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Tumor Markers; AFP, HCG, CA-125
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 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.
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.
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.
Tumor 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.
Tumor Antigens
Include 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.
Carcinoembryonic Antigen
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 blood.
Although 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.
As a 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.
The 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.
Although 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 laboratory error.
The 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.
The 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 treatement.
Alpha-Fetoprotein
Alpha-Fetoprotein 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.
AFP 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.
AFP 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.
An 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.
AFP 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.
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. 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.
Thus, 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.
CA 125
CA125 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.
CA125 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.
The 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.
Because of the low prevalence of ovarian cancer, the test
is not itself useful in screening.
CA19-9
CA19-9 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.
Prostate-Specific Antigen
The 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 ng/ml.
PSA 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.
PSA 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 seminal clot.
PSA 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.
Unfortunately, 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 exam
alone.
Hormones:
Hormones 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.
In this section, discussion is limited to human chorionic
gonadotropin. Other hormones will be discussed in another
review.
Human Chorionic Gonadotropin
HCG 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.
All 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 trophoblastic neoplasms.
The 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.
Enzymes
Investigators observe either enzymes that are native to
normal tissue or those that could be associated with changes
in metabolism that are unique to cancer tissue.
Acid Phosphatase
This 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.
The 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 disease.
Because 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
Neuron 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 APUD tumors.
Use of NSE has been evaluated in lung cancer and neuroblastoma.
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.
Immunoglobulins
Production 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.
Immunoglobulins 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 to
relapse.
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tumormarkers.html
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