TUMOR MARKERS

What Is a Tumor Marker?

Tumor markers are molecules that can be detected in blood, body fluids, or tissue of a host with underlying cancer. It is
not unusual for tumor cells to secrete or shed molecules or parts of a molecule. Occasionally, these molecules can be
useful tumor markers, as evidenced by the monitoring of prostatespecific antigen !"#$% or prostate serum acid
phosphatase !"#$"% levels in serum.
&'()
*levated levels of "#$ or "#$" are indicative of prostate cancer. "#$ is a
proteolytic en+yme that is secreted by the prostate into the glandular lumina, where it is contained and e,creted with
prostatic fluid. -ancer in the prostate can cause "#$ to leak out of the gland into the blood. .ote that other disease
forms in the prostate, such as benign hyperplasia of the prostate and prostatitis, may also induce leakage of "#$.
"#$" is another proteolytic en+yme that may leak into the blood, but it is associated with a more advanced disease
stage. /ikewise, elevated levels of -$ 0(1 and mucin !M2-%0 are associated with disease progression of ovarian and
breast carcinoma, respectively.
&'')

-lassically, tumor markers are macromolecules such as proteins, carbohydrates, and 3.$ released by the tumor and
detected in blood. 4or e,ample, -*$ is a modified protein secreted by multiple tumor types such as colorectal,
pancreatic, breast, and lung cancers.
&'5)
6owever, tumor markers may also be molecules released by the normal host
tissue in response to the invasion of cancer. The first tumor marker described 7acid phosphatase8 was such a normal
host en+yme secreted by bone in response to invading prostate carcinoma.
The ideal tumor marker should have several characteristics to be useful clinically. 4irst, a simple test should detect a
tumor marker long before the malignancy spreads widely. In many occasions, tumors are diagnosed by microscopic
e,amination after obtaining a biopsy specimen of the tumor. 6owever, by the time a tumor becomes clinically apparent
enough to prompt a biopsy e,amination, the tumor has already spread widely. This can be avoided by using a tumor
marker that can be detected long before a biopsy is possible, allowing the clinician to alter the natural history of the
tumor in the host. #econd, testing for a tumor marker should be sensitive9 that is, the test for the tumor marker should
be positive in all patients with a particular cancer !no falsenegative results%. Third, the test for the tumor marker should
be specific, meaning that the test should be positive for the marker only when the patient has that particular cancer !no
falsepositive results%. 4ourth, the level of the tumor marker detected in the biologic sample should correlate with the
si+e of the tumor. 4ifth, the test for the tumor marker should be cheap enough to allow use of the marker in screening of
large numbers of individuals.
The sensitivity of a tumor marker is determined by three interrelated factors: !0% the ability of the assay to reliably detect
the tumor marker in a given biological sample9 !(% the critical tumor mass that should be present before the marker can
be detected9 and !'% the percentage of tumors that e,presses the particular tumor marker being tested. 3evelopment of
highly sensitive immunoassays has decreased the threshold concentration of detection as well as the si+e of the tumor
needed to achieve that concentration. 6owever, discovering tumor markers that are uniformly e,pressed by all tumors
with the same classification has been more of a problem.
The specificity of a tumor marker is also dependent on three factors: !0% the fidelity with which the assay detects only
the tumor marker9 !(% presence of other tumors that test positive for the same marker9 and !'% other nonmalignant
conditions in which the tumor marker is elevated.
The ideal tumor marker with all the desired characteristics has not been found yet. 3espite advances in molecular
biologic techni;ues and discovery of many new markers, all known tumor markers have characteristics that limit their
clinical utility. -linical applications of tumor markers in screening, diagnosis, prognosis, evaluation of success of
therapy, and monitoring for recurrence are limited by problems in sensitivity and specificity. 6owever, a marker that is
not ideal for one application may be useful in another application. 4or e,ample, a marker such as -*$ may not be ideal
for screening for colorectal cancer in large populations of people, but it may be useful in detecting recurrence in a
patient who has undergone resection of the primary tumor. *,amples of tumor markers with their clinical utility and
potential limitations are listed in Table (<=< .
Table 28-8 -- Tumor Markers in Clinical Application
Tumor Marker Type of Molecule Tumor Type Type of Application
onmali!nant
Con"itions #it$ Ele%ate"
&e%els
-*$ >lycoprotein
#tomach, liver, pancreas,
breast, and colorectal
cancer
"rognosis and
monitoring therapeutic
response
6epatitis, cirrhosis,
?aundice, -O"3,
inflammatory bowel
disease, smoking
-$ 0@=@
Mucintype
glycoprotein
"ancreas cancer
3iagnosis, prognosis,
and monitoring
therapeutic response
6epatitis, cirrhosis,
sclerosing cholangitis, and
e,trahepatic biliary stasis
$4"
Oncofetal
glycoprotein
/iver and testicular cancer
3iagnosis, prognosis,
and monitoring
therapeutic response
6epatitis, cirrhosis,
pregnancy, inflammatory
bowel disease
"#$
Oncofetal
glycoprotein
"rostate cancer
#creening, diagnosis,
prognosis, and
monitoring therapeutic
response
A"6, prostatic massage or
biopsy
B6->
Trophoblastic
protein
-horiocarcinoma,
hydatidiform mole, and
invasive mole
3iagnosis, prognosis,
and monitoring
therapeutic response
"regnancy
-$ 0(1
Ovarian cell
surface protein
Ovarian cancer
"rognosis and
monitoring therapeutic
response
"regnancy, endometriosis,
menstruation, ?aundice,
and pancreatitis
-$ 01='
Membranes of
breast cancer cells
Areast cancer "rognosis
-irrhosis, hepatitis, and
benign breast disease
"rostatic acid
phosphatase
"rostate cellular
protein
"rostate cancer
"rognosis and
monitoring therapeutic
response
A"6, dermatologic
disorders
1
6ydro,yindoleacetic
acid
"eptide metabolite
of indoleacetic acid
-arcinoid 3iagnosis C
-alcitonin 6ormone Medullary thyroid cancer
3iagnosis, prognosis,
and monitoring
therapeutic response
C
Metanephrine
-atecholamine
metabolite
"heochromocytoma
3iagnosis, prognosis,
and monitoring
therapeutic response
C
-*$, carcinoembryonic antigen9 -$, carcinoma antigen9 $4", Dfetoprotein9 "#$, prostatespecific antigen9 B6->,
betahuman chorionic gonadotropin9 -O"3, chronic obstructive pulmonary disease9 A"6, benign prostatic hypertrophy.
Molecular 'asis of Tumor Markers
Tumor markers are a result of genetic alterations that occur in tumor cells that directly or indirectly affect the gene
e,pression pattern of the tumor cells or the surrounding tissue. Molecular changes that occur in a cell that leads to the
e,pression of a tumor marker can stem from incorporation of viral genes into the tumor cell, chromosomal translocations
in the tumor cell, changes in the 3.$ methylation pattern, or any other genetic change such as point mutations and
deletions.
Two categories of abnormalities can be distinguished based on their importance in oncogenesis: primary abnormalities
that are essential at the tumor initiation stage, and secondary abnormalities that occur later and are thought to play a
role during tumor progression. The primary abnormalities, such as the "hiladelphia chromosome,
&'1)
are specific for a
particular tumor, whereas the secondary abnormalities are less specific. "rimary abnormalities are mostly detected in
leukemias, non6odgkinEs lymphoma, and mesenchymal solid tumors and are of diagnostic value. In general, the
genetic changes are reciprocal translocations leading to disruption of genes controlling growth, differentiation, and
apoptosis. In epithelial solid tumors, the high incidence of chromosomal rearrangements with gross aneuploidy
complicates karyotyping. In addition, these tumors are usually studied at later stages of development, at which time the
tumor cells have undergone many additional genetic changes. .onetheless, several primary abnormalities have been
proposed in lung carcinoma, nonpapillary renal cell carcinoma, transitional cell carcinomas of the bladder, and
adenocarcinoma of the prostate. Most chromosomal aberrations in these tumors involve deletions, unbalanced
translocations, and loss of entire chromosomes. This may suggest that loss or inactivation of tumor suppressor genes
plays an important role in these tumors.
(iral )enes
Tumors induced by viruses such as the *psteinAarr virus !*AF% implicated in AurkittEs lymphoma, human
papillomavirus !6"F% linked to cervical cancer, hepatitis A virus !6AF% associated with hepatocellular carcinoma, and
human Tlymphotropic virus type 0 !6T/F0% associated with Tcell leukemia may e,press viral gene products that are
easily detectable because they are not e,pressed in normal cells. The viral 3.$ may be inserted into the host genome
or e,ist in the cytoplasm, but in both cases, the cellular mechanisms of the host are manipulated to serve the virus.
"apillomavirus 3.$, for e,ample, encodes genes of which the product inactivates the p53 and the Rb genes. In
addition, viral genes are transcribed that are involved in viral replication.
C$romosomal Translocations
-hromosomal translocations occur fre;uently and often nonrandomly. Aecause of the breakpoint and annealing at a
different location, hybrid proteins may be e,pressed that could be used as markers.
&'G)
>ood e,amples of hybrid proteins
with diagnostic value are the "hiladelphia chromosome in chronic myeloid leukemia !-M/% !@HI of cases% and the *>4
receptor in glioblastomas. The "hiladelphia chromosome is a shortened version of chromosome (( that resulted from
the reciprocal translocation of part of chromosomes @ and ((, resulting in a longer chromosome @ and shorter
chromosome ((.
&'1)
The *>4 receptor, which is e,pressed in about 5HI of gliomas, has an internal deletion resulting in
a characteristic fusion protein that contains one or more new amino acids at the fusion point.
&'J)
The fusion protein still
has the ability to bind *>4 and may in fact be more stable than the wildtype *>4 receptor, resulting in overe,pression.
The overe,pression may give glioma cells an advantage over normal cells when the amount of available *>4 is limiting.
3.$ Methylation
$ltered 3.$ methylation patterns are also common in cancer cells and may be responsible for e,pression of some
types of tumor antigens such as oncofetal antigens. Methylation of 3.$ at restricted cytosine phosphate guanine !-p>%
se;uences is a mechanism of regulating e,pression of certain genes. >enes that are e,pressed in fetal development
are later silenced in adult life by methylating areas known as -p> islands near the promoter regions.
&'<)
Methylation of
-p> se;uences in promoter regions blocks directly or indirectly the binding of transcription factors and thereby blocks
transcription. When the distribution of methylation sites was evaluated in tumors, it was found that areas of
hypomethylation e,ist as well as areas of hypermethylation. 6ypomethylation may increase gene e,pression and may
also decrease chromosome stability and lead to allelic loss. 6ypermethylation, on the other hand, could suppress gene
transcription.
With the isolation and characteri+ation of oncogenes and tumor suppressor genes, another feature of 3.$ methylation
became apparent. "oint mutations in those genes are fre;uently associated with -p> sites. The methylation of cytosine
is thought to increase the chance for a -toT or -to$ transition by 0(fold to 'Hfold. Thus, 1methylcytosine is
considered an endogenous mutagen that contributes to about 'HI of all point mutations despite the fact that 1
methylcytosine constitutes only 0I of human 3.$. 4or e,ample, when all human tumors are considered together, one
third of all inactivating point mutations in the tumor suppressor gene p53 occur at methylation sites. .ote that the point
mutations related to methylation are not restricted to p53 only but rather occur in many genes.
*oint Mutations an" +eletions
>ene mutations have been identified in various human cancers, and the list of mutated genes includes tumor
suppressor genes (BRCA-1, BRCA-2, APC, p53, nm23), oncogenes !ret, Bcatenin, ras, bcl), and genes involved in cell
growth (cdk)!
Other genetic changes affect the transcription level of genes: transcription of previously silent genes may be induced9
the transcription level may be enhanced over the normal level, leading to overe,pression of the gene product9 or
transcription may be reduced or entirely blocked. Mutations occur at various locations in genes, but often 7hot spots8 are
present. These hot spots are gene restricted and not specific for the type of tumor. .onetheless, certain of these
mutations have diagnostic value, such as mutated ras, p53, and others, because they confirm the malignant state of a
cell.
+etection Met$o"s of Tumor Markers
,mmunolo!ic +etection
Immunologic techni;ues have long been used to identify e,isting specific tumor markers and to discover new markers.
The discovery of monoclonal antibodies and the generation of antibodyproducing hybridomas
&'@)
have greatly e,panded
the repertoire of clinicians and pathologists in the detection of malignant cells. More recently, the immunologic
discoveries of tumorspecific T cells further e,panded the available techni;ues to identify new tumor markers. Tumor
specific T cells are currently not used for detection purposes since the generation and maintenance is too labor
intensive. 6owever, the use of tumorspecific T cells, in particular cytoto,ic T lymphocytes, in vitro has clearly helped to
identify tumor antigens in a variety of tumors and has formed the rationale for immunebased therapies !see Tumor
Aiology section%.
In general, monoclonal antibodies that bind specifically to epitopes on tumor markers are used for detection of tumor
cells in biopsy specimens, blood cells, or other body fluids. The first and still most commonly used method for the initial
diagnosis of cancer is through microscopic evaluation of tissue sections or cytologic preparations. Koutinely, tissue is
fi,ed in formalin to preserve morphologic structures and is embedded in paraffin or plastic. The fi,ation process,
however, may negatively affect the threedimensional structure of antigens recogni+ed by antibodies. $n alternative
method involves the snapfree+ing of tissue, which does not include a fi,ation step and does not denature antigens. The
downside of this method, however, is that the morphology is poorly preserved. To use antibodies in paraffin sections,
secondgeneration antibodies are developed that are selected to recogni+e antigens that are not destroyed by the
fi,ation process.
$ntibodies that recogni+e interesting epitopes in cryostat sections are used to identify the gene encoding the antigen.
#ubse;uently, animals are immuni+ed with the recombinant protein or protein fragments, and hybridomas are
generated. The hybridomas are tested for secretion of antibodies that are reactive with the antigen of interest in paraffin
sections. #econdgeneration antibodies have been made, for e,ample, against the cell cycle=dependent nuclear
proliferation marker, LiGJ, e,pressed in many cancers.
Instead of immunohistology, flow cytometric analysis of antibodystained cells is usually performed on hematopoietic
tumors, mainly to facilitate classification. This method permits evaluation of the percentage of positive cells in a
population of cells in suspension. In situ hybridi+ation can be used to detect specific antigens in paraffinembedded
tissues. #pecific oligonucleotide probes are incubated with the tissue slide to permit hybridi+ation with the messenger
K.$ of the antigen of interest. The probe is labeled with a fluorescent or other dye to permit detection. 4inally, en+yme
linked immunosorbent assays or radioimmunoassays are antibodybased detection methods to ;uantify the level of a
particular marker in blood or other body fluids. Aoth procedures take less than a day and can detect ;uantities in the
nanogram to picogram range !0H=
&G)
to 0H=
&@)
g%. These types of assays are used for routine measurement of known
markers, such as -$ 01=' in serum from breast cancer patients.
Cyto!enetic Analysis
$nother screening method used primarily to support the diagnosis of hematopoietic cancers is cytogenetic analysis.
-hromosome aberrations can be the result of incorrect separation of chromosome pairs during mitosis !numerical
chromosome change%. One of the daughter cells may end up with an additional copy of the chromosome, whereas the
other daughter cell is one copy short. #tructural chromosome changes are initiated with 3.$ damage and incorrect
3.$ repair, leading to abnormal reconfiguration of broken chromosome ends. There is evidence that cancerassociated
chromosomal aberrations are not random, although e,act mechanisms are not fully understood. The first specific
chromosome abnormality was observed in 0@GH in patients with -M/. The abnormality involves the earlier mentioned,
unusually small chromosome ((.
&'1)
#ince the discovery was made in "hiladelphia, the chromosome was named
P"iladelp"ia c"r#m#s#me! It was subse;uently found that chromosomal aberrations in hematopoietic cancers are
restricted to a few chromosomes with an otherwise normal diploid karyotype.
-ytogenetics, especially in solid tumors, is used to identify possible locations of new tumor suppressor genes. Ay
comparing numerous chromosomal aberrations in tumors of a particular histologic type, certain abnormalities may show
up with an elevated fre;uency, which may indicate a common loss of a tumor suppressor gene. This mapping strategy
has helped significantly in identification of the BRCA-1 and BRCA-2 genes in breast carcinoma.
&5H)

)enetic Analysis
In addition to immunologic techni;ues, molecular biologic techni;ues have been developed for detection of tumor
markers. One such techni;ue is based on gene analysis for detection of mutations in known molecules suspected of
carrying a mutation. >enerally, messenger K.$ is isolated from the tumor cells and reverse transcribed into
complementary 3.$. The complementary 3.$ is incubated with an oligonucleotide specific for the tumor marker of
interest, and the 3.$ is amplified by polymerase chain reaction !"-K%, introduced in 0@<1.
&50)
Aecause of the specific
primer, only the gene of interest is amplified by "-K. The "-K product is subse;uently analy+ed using a variety of
techni;ues, such as analysis by gel electrophoresis, #outhern blotting, and se;uencing. Mutations in oncogenes (ras)
and tumor suppressor genes (p53), are easily detected with these procedures. The "-K amplification method of genetic
material can also be performed on formalinfi,ed, paraffinembedded tissues.
-linical $pplications of Tumor Markers
3iagnosis
Koutinely, the first diagnosis of tumor is performed by the pathologist based on histologic and cellular characteristics
!morphologic markers%. 6istopathologic classification is essential because not all tumors are e;ual, and they re;uire
differential treatment. In addition, within a particular histologic type, treatment strategies vary depending on the grade
and stage of the tumor. Immunohistology using antibodies to detect specific markers is helpful for classification of the
problem cases, such as apparently undifferentiated tumors. These tumors include large cell tumors, such as anaplastic
carcinoma, and round cell tumors, such as *wingEs sarcoma.
$ntibodies reactive to components of the intermediatesi+ed filaments can be helpful to classify tumors because their
e,pression is tissue specific and is often preserved in malignancies. The intermediatesi+ed filaments are part of the
intracellular matri, and comprise cytokeratins !carcinoma%, vimentin !lymphoma, sarcoma, melanoma%, desmin
!myosarcoma%, neurofilaments !neuroblastoma%, and glial fibrillary acidic protein !astrocytoma%. Within the more than 0<
different keratins, celltype=specific combinations occur, and antibodies against individual keratins may help in
subclassification. /ikewise, antibodies have been generated against a number of celllineage= associated markers,
such as -351 !common leukocyte antigen%, "#$ and "#$" !prostate epithelium%, >(1H !renal cell carcinoma%, gp0HH
!melanoma%, and polymorphic epithelial mucins !secretorial epithelia%. $ntibodies reactive with leukocyteassociated
antigens are used for the subclassification of lymphomas and leukemias.
The list of clusters of differentiation, or -3, numbers contains more than (1H different antigens and keeps growing.
&5()
$
similar, albeit much smaller, list of clusters has been prepared for differentiating antigens in lung cancer.
"rognosis
"rognosis is related to treatment. Morphologic criteria and the e,tent of metastatic disease are important prognostic
parameters. Thus, factors that determine tumor growth, such as e,pression of particular growth factor receptors, the
rate at which the tumor is growing, metastatic potential mediated through e,pression of certain receptors for *-M
molecules, and sensitivity to therapy, all are important for prognosis. $ marker indicative of tumor growth is the cell
cycle=dependent proliferation marker LiGJ. $ high proportion of LiGJ=positive cells is inversely correlated with survival.
/ikewise, overe,pression of $er2%ne& and the *>4 receptor on breast cancer cells and high levels of M2-0 in the
serum of breast cancer patients is associated with poor prognosis. $ high e,pression of integrin molecules !involved in
attachment to *-M molecules% is related to poor prognosis. Many factors are found to be involved in tumor
development, and therefore many are related to prognosis.
Monitoring *fficacy of Therapy
Tumor markers such as -*$, "#$, and -$ 0(1 are easily detectable in serum. Their e,pression levels in serum
correlate with tumor volume, which means that levels that are significantly higher than average baseline levels indicate
the presence of malignancy. Ay evaluating levels pretherapy and posttherapy, the clinician can monitor the efficacy of
therapy and detect recurrences. 4or e,ample, a patient with very high -*$ level will e,perience a drastic decrease in
that level immediately after the successful removal of his or her colon cancer. Thereafter, any significant increase in that
level in the years after the operation may signify recurrent colon cancer or metachronous cancer, and the patientEs
physician can have a higher inde, of suspicion to prompt a cancer detection test such as colonoscopy early.
>uiding -hoice of Therapy
#ome tumor markers that can be easily evaluated through immunohistology may provide clinically important
information, such as the evaluation of hormone receptor status in breast carcinoma. *strogen receptor status has been
for years the basis of selecting patients for potential therapy. *strogen receptor=positive patients !especially
postmenopausal patients% have been treated with tamo,ifen. In contrast, estrogen receptor=negative patients
!especially premenopausal patients% have been treated with chemotherapy. $lthough physicians rely on a number of
markers, such as -*$, "#$, and Dfetoprotein !$4"%, to treat patients, they do not necessarily select treatment on the
basis of the level of e,pression.
"revention of -ancer
*,amples of markers that may help prevent tumor development are the genes with inheritable mutations such as
BRCA-1, BRCA-2, ret !associated with multiple endocrine neoplasia%,
&5')
and APC, or other genes that are commonly
mutated in the initial stages of tumor development. Mutations in these genes are likely to cause cancer at some stage in
life. *arly screening for the known gene mutations !i.e., before the development of cancer% may permit corrective
therapy, such as prophylactic surgery. $nother such treatment may be gene therapy in which an intact copy of the
mutated gene is transferred into cells with the defective gene.
#ome Tumor Markers Most 4re;uently 2sed in #urgical Oncology
-*$ is among fre;uently used markers in surgical oncology and is discussed here as a representative e,ample !see
also Table (<=< %. -*$ is an oncofetal protein with a molecular weight of (HH,HHH k3 that is e,pressed in embryonic
tissue. In adults, -*$ is found in the mucous membranes of stomach, small intestine, and the biliary tree as a
component of the glycocali,. Malignant epithelial type tumors such as colon cancer, lung cancer, and others may
e,press higher levels of -*$ on the cell surface and release -*$ into blood. -*$ in the normal cell is thought to
function as a cell adhesion molecule. 4or cancer cells, -*$ may offer a survival advantage by allowing adhesion into
other cells and allowing metastasis. It may also offer some refuge from immune attack of the host due to the large
glycosylated nature of the molecule creating a physical barrier between the immune effector cells and the cancer cell.
-*$ is detected in serum by commercially available immunoassay kits that very specifically measure the level of -*$.
6owever, the measured level can vary depending on the brand of kit used, although the measured level is reproducible
within the brand and the laboratory. In general, normal individuals have less than (.1 ngMm/. Aenign conditions listed in
Table (<=< can raise this level to higher than 0H ngMm/. -*$ is cleared from serum by hepatocytes and Lupffer cells.
$ny benign liver condition that affects hepatocellular function or causes cholestasis can decrease clearance of -*$,
resulting in higher plasma levels.
#erum -*$ level is not a useful test for screening for colorectal cancer for several reasons. In large studies, only about
5HI patients with locali+ed, potentially curable cancers had serum -*$ levels higher than 1 ngMm/ !sensitivity of 5HI%.
This results in a large falsenegative rate. If one uses the same 1ngMm/ level as cutoff for a normal -*$ level, the test
is @1I specific. 6owever, due to the very low prevalence of colorectal cancer in large populations !0M0HHH%, that @1I
specificity still yields a large fre;uency of falsepositive tests.
$lthough -*$ is not useful in screening large populations, the level of -*$ in colorectal cancer patients is of prognostic
value. In general, the higher the preoperative -*$ level, the poorer the rate of longterm survival. "atients with normal
preoperative -*$ levels have lower recurrence rate than patients with elevated -*$ levels. If the -*$ level does not
decrease to normal levels after resection of the cancer, the risk of recurrence is higher.
Kelated to -*$ are -$ 0(1, -$ 01=', and -$ 0@=@, serum markers for detection of ovarian cancer, breast cancer, and
pancreas cancer, respectively. $ll four molecules are highmolecularweight molecules e,pressed on the respective
tumors but not on normal tissues. Their e,pression levels correlate with tumor volume and as such they are useful
indicators to monitor response to therapy and recurrence.
$s mentioned earlier, estrogen and progesterone receptor status is routinely determined on breast biopsies to
determine choice of treatment. $dditionally, 6er(Mneu status is evaluated using specific antibodies. "atients with
disseminated 6er(Mneupositive tumors are potentially eligible for treatment with the anti6er(Mneu antibody, 6erceptin.
"#$ and $4" are the standard markers for detection of prostate cancer and hepatocellular carcinoma, respectively, and
for monitoring the response to therapy.
4inally, neuronspecific enolase !.#*%, -*$, and s;uamous cell carcinoma !#--% antigen are commonly used markers
for lung cancer. .#* detected in serum helps to support a diagnosis of small cell lung carcinoma and a postoperative
decrease of serum level of .#* is the first sign of curative resection. #-- antibody measurement in serum of lung
cancer patients is an aid to histologic analysis: "atients with an #-- antibody level higher than ( NgM/ have a @1I
probability of having non=small cell lung cancer and <HI probability of having a s;uamous tumor.
In spite of the usefulness of many markers as outlined earlier, caution should be taken with the interpretation of the
observed values. In addition to malignancy, several benign conditions may increase the value of serum markers. 4or
e,ample, many acute and chronic conditions of the biliary tract as well as cancers of the pancreas, colon, and stomach
result in increased levels of -$ 0@=@. /ikewise, the level of $4" is elevated in serum during pregnancy and cancers
such as hepatocellular carcinoma and nonseminomatous testicular cancer. .onmalignant conditions such as
inflammatory bowel disease, hepatitis, and cirrhosis can also give rise to elevated $4" levels. 4inally, benign conditions
such as pregnancy, menstruation, endometriosis, pelvic inflammatory disease, hepatitis, cirrhosis, and renal failure may
increase -$ 0(1 levels.
-onclusion
Many tumor markers e,ist, and most are diagnostic markers. There is still a need for additional markers, however,
especially those that indicate the presence of a tumor at very early stages. The completion of the se;uencing of the
human genome may increase the number and ;uality of available markers for all possible applications. The availability
of markers for early diagnosis can be combined with more refined treatment modalities !e.g., gene therapy, vaccine
therapy, and others% or with finding new indications for old treatments !e.g., prophylactic surgery%.