Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 25 Tumor Markers
commonly used in veterinary medicine, have been rigorously
tested. To determine whether a candidate tumor marker has
clinical utility, it is vital that it undergo critical evaluation. In
evidence-based medicine, there are several criteria for interpreting
the usefulness of a diagnostic test ( Jaeschke et al. ,
2002 ). First, it should be useful for situations or cases where
clinicians routinely face diagnostic uncertainty. For example,
the diagnostic evaluation of hematuria in an older dog
is one situation in which an effective tumor marker would
be highly useful. Second, candidate tumor markers should
be blindly evaluated against an independent “ gold standard ”
diagnostic test in cancer patients, sick noncancer patients,
and healthy patients. Only after the usefulness of a tumor
marker has been established can clinicians begin to determine
how effectively the test result and its interpretation will
improve patient management. The likelihood ratio ( Letelier
et al. , 2002 ) is one tool that can help clinicians interpret
and apply test results, and it may be useful to apply to veterinary
tumor markers. Briefly, the clinician must have an
idea about the patient’s probability for having cancer based
on signalment, history, physical findings, and other factors
before tumor marker testing. Given knowledge of the likelihood
of a high test value occurring in a patient with cancer
compared to the likelihood of a high test value occurring in
a patient suspected of cancer that was later ruled out, it is
possible to calculate the posttest probability for the patient
having cancer given a high, low, or intermediate test result.
For the interested reader, the Evidence-Based Medicine
Working Group has detailed the critical evaluation of diagnostic
tests, results interpretation, and application to clinical
patients ( Users ’ Guide to the Medical Literature: A Manual
for Evidence-Based Clinical Practice, 2002) .
Historically, using a broad definition, veterinary tumor
markers have included various molecules found in serum,
flow cytometry, proliferation and apoptosis markers, immunohistochemistry,
cytochemistry, and cytogeneticis. With
the advent of new technologies, molecular markers of cancer
will become more important in human and veterinary
oncology. Likewise, the explosion of the “ -omics, ” including
genomics, proteomics, and metabolomics, may also be
important to the diagnosis and management of cancer in the
future. Each of these issues will be considered in turn.
II. SERUM TUMOR MARKERS
A. Oncofetal Proteins
Oncofetal proteins originate within tumor cells and enter
the bloodstream either by secretion from the tumor or as a
breakdown product of tumor cells. Normally oncofetal proteins
are present during embryogenesis and may increase
with certain cancers, making them potentially useful tumor
markers. Carcinoembryonic antigen (CEA ) and alpha-fetoprotein
(AFP ) are the most widely used oncofetal protein
tumor markers ( Garrett and Kurtz, 1986 ). CEA has been well
studied in human medicine, and since the 1970s it has been
recognized as a useful marker for cancers of the lung, colonrectum,
breast, ovary, and prostate gland ( Go, 1976 ). CEA
is the most useful tumor marker to distinguish benign from
malignant pleural effusions ( Shirit et al. , 2005 ). Preoperative
serum CEA levels may also predict survival in human
colorectal cancer patients ( Park et al. , 2005 ). In veterinary
medicine, CEA has received little attention, and its role as a
tumor marker in domestic animal species remains undefined.
In humans, AFP is commonly used to diagnose hepatocellular
carcinoma and predict its prognosis ( Zhou et al. ,
2006 ). AFP has been measured in the serum of cancerbearing
dogs ( Hahn and Richardson, 1995 ). However, in
this report, the mean serum concentration of AFP in dogs
with various malignancies was not significantly different
from the mean serum AFP concentration of the 16 dogs
without cancer. A single dog with hepatic involvement
with lymphoma had a serum AFP concentration 225 ng /
ml, suggesting AFP may have a role for diagnosing primary
or secondary hepatic cancer in the absence of other
serum biochemical abnormalities. Indeed high serum concentrations
( 250 ng/ml) of AFP have been detected in a
small number of dogs with primary liver tumors ( Lowseth
et al. , 1991 ). Because serum AFP concentration is higher
in canine hepatocellular carcinoma compared to other
hepatic diseases, it may be a useful tool for diagnosing
hepatocellular carcinoma in dogs ( Yamada et al. , 1999 ).
In a study of serum AFP concentrations in healthy dogs
and dogs with multicentric lymphoma ( Lechowski et al. ,
2002 ), the mean serum AFP concentration was higher in
dogs with lymphoma compared to the healthy dogs. Serum
AFP concentration was also found to increase with advancing
clinical stage of lymphoma, and decrease to levels
similar to normal dogs as the lymphoma went into remission
with chemotherapy. These observations suggest serum
AFP may be a useful biomarker for determining lymphoma
remission in the dog and potentially an early indicator of
relapse. Serum AFP has not been carefully evaluated as a
tumor marker in other domestic species.
B. Hormones and Ectopic Hormones
1 . Inhibin
Inhibin is a nonsteroidal hormone that is involved in the
follicular phase of the human menstrual cycle ( Groome
et al. , 1996 ). Inhibin has also been identified as a regulatory
hormone in the follicular phase of the equine estrous cycle
( Medan et al. , 2004 ). Serum inhibin concentrations have
been shown to be elevated in mares with granulosa theca
cell tumors (GTCT) ( Christman et al. , 1999 ). Measuring
inhibin concentrations can be helpful in diagnosing equine
GTCT, especially if serum testosterone concentrations are
not elevated, and distinguishing GTCT from other diseases
of the ovary. Increased serum inhibin concentrations have