expressed at extremely low levels or not at all, so
that it is present in only trace concentrations in the
plasma. Its expression in cancers that have cells of
yolk sac lineage (germ cell tumors) or of hepatocyte
lineage (primary liver cancers) results in markedly
elevated plasma concentrations. Its specificity for
cancer is fairly high but increased plasma concentra-
tions are sometimes seen in conditions associated
with extensive hepatocellular injury, such as acute
viral hepatitis and liver metastases. Elevated plasma
concentrations can also be seen in cirrhosis,
presumably as a result of alpha-fetoprotein expres-
sion in regenerative hepatocytes.
Carcinoembryonic antigen (CEA) and prostate
specific antigen (PSA) are examples of marker
substances that are expressed at somewhat higher
than normal levels in certain cancers (Hammarström
1999, Stenman
et al.
1999, respectively). CEA is
an adhesive protein found in the glycocalyx of the
microvillar surface of intestinal cells. PSA is a
serine protease secreted by prostate epithelial cells
into seminal fluid. Both proteins are expressed in
mature tissue. They are normally present in low
concentration in the plasma, lower than expected
based on the level of expression of the proteins. The
probable reason for this is that, following epithelial
cell death, the majority of the released substance is
lost into the respective organ lumen, CEA into the
bowel lumen and PSA into the prostatic ducts, rather
than entering the local extracellular space where it is
available for lymphatic uptake.
Cancer cells express these marker substances at
higher than normal levels. This cellular over-
expression and the increased turnover typical of
cancer cells increase the plasma concentrations of
the substances. In addition, derangement of the
glandular architecture in cancer contributes to the
elevated plasma concentrations. Many of the glands
do not have ductular connections. All of the marker
substance released by cell turnover in such glands
enters the extracellular space, with no loss into a
lumen, and ends up contributing to the circulating
pool of the substance. The same is true of cancer
cells not forming glands. Because these marker
substances are expressed in normal tissue, their
plasma concentrations are increased in conditions
causing injury to the respective organs. For CEA,
injury to embryologically related organs that express
the substance at low levels, such as the pancreas, can
also elevate its plasma concentration. Benign prolif-
erative disorders also lead to increased marker
substance concentrations. Such behavior is charac-
teristic of all marker substances that depend upon
differential expression for their specificity. It is the
major limitation to the specificity of such marker
substances.
Hormones are also thought of as tumor markers
but they are generally not at all specific for cancer.
Cancers of the endocrine organs only infrequently
secrete hormones; hypersecretion of hormones
instead usually indicates benign disorders, either
hyperplasia or an adenoma. Calcitonin secretion by
medullary carcinoma of the thyroid is one exception
(Giuffrida and Gharib 1998). Calcitonin is secreted
by the thyroid C-cells, also called parafollicular
cells. Proliferative disorders of C-cells are rare in
the general population but are always present in
individuals with one of the familial C-cell syn-
dromes: multiple endocrine neoplasia types 2a,
multiple endocrine neoplasia types 2b, and familial
medullary carcinoma of the thyroid. In these syn-
dromes, C-cell disease is invariably malignant
(medullary carcinoma of the thyroid) or premalig-
nant (C-cell hyperplasia). Calcitonin hypersecretion
is usual in both malignant and premalignant disease
making plasma calcitonin a sensitive and specific
marker substance for C-cell cancer. Another hor-
mone that, outside of pregnancy, is specific for
cancer is
β
-chorionic gonadotropin which marks
choricarcinomatous elements in germ cell tumors
(Abelev and Eraiser 1999).
DIAGNOSIS
Markers of cancer are used in every aspect of
medical care for cancer (Hayes
et al.
1996). They
are employed in screening for cancer and are very
important in monitoring for post-therapeutic recur-
rence of disease. Markers have a lesser role in
establishing the diagnosis of cancer; because of its
superior reliability, pathologic examination is almost
always considered necessary for the diagnosis of
cancer. However, markers, especially cellular
markers, can be useful in supporting a microscopic
diagnosis of cancer, in elucidating the cellular
lineage of the cancer, and in classifying therapeutic
subgroups. Prognosis in cancer relates most directly
to tumor type and to anatomic markers of invasive-
ness and metastatic spread but considerable efforts
are currently being made, and some success has been
achieved, in identifying markers that aid in refining
prognostic classification.
Cancer
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