, and pancreatitis. The CEA was found to
be elevated in up to 19 percent of smokers and in 3 percent of a
healthy control population. Thus, the test for CEA cannot substitute
for a pathological diagnosis.
screening test, the CEA is also inadequate. Since cancer prevalence in
a healthy population is low, an elevated CEA has an unacceptably low
positive predictive value, with excess false positives. Also, since
elevated CEA occurs in the advanced stage of incurable cancer but is
low in the early, curable disease, the likelihood of a positive result
affecting a patient's survival is diminished.
CEA has been sugested as having prognostic value for patients with
colon cancer. Preoperative CEA values have been positively correlated
with stage and negatively correlated with disease free survival.
not satisfactory for screening a healthy population, CEA has been used
to monitor recurrence. Early data suggested that CEA prededed clinical
relapse by several months. Subsequently, several investigators have
examined intensive, serial CEA monitoring as an indicator for second
look surgery in the hope that relapse could be detected at a time when
surgical ressection for cure was still possible. Criteria for
reoperation included a significant rise of CEA above a base line level
on serial determinations and absence of obvious unresectable disease on
staging workup. Determinations of CEA should be done frequently: at a
minimum of every 3 months and if possible every 1 month to 2 months.
Elevations above baseline should be verified rapidly to exclude
CEA is of some use as a monitor in treatment. Usually the CEA returns
to normal within 1 to 2 months of surgery, but if it returns elevated
persistent disease may be indicated. The test is not infallible in
patients treated with radiotherapy and chemotherapy but can be useful
in those whose tumor is not measurable.
CEA is often positive in malignancies other than colonic. In cancer of
the breast, lung, pancreas, stomach, and ovary the CEA may be elevated
and can be used to monitor the progress of disease or response to
is a normal fetal serum protein synthesized by the liver, yolk sac, and
gastrointestinal tract that shares sequence homology with albumin. 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 rapidily
from the circulation, having a half life of 3.5 days, and its
concentration in adult serum is less than 20 ng/ml.
is of importance in diagnosing hepatocellular carcinoma and may be
useful in screening procedures. AFP elevation is more common in areas
where hepatocellular carcinoma is endemic, such as Africa and in
patients who are HBsAg positive.
is a marker for hepatocellular and germ cell (nonseminoma) carcinoma.1
It is a glycoprotein produced in large amounts during fetal life and is
homologous to albumin. In healthy adults, less
than 10 µg/L of AFP is found in the circulation. AFP is
elevated in normal pregnancy, benign liver disease (hepatitis,
cirrhosis), as well as in cancer.
elevated AFP has been termed by Sell "the single most discriminating
laboratory test indicative of malignant disease now available." As
such, it could be valuable in screening for hepatocellular carcinoma in
high risk populations.
is elevated in testicular germ cell tumors containing embryonal or
endodermal sinus elements. A defenitive positive marker value is highly
sensitive in indicating relapse or response to treatment.
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
AFP is rarely elevated in healthy persons, and a rise is seen in only a
few disease states. Elevation occurs in certain liver diseases,
especially acute viral or drug induced hepatitis and conditions
associated with hepatic regeneration. In general, the elevations are
under 500 ng/ml and do not denote hepatocellular carcinoma. Is also
elevated in ataxia-telangiectasia and in hereditary tyrosinosis.
AFP is a useful marker in hepatocellular carcinoma and germ cell
tumors, the only conditions associated with extreme elevations greater
than 500 ng/ml. In both tumors it has value in diagnosis and monitoring
of therapy. In the former, wich is one of the most common tumors
worldwide, AFP may be of use in screening.
is an antigen present on 80 percent of nonmucinous 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 was therefore investigated for possible use as a marker.
is often elevated in patients with ovarian cancer, its level following
the patient's clinical course. With surgical resection or chemotherapy,
the level correlates with patient response. Thus, it is superior to
other markers such as CEA.
CA125 is elevated in other cancers including endometrial, pancreatic,
lung, breast, and colon cancer, and in menstruation, pregnancy,
endometriosis, and other gynecologic and non gynecologic conditions.
of the low prevalence of ovarian cancer, the test is not itself useful
is a monoclonal antibody generated against a colon carcinoma cell line
to detect a monosialoganglioside 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, but
this capability remains to be established.
PSA screening test is a blood test that looks for a specific tumor
marker. In general, tumor markers are produced by the tumor itself or
by our body in response to the presence of cancer or non-cancerous
conditions. If a tumor marker level is higher than normal, the patient
is examined more closely to look for cancer or other conditions. The
most commonly tested tumor marker for the prostate gland is prostate
specific antigen. It is normally present in low levels in the blood of
all adult men. The normal range is 0 to 4
is prostate-specific, not cancer-specific. A variety of conditions can
raise PSA levels: prostatitis (prostate inflammation), benign prostatic
hypertrophy (prostate enlargement), and prostate cancer. PSA levels can
also be influenced by a number of other things. Some prostate glands
normally produce more PSA than others. PSA levels tend to increase with
age. And, PSA levels can vary with race: African Americans often have
higher PSA levels; Asian men often have lower PSA levels.
seems to have the capability of achieving at least one of the
characteristics of an ideal tumor marker- tissue specificity; 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
is highly sensitive for the pesence of prostatic cancer. The elevation
correlated with stage and tumor volume. It is predictive of recurrence
and response to treatment. Finally, the antigen has prognostic value in
patients with very high values prior to surgery are likely to relapse.
PSA is detectable in normal men and often is elevated in benign
prostatic hypertrophy, which may limit its value as a screening tool
for prostate cancer. A recent study has shown that PSA combined with
rectal exam is a better method of detecting prostate cancer than rectal
Reference for Serum PSA (Reference
40 - 49
0.0 - 2.0
0.0 - 2.5
0.0 - 2.0
50 - 59
0.0 - 4.0
0.0 - 3.5
0.0 - 3.0
60 - 69
0.0 - 4.5
0.0 - 4.5
0.0 - 4.0
70 - 79
0.0 - 5.5
0.0 - 6.5
0.0 - 5.0
are produced by many tumors. The hormone may be a natural product of
its associated organ or represent abnormal synthesis reflecting
unregulated cancer cell metabolism. Examples include insulin production
by islet cell tumor, calcitonin by medullary thyroid carcinoma, and
catecholamines by pheochromocytoma. Or it may be that 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.
this section, discussion is limited to human chorionic gonadotropin.
Other hormones will be discussed in another review.
Human Chorionic Gonadotropin
is a glycoprotein consisting of subunits a e b, which are
nonconvalently linked. The hormone is normally produced by the
syncytiotrophoblastic cells of the placenta and is elevated in
pregnancy. Its most important uses as a tumor marker are in gestational
trophoblastic disease and germ cell tumors.
gestational trophoblastic tumors produce HCG, and it is a valuable
marker in these tumors, screening reliably in all cases and indicating
poor responses to treatment. The level correlates with tumor mass and
thus has prognostic value. HCG is extremely sensitive, being elevated
in women with minute amounts of tumor. The patient is followed weekly
during treatment, and at the completion of treatment indefinite follow
up is advised to detect recurrence. HCG is essential in managing
level of HCG is occasionally elevated in other cancers including those
of breast, lung, and gastrointestinal tract, but in these diseases it
has found little clinical application.
observe either enzymes that are native to normal tissue or those that
could be associated with changes in metabolism that are unique to
enzyme is found in high concentraitions in the normal prostate as well
as in primary and metastatic prostate cancers. Acid Phosphatase may
also originate from other tissues.
more sensitive immunological test (RIA or counterimmunoelectrophoresis
for prostatic acid phosphatase, wich are specific for the enzyme of
prostate tissue) often gives positive results in the early stages of
of the reliability of acid phosphatase as a marker in early disease, it
was hoped that the test could be used as a screening tool. However, it
may also be elevated in up to 6 percent of cases of benign prostatic
hypertrophy and other conditions. Thus, its predictive value is low on
theoretical grounds. So, acid phosphatase is useful in following
patients with advanced disease.
Neuron Specific Enolase
specific enolase is an isozyme of the glycolytic pathway that is found
only in brain and neuroendocrine tissue. Its an immunohistochemical
marker for tumors of the central nervous system, neuroblastomas, and
of NSE has been evaluated in lung cancer and neuroblastoma.
Galactosyl Transferase II
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.
of a monoclonal immunoglobulin molecule is characteristic of multiple
myeloma. These 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.
are valuable in the staging and treatment of myeloma, the amount of
paraprotein serving as an index of tumor volume. Response to treatment
is indicated by a fall in paraprotein production, whereas a rise points