r e v i e w A rtic l e

Tumor markers in clinical practice: General

principles and guidelines
S. Sharma A B S T R A C T
Department of Surgical
Oncology, Amrita Institute of Tumor markers are assuming a growing role in all aspects of cancer care, starting
Medical Sciences & Research from screening to follow-up after treatment, and their judicious application in clinical
Centre, Ernakulam – 682026, practice needs a thorough understanding of the basics of pathophysiology, techniques
Kerala, India of identification or testing, reasons for out-of-range levels of tumor markers, as well
as the knowledge of evidence of their role in any given malignancy. These are, at the
most, just an adjunct to diagnosis, and establishing a diagnosis on the basis of tumor
markers alone (especially a single result) is fraught with associated pitfalls because of
the problem of nonspecificity. In reality an ideal tumor marker does not exist. Detection
can be done either in tissue or in body fluids like ascitic or pleural fluid or serum. Clinical
uses can be broadly classified into 4 groups: screening and early detection, diagnostic
confirmation, prognosis and prediction of therapeutic response and monitoring disease
and recurrence. In addition to variable sensitivity and specificity, the prevalence of a
particular malignancy may be a major determinant in the application of a particular
test as a screening tool. Serum levels, in certain situations, can be used in staging,
prognostication or prediction of response to therapy. Monitoring disease is, perhaps,
the most common clinical use of serum tumor markers. Rising trend in serum levels
may detect recurrence of disease well before any clinical or radiological evidence of
Address for correspondence: disease is apparent (“biochemical recurrence”). Sampling should ideally be repeated
Dr. Shekhar Sharma,
after 5-6 half-lives of the marker in question (or the marker with the longest half-life if
Associate Professor, Department
of Surgical Oncology, Amrita
multiple markers are being considered); but if found elevated, the next sampling after
Institute of Medical Sciences & 2-4 weeks, for additional evidence, may be justified.
Research Centre, Ernakulam –
682026, Kerala, India. Key words: Tumor markers, serum tumor markers, early diagnosis, malignancy
E-mail: drshekharsharma@
[Link] DOI: 10.4103/0971-5851.56328

Today there are literally hundreds of tumor markers,

INTRODUCTION
although their clinical utility or application is, of course,
Current clinical practice in oncology has a growing impetus a different issue!
on early diagnosis, proper prognostication and (of late)
screening for malignancy in asymptomatic groups. Tumor Tumor markers include a variety of substances like
markers are assuming a growing role in all aspects of cancer cell surface antigens, cytoplasmic proteins, enzymes,
care, starting from screening to follow-up after treatment. hormones, oncofetal antigens, receptors, oncogenes and
Important clinical decisions are increasingly likely to be their products.[4] There have been numerous attempts
made on the basis of these results, whether for diagnosis, to broaden the definition to accommodate the rapidly
screening, prediction or treatment monitoring.[1] expanding set of identified tumor markers and include
the following:
The first known attempt to find markers for malignancy was
made 2000 years ago and is described in an Egyptian papyrus, 1. Substances present in, or produced by, a tumor itself
where breast cancer was distinguished from mastitis. [2] or produced by host in response to a tumor that can
Incidentally the first tumor marker in modern medicine be used to differentiate a tumor from normal tissue
was identified by Bence-Jones, who in 1846 detected a or to determine the presence of a tumor based on
heat precipitate in samples of acidified urine from patients measurements in blood or secretions.[4,5]
suffering from “Mollities osseum”.[2] In 1965, Gold et al., 2. A molecule, a process or a substance that is altered
isolated a glycoprotein molecule from specimens of human quantitatively or qualitatively in precancerous or
colonic cancer and thus discovered the first “tumor antigen,” cancerous conditions, the alteration being detectable
later identified as carcino-embryonic antigen (CEA).[3] by an assay.[6]

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 Sharma: Interpreting tumor markers in clinical practice

3. Biochemical indicators of the presence of a tumor.[7] Immunological detection usually relies on monoclonal
However, in common clinical practice, the term usually antibodies that specifically bind to epitopes on tumor
refers to a molecule that can be detected in plasma or markers and are in turn tagged for identification with
other body fluids. dyes in immunohistochemistry (IHC), radioactive tags in
radio-immuno assay (RIA), or enzymes in enzyme-linked
Ideal tumor marker immunosorbent assay (ELISA).[2,5,6,10,11] Alternatively, in a
suspension, flow cytometry can analyze the presence and
Only a few tumor markers have stood the test of time and percentage of antibody-tagged cells.[9-11] These methods are
entered in the diagnostic or management algorithms for highly sensitive and can detect quantities in the nanogram
clinicians.[1,2,5]

The three most important characteristics of an ideal tumor Table 2: Molecular basis of tumor markers[8]
marker are (a) it should be highly specific to a given Levels of classification Examples
tumor type, (b) it should provide a lead-time over clinical DNA
diagnosis and (c) it should be highly sensitive to avoid Epigenetic Promoter Hyper-methylation, e.g.,
false positive results. Additionally, the levels of the marker GSP1, DAP in lung cancer; p15, p16 in
should correlate reliably with the tumor burden, accurately liver cancer
Endogenous Mutations, e.g., NADH dehydrogenase 4
reflecting any tumor progression or regression, along with Mitochondrial genetic (ND4) in urine in bladder cancer
a short half-life allowing frequent serial measurements. Oncogene Mutation, e.g., K-ras in pancreatic
The test used for detection should be cheap for screening cancer; micro-satellite alterations in
application at mass level and should be of such nature as to head and neck cancers
be acceptable to the target population [Table 1]. In reality Exogenous viral EBV in NPC, Burkitt’s lymphoma; HPV in
cervical cancer
an ideal tumor marker does not exist.
RNA
Cell based Tissue-specific markers, e.g., PSA mRNA
Molecular basis of tumor markers endogenous in prostate cancer, cytokeratin 20 mRNA
in breast cancer
Cell free Circulating mRNA, e.g., Tyrosinase
Genetic alteration in a tumor cell affects directly or
mRNA in melanoma
indirectly the gene expression pattern of the tumor cell Exogenous viral Viral RNA, e.g., EBV-coded RNA in NPC
or the surrounding tissue.[7] These genetic alterations can Translational protein
be reflected at various levels [Table 2], from viral genomic Native protein PSA in prostate cancer, CEA in colonic
incorporation to genetic defects, forming the molecular (Conventional cancer
basis of tumor markers.[8] markers)
Glycan Aberrant glycosylation, e.g.,
monosialytactec AFP in HCC
Methods of detection
AFP: Alfa fetoprotein; CEA: Carcinoembryonic antigen; EBV: Epstein-Barr virus;
HCC: Hepatocellular carcinoma; HPV: Human papilloma virus; mRNA: Messenger
The methods of detection can be classified into 6 major RNA; NPC: Nasopharyngeal carcinoma; PSA: Prostate-specific antigen
groups [Table 3].[2,5,6,9,10] The most common method in use
today is serological enzyme assays. Table 3: Methods of detection of tumor
markers[2,5,6,9,10]
Serology Enzyme assays
Table 1: Characteristics of an ideal tumor
Immunological Immuno histo chemistry
marker[5]
Radio immuno assay
Characteristics Remarks
Enzyme-linked immuno sorbent assay
Highly specific Detectable only in one tumor type
Flow cytometry
Highly sensitive Non-detectable in physiological or
Cytogenetic analysis Fluorescent in-situ hybridization
benign disease states
Spectral karyotyping
Long lead-time Sufficient time for alteration of
natural course of disease Comparative genomic hybridization
Levels correlate with tumor Prognostic and predictive utility of Genetic analysis Sequencing (automated)
burden the tumor marker Reverse transcription
Short half-life Frequent serial monitoring of the Gel electrophoresis
marker levels after 5-6 half lives DNA micro-array analysis
Simple and cheap test Applicability as screening test Proteomics Surface-enhanced laser desorption/
Easily obtainable specimens Acceptability by target population Ionization

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 Sharma: Interpreting tumor markers in clinical practice

to picogram range (1026 to 1029 g). Of these, the most Table 4: Classification scheme for tumor
commonly used technique today is IHC. Uses of IHC markers[2]
in oncology include categorization of undifferentiated Category Subcategory Examples
malignant tumors, categorization  of leukemias and Oncofetal antigens AFP, CEA
lymphomas, determination of site of origin of metastatic Hormones Catecholamines,
tumors and detection of molecules of prognostic or Calcitonin, b-hCG
therapeutic significance (e.g., Estrogen/progesterone Glycoproteins CA 125, CA 15-3, CA
receptors (ER/PR) in breast cancer). [2,5- 7,10] 19-9, CA 72-4, PSA
Metabolites VMA, HIAA
Tumor-associated Viral antigens Polyoma, SV 40
Classification and uses antigens
MHC-related H-2 k antigen
Tumor markers can be detected either in tissue (tissue antigens
Enzymes PAP, NSE, PLAP
tumor markers; for example, in solid tumors, lymph nodes,
Oncogene products c-myc, c-erbB2
bone marrow or circulating tumor cells in the blood) or in
Cytogenetic Philadelphia
body fluids like ascitic or pleural fluid or serum (serological products chromosome
tumor markers).[9,10] Tissue tumor markers are of prime Tumor-associated Proteins Immunoglobulins,
importance to a diagnostic pathologist, while the serological markers b-2M
tumor markers are more often used by a clinician and will Enzymes Lactate
be discussed in more detail in this review. dehydrogenase,
alkaline phosphatase,
pteridines, pterines
Many classification schemes exist based on differences in Acute-phase C-reactive protein,
origin, structure, biological function or their relationship proteins ferritin
to the event in tumor growth or formation [Table 4].[1,11] Inflammatory ESR, viscosity
makers
Clinical application of tumor markers can be broadly Ultrastructural Intermediate Desmin, vimentin
components filament
classified into 4 groups: Screening and early detection, components
diagnostic confirmation, prognosis and prediction AFP: Alfa fetoprotein; CEA: Carcinoembryonic antigen; ESR: Erythrocyte
of therapeutic response and monitoring disease and sedimentation rate; HIAA: Hydroxy indole acetic acid; NSE: Neuron-specific enolase;
recurrence.[5,7,9,10] Some of the recommended uses of PAP: Prostatic acid phosphatase; PLAP: Placental alkaline phosphatase; PSA:
Prostate-specific antigen; SV: Simian virus; VMA: Vanillmandelic acid
tumor markers in routine clinical practice are summarized
in Table 5. Canadian Task Force,[29] American Association for Clinical
Chemistry,[1] etc., but the only tumor marker that finds a place
Although extremely appealing, the concept of screening a in any screening algorithm is prostate-specific antigen (PSA).
large apparently healthy population for occult tumors using
a tumor marker and thereby enabling early therapeutic Attempts to improve the sensitivity and/ or specificity
intervention is not currently possible because no test yet of tumor markers have led to combination of tumor
devised is 100 percent specific and many tumor markers markers with other procedures (e.g., combination of
may be elevated in benign conditions [Table 6].[2,7,10,11] Carbohydrate antigen (CA) 125 with ultrasonography for
early detection of ovarian malignancy) or to refining the
Importance and use of a particular tumor marker may evaluation criteria for tumor markers (e.g., PSA density
change depending upon the clinical scenario, ranging or PSA velocity or age-specific PSA cut off ranges for
from initial presentation to differential diagnosis to early detection of prostate cancer). However, these have
recurrence. [2] Thus, for example, while tissue tumor markers either not stood the rigorous evaluation of randomized
like Cytokeratin, smooth muscle antigen (SMA), etc., may trials or have still not received widespread approval of
be extremely useful in categorization of malignancy, they professional clinical organizations.[1,12-14]
are of no use in prognosis or monitoring; on the other
hand, markers like Ki-67 (proliferation index) may help in In addition to variable sensitivity and specificity of tumor
prognostication or choice of therapy but have no role in markers, the prevalence of a particular malignancy may be a
the diagnostic arena. major determinant in the application of a tumor marker as a
screening tool. A stark example of this effect is seen in China,
A large body of literatures exists on guidelines suggested for where serum alfa fetoprotein (AFP) has been successfully
clinical application in various malignancies by professional used as a screening tool for primary hepatoma in endemic
bodies like American Society of Clinical Oncology,[12,13] regions in contrast to its failure in rest of the world.[15]

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 Sharma: Interpreting tumor markers in clinical practice

Table 5: Common clinical uses of some tumor markers[2,5,9]

Malignancy Tumor marker (s) Tumor marker detection method Suggested roles
Adrenal carcinoma Steroids, Catecholamines Serology D
Breast CA 15-3, CA 27.29 Serology / Tissue IHC M, R
ER / PR / Her-2neu Tissue IHC RT
Carcinoid 5-HIAA Serology / Urine D
Colorectal, stomach, pancreas CEA, CA 19-9 Serology / Tissue IHC P, M
Choriocarcinoma b-hCG Serology / Tissue IHC D, P, M
Germ cell tumors AFP, b-hCG Serology / Tissue IHC D, P, M
LDH, PLAP (Seminoma) Serology P, M
Hepatoma AFP Serology / Tissue IHC S, D, P, M
Lymphomas LDH Serology D, P
Cytogenetic alterations Genetic analysis D
Melanoma Tyrosinase Serology D
Myeloma Immunoglobulins Serology D, P
Ovarian CA 125 Serology / Tissue IHC M, D, R
Prostate PSA Serology / Tissue IHC S, M, D, P
Sarcomas Cytogenetic alterations Genetic analysis D
Thyroid Thyroglobulin Serology / Tissue IHC S, M
Calcitonin (medullary carcinoma) Serology S, M, P
M 5 Monitoring; R 5 Recurrence; S 5 Screening; P 5 Prognosis; D 5 Diagnosis; RT 5 Response to therapy; AFP: Alfa fetoprotein; b-hCG: Beta human chorionic;
gonadotropin; CA: Carbohydrate antigen; CEA: Carcinoembryonic antigen; ER: Estrogen receptor; HIAA: Hydroxy indole acetic acid; LDH: Lactate dehydrogenase;
PLAP: Placental alkaline phosphatase; PR: Progesterone receptor; PSA: Prostate-specific antigen

benign conditions.[16] Another example is the role of

Table 6: Some benign conditions associated
with rise in tumor markers[2]
AFP in classification of germ cell tumors. Seminomatous
germ cell tumors are typically associated with increase
Marker Associated nonmalignant conditions
in Beta human chorionic gonadotropin (b-hCG) in 10%
AFP Viral hepatitis, liver injury, IBD, pregnancy
b-hCG Testicular failure, marijuana smokers, pregnancy
to 30% of cases, but an increased AFP level is never
CEA Smokers, IBD, hepatitis, cirrhosis, pancreatitis,
seen. A case of germ cell tumor with an elevated AFP
gastritis level is treated as a case of non-seminomatous variant
CA 125 Peritoneal irritation, endometriosis, pelvic irrespective of histopathological classification.[17] It is
inflammatory disease, hepatitis, pregnancy worth pointing out here that the use of tumor markers
PAP / PSA Prostatitis, benign prostatic hyperplasia in differential diagnosis is gaining more and more
AFP: Alfa fetoprotein; b-hCG: Beta human chorionic gonadotropin; acceptance for histopathological classification using
CA: Carbohydrate antigen; CEA: Carcinoembryonic antigen; IBD: Inflammatory
bowel disease; PAP: Prostatic acid phosphatase; PSA: Prostate-specific antigen tissue tumor markers.
Tumor marker levels, in certain situations, reflect tumor
By and large, tumor markers cannot be construed as burden in the body and hence can be used in staging,
primary modalities for the diagnosis of cancer, mainly prognostication or prediction of response to therapy.[5]
because of the lack of sufficiently high specificity Malignancies where serum tumor markers are included
and sensitivity. Their main utility in clinical medicine in the staging protocols include testicular germ cell
is as a laboratory test to support the diagnosis or in tumors (LDH, AFP, b-hCG)[18] and lymphoma (LDH). [19]
follow-up of patients being treated for malignancy.[10] Tumor marker levels can also be used to evaluate the
However, since the prevalence of disease is likely to response to therapy, although there may be an initial
be higher in diagnostic situations, tumor markers, in delay before the tumor marker levels register a decline
conjunction with other diagnostic modalities, are helpful following treatment. [5,20,21]
in differentiating between benign and malignant diseases.
A good example can be CA 125, which at levels more Monitoring disease, perhaps, constitutes the most
than 95 IU/mL, especially in postmenopausal women common clinical use of serum tumor markers.[5] Markers
with adnexal mass on radiological imaging, is virtually usually increase with progressive disease, decrease
confirmatory of ovarian malignancy. This may not with remission and do not change significantly with
be true in premenopausal ladies, wherein conditions stable disease. Tumor marker kinetics is generally more
like pelvic inflammatory disease, endometriosis, etc., important than individual values.[20,21] Rising tumor marker
represent examples of elevation of CA 125 levels in levels may detect recurrence of disease well before any

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 Sharma: Interpreting tumor markers in clinical practice

clinical or radiological evidence of disease is apparent Tumor marker kinetics should always be factored before
(“biochemical recurrence”). repeating the tests. Too frequent estimation of the tumor
marker may misrepresent the course of the disease due to
Determination of risk usually involves genetic probes distribution and elimination kinetics. As a general guideline,
or tools to evaluate any specific genetic abnormality or the time interval between serial determinations should
mutation noted to confer an increased risk of a particular be 3 months; but in case of an abnormal value, a repeat
malignancy. Examples of such abnormalities would include estimate can be ordered within 2 to 4 weeks irrespective
carriers of Philadelphia chromosome for hematological of the initial reading. The success of surgical removal of
malignancies; and BRCA 1 or 2 genes, which confer a a tumor as determined by tumor marker concentrations is
higher risk of breast or ovarian malignancies.[22] ideally ascertained after a period not less than 5-6 half-lives,
to allow tumor marker levels to make a plateau or fall to
Recommendations for ordering tumor marker normal. This period may be even longer in case of treatment
with chemotherapy or radiotherapy, wherein the therapeutic
tests
effects themselves are manifested after a lag period.[20,21]
It is imperative to remember that though an aggressive
Patient characteristics affect the tumor marker values to
investigative approach may be warranted on the basis of raised
a significant degree. The anticipated fall in levels may not
tumor marker values, treatment cannot be initiated without
be evident in situations where the metabolism or excretion
undisputable documentation (often histological) of the
of the tumor marker is altered, like in patients with renal
disease.[23] There may be instances such as initiation of therapy
or liver disease, depending on whether the tumor marker
on the basis of b-hCG levels in cases of choriocarcinoma,
is removed through glomerular filtration or metabolized
but these are few, exceptional and clearly defined.
by the liver. For example, serum CEA is often elevated
A single value or test is unreliable in itself.[6] It is noteworthy in patients with liver diseases because the metabolism of
that in most situations, elevations of markers in nonmalignant CEA by the diseased liver is subnormal. False tumor marker
elevation is also known to occur in other confounding
diseases are often transient, whereas elevations associated
situations like smoking, ethanol consumption, COPD,
with cancer either remain constant or continuously rise.
etc., especially if there has been a recent change in habits.[5]
Ordering serial testing can help detect falsely elevated
levels due to transient elevation. Establishing a diagnosis
Usually multiple tumor markers are associated with
on the basis of tumor markers (especially a single result) individual malignancy [Table 7]; vice versa, individual
is fraught with associated pitfalls because of the problem tumor markers may be associated with various malignancies
of nonspecificity.[24-31] [Table 8].[28] Thus the use of multiple markers based on
the combination pattern for the selected malignancy will
Knowledge of the assay method is important in improve sensitivity and specificity of the detection.[32,33]
interpretation of either an abnormal value or a serial change However, tumor markers that run parallel to each other,
in tumor marker values.[20,29,30] Various methods of detection when correlated with tumor behavior, should not be
have their own specific cut off values and sensitivities.[20,21] selected for this purpose.[32-34]
Thus, for any set of serial values to be meaningful, they
have to come from the same assay methods and preferably Nonspecific tumor markers are a good choice for
from the same laboratory. In certain situations of so-called monitoring disease activity. Although nonspecific tumor
biochemical recurrences, it is always useful to go back to markers, by definition, have a poor sensitivity, nevertheless
the laboratory to confirm this before beginning (at times) their concentrations are sensitive to any alterations in tumor
a frustrating search for the elusive recurrence. volume. They are usually inexpensive and simple to measure.
For example, lipid-associated sialic acid P (LASA-P) can be
It is imperative to be certain that the marker in question quantified with a simple, rapid and inexpensive calorimetric
was, in fact, elevated before relying on it for monitoring procedure, and its serum concentration is closely parallel
disease activity, the reason being that none of the tumor to the serum concentrations of many tumor markers of
markers are 100% sensitive (may not be elevated in some higher specificity in various malignancies.[34]
cases).[2,5,7,10] In tumors with multiple raised markers
measured prior to definitive therapy, the marker showing An important interfering factor to be considered before
highest elevation should be used for follow-up.[7,10] If in any interpretation is presence of a hook effect.[30] This
a given case, tumor markers were not evaluated in the is especially true if the value of a tumor marker does
pretreatment setting, it is advisable to use multiple markers not correlate to the clinical situation. Hook effect
for monitoring in the post-therapy setup.[5,7,10] is an inherent flaw of certain methods of detection

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 Sharma: Interpreting tumor markers in clinical practice

Table 7: Selected examples of malignant diseases with associated tumor markers[27]

Malignant disease Major marker Other markers
Bone cancer Alkaline phosphatase Bence Jones protein, serum calcium
Breast cancer CA 15-3 CEA, calcitonin, b-hCG, LASA-P, Prolactin
Carcinoid tumors Chromogranin A Histamine, ADH, Bradykinin
Cervical cancer SCC-A AG-4 antibodies, CA 125, CEA, TPA
Colorectal cancer CEA CA 19-5, CA 19-9, CA 72-4, CK-BB, NSE
Gastric carcinoma CA 72-4 CA 19-9, CA 50, CEA, ferritin, CK-BB, b-hCG, LASA-P, pepsinogen II, prothrombin
HCC AFP CEA, ferritin, ALP, g-glutamyl transpeptidase
Insulinoma Insulin C-peptide, IGF-1–binding protein
Leukemia TdT ALP, b2M, ferritin, LDH, myelin basic protein, adenosine deaminase, PNP
Lung cancer NSE ACTH, CK-BB, calcitonin, CA 72-4, CEA, AFP, ferritin, LASA-P, TPA
Lymphoma b2M TdT, Ki-67, LASA-P
Medullary thyroid cancer Calcitonin NSE
Multiple myeloma Immunoglobulin heavy and light chain Bence Jones protein, b2M, IgA
Non-seminomatous AFP b-hCG, LDH
testicular tumor
Ovarian carcinoma CA 125 Inhibin, AFP, CEA, CK-BB, b-hCG, galactosyl transferases, LDH, TPA
Pancreatic carcinoma CA 19-9 CA 19-5, CA 50, CA 72-4, CEA, CK-BB, ADH, ALP, g-glutamyl transpeptidase, PAP
Pheochromocytoma Metanephrine Chromogranin A, plasma catecholamines
Prostate carcinoma PSA PAP, ALP, CEA, CK-BB, TPA
RCC Rennin, erythropoietin, IL-4, prostaglandin A, VA 15-3, PTH, NSE, prolactin
ACTH: Adrenocorticotropic hormone; ADH: Antidiuretic hormone; AFP: Alfa fetoprotein; ALP: Alkaline phosphatase; b2M: Beta 2 microglobulin; CA: Carbohydrate antigen;
CEA: Carcinoembryonic antigen; CK-BB: Creatine kinase BB isoenzyme; HCC: Hepatocellular carcinoma; IGF-1: Insulin-like growth factor 1; IL: Interleukin; LASA-P: Lipid-
associated sialic acid P; LDH: Lactate dehydrogenase; NSE: Neuron-specific enolase; PAP: Prostatic acid phosphatase; PNP: Purine nucleoside phosphorylase; PSA: Prostate-
specific antigen; PTH: Parathyroid hormone; RCC: Renal cell carcinoma; SCC-A: Squamous cell carcinoma antigen; TdT: Terminal deoxynucleotidyl transferase; TPA: Tissue
polypeptide antigen

Table 8: Selected examples of serologic tumor markers and malignant diseases associated with
each[27]
Tumor marker Associated malignancy
Primary Other malignancies
Oncofetal antigens
AFP Primary HCC Teratoblastomas of the ovary and testes
CEA Colorectal carcinoma Various carcinomas
Hormones
b-hCG Choriocarcinoma Testicular cancers (non-seminomatous), trophoblastic tumors
Calcitonin Medullary carcinoma Cancer of the thyroid, liver cancer, renal cancer
Metanephrines Pheochromocytoma Neuroblastoma, ganglioneuromas
Chromogranin A Pheochromocytoma, neuroblastoma MEN, small-cell lung cancer, carcinoid tumors
IGF- 1 Pituitary cancer Insulinoma
Glycoproteins
CA 15-3 Breast cancer Various carcinomas
CA 19-9 Pancreatic and gastric carcinomas Various carcinomas
CA 72-4 Gastric carcinoma Various carcinomas
CA 125 Ovarian carcinoma Various carcinomas
Isoenzymes
PSA Prostate cancer
NSE Small-cell lung carcinoma Neuroblastoma, kidney tumors
Cellular components/products
LASA-P Various carcinomas, leukemia, lymphoma, Hodgkin’s disease
SCC-A Squamous cell carcinoma of the uterus, cervix, lung, and head and neck
TAG 72 Gastric carcinoma Colorectal, lung, pancreatic and ovarian cancers
Immunoglobulins Multiple myeloma Gammopathies
AFP: Alfa fetoprotein; b-hCG: Beta human chorionic gonadotropin; CA: Carbohydrate antigen; CEA: Carcinoembryonic antigen; HCC: Hepatocellular carcinoma; LASA-P: Lipid-
associated sialic acid P; MEN: Multiple endocrine neoplasia; NSE: Neuron-specific enolase; PSA: Prostate-specific antigen; SCC-A: Squamous cell carcinoma antigen

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(specifically immunoassay) due to which the serum tumor

Table 9: Ectopic tumor markers[27]
marker levels may be reported to be falsely low if the
Ectopic tumor marker Primary tumor site
concentration rises above a particular level.[30,35] Testing
AFP Gastrointestinal, renal, breast, bladder
the same sample at two separate dilutions (no dilution and and ovary carcinoma
1:10 dilution), if the clinical picture warrants, will detect Calcitonin Carcinoma of lung, islet cell, carcinoid,
this phenomenon. In the presence of a hook effect, the breast and ovary; medullary carcinoma;
10-fold diluted sample will yield a value that is higher pheochromocytoma
than the value from the original specimen extrapolated Chromogranin A For endocrine tumors (medullary thyroid
carcinoma, anterior pituitary adenoma,
to the same dilution. pancreatic islet-cell carcinoma)
b-hCG Gastric and pancreatic carcinomas,
Additionally, ectopic tumor markers can be a source of hepatoma, ovarian adenocarcinoma,
diagnostic dilemma.[28] Malignant cells, by definition, have germinal-cell tumors of the testis
lost inherent control of the synthetic and multiplicative Thyroglobulin WD thyroid carcinoma

machinery, and the cell becomes autonomous. Autonomic AFP: Alfa fetoprotein; b2M: Beta 2 microglobulin; WD: Well differentiated
expression of various unrelated genes (for the given tumor
tissue type) is the reason for the expression of ectopic Physiological influences that need to be considered in
tumor markers in advanced malignant diseases [Table 9]. interpreting the results include effects of aging and
Ectopic tumor markers denote dedifferentiation by menopause; metabolism and route-of-elimination kinetics
indicating activation of unrelated genes and, in other words, of the tumor marker; coexisting disease, like renal or
are associated with poorer prognosis or metastases. For liver failure; hormonal imbalances, like hyperthyroidism/
example, elevated levels of AFP may be detected in patients hypothyroidism; etc.[20,21] Life-style influences on tumor
with gastrointestinal tract malignancy with metastases to marker values include states like smoking (increases
liver, although the liver function tests may be normal. levels of CEA, AFP, etc.), alcoholism (altered liver and
renal parameters), obesity (hormonal imbalances, altered
Interpretation steroidal metabolism in peripheral fat), etc.

According to guidelines published by Working Group on CONCLUSIONS

Tumor Marker Criteria, interpretation should take into
account the therapy status of the patient.[36-38] The use of tumor markers in clinical oncology has increased
tremendously with rapid expansion of techniques of
If the patient is under active treatment or has received
treatment in the recent past, changes in marker levels detection and identification of new markers in recent times,
may reflect the clinical progression of the disease. Partial a trend that continues to grow as technology progresses
remission is defined as a decrease in marker levels by at least and our understanding about our body and the disease
50%; and progressive disease, as an increase in marker levels processes increases. However, such use is not without its
by at least 25%, on the basis of the concept that tumor pitfalls; in fact, injudicious application of tumor markers
load is related to changes in serum tumor marker levels. is fraught with risks of mistreatment (under-treatment or
over-treatment) and its consequences.
An important caveat put forth by this working group in the
use of tumor markers in monitoring response to therapy is Of the numerous tumor markers identified, described and
that “a complete remission cannot be determined by tumor marker levels, extensively researched upon, only a handful of them are
but if tumor marker levels are elevated, the clinical decision of complete used in routine clinical practice; and even of these, only
remission based on conventional methods should be considered incorrect a few have established consensus guidelines for use in
unless an explanation for the presence of an elevated level is given”.[37,38] day- to-day care of patients.

However, if no therapy has been given in the recent past, during With the explosion in the pool of knowledge, clinical
monitoring for a malignancy, a linear rise in three consecutive application of tumor markers in the field of oncology
samples (i.e., over a two time intervals) on a log scale should represents a classical example of “losing sight of the forest
be noted before a recurrence can be established. [37,38] Sampling for leaves of a tree.” It is indeed unfortunate that the
for tumor marker levels should ideally be repeated after 5-6 emphasis (in medical education, research and literature) has
half-lives of the marker in question (or the marker with the been on more and more extensive and in depth knowledge
longest half-life if multiple markers are being considered); of individual tumor markers, their pathophysiology, genetic
but if found elevated, the next sampling after 2-4 weeks, for origin, etc., rather than basic broad understanding and its
additional evidence, may be justified.[36] application in routine clinical practice.

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 Sharma: Interpreting tumor markers in clinical practice

Judicious application of tumor markers to clinical 17. Einhorn LH, Lowitz BB. Testicular Cancer. In: Casciato DA,
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8 Indian J Med Paediatr Oncol | Jan-Mar 2009 | Vol 30 | Issue 1