- 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
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.
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
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
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 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
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
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.
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
Because of the low prevalence of ovarian cancer,
the test is not itself useful in screening.
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.
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.
Age-Specific Reference for
Serum PSA (Reference Range [ng/ml])
Age Range (Years)
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
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
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.
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.
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 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
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.
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
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.