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CARCINOEMBRYONIC ANTIGEN

C 1ini cal Ajip 1i cat i o n


I'AYLIANC
W. Go, M D

Carcinoembryionic antigen (CEA) a glycoprotein extracted from colonic cancer


tissue (P-globulin electrophoretic mobility, sedimentation coefficient 7 to 8S, and
mol wt -200,000) can be detected and measured by radioimmunoassay. Clinical
evaluations of CEA determination have given the following results: In health:
(1) Serum CEA level is not influenced by sex, age, blood type, time of blood
sampling, or family history of cancer; (2) serum CEA level is influenced by a his-
tory of smoking or inflammatory disease of the bowel, lung, pancreas, and other
organs (occasionally, a CEA level as high as 10 ng/ml is noted); and (3) currently,
CEA positivity is defined as >2.5 ngiml, however, 5 ng/ml may be more realistic.
I n cancer: (1) CEA level may be increased in primary cancer of the gastroin-
testinal (GI) tract as well as in non-GI neoplasia; (2) the CEA test is not recom-
mended for screening to detect early cancer; (3) serum CEA level depends on
the stage of the neoplasia and usually is not influenced by the grade of differen-
tiation; and (4) markedly increased (>25 ng/ml) serum CEA values are highly
suggestive of metastatic cancer, particularly hepatic metastasis. I n biological
fluid: The CEA or CEA-like activity can be measured in gastrointestinal secre-
tions. Quantitative studies of CEA levels in such fluids may yield more informa-
tion than is obtainable from studies of serum. However, this possibility needs
more study at present. Therefore, the currently available CEA tests cannot re-
place any of the now standard diagnostic methods for cancer detection. This
use for assessment of therapy in selected patients or for following those known
to be at high risk for cancer appears promising in preliminary studies, but
clinical value, if any, remains to be determined.
Cancer 37:562-566, 1976.

I N1965, GOLDA N D FREEDMAN REPORTED THAT


carcinomas of the colon contained an anti-
gen that was absent from normal adult intesti-
nosis of colonic cancer. Subsequently, immu-
nochemicnl tests showed that this material
could be detected in the serum of patients
nal mucosa but was present in primitive ento- with gastrointestinal or nongastrointestinal
derm.1g.2" T h e authors named this material malignancy, in extracts from gastrointestinal
carcinoembryonic antigen (CEA) of the diges- a n d nongastrointestinal tumors, and in tissue
tive system. In 1969, Thomson et al. described extract? of the fetal gastrointestinal t r a ~ t . ~ J ~ $
a radioimmunoassay for CEA in serumBoand ~ 1 4 4 Recently several laboratories have re-

reported positive findings in 97yo of a series ported CEA immunoreactivity in urine,7,13.21


of patients with cancer of the colon. So CEA stool,l2 14 and intestinal secretionsl~l"~'~3"45of
was acclaimed in the medical and lay litera- cancer patients and of normals.
ture as a tumor-specific antigen whose detec- T w o coopeiative trials of the CEA test in
tion in the serum may be helpful in the diag- blood have been carried out in a number of
centers in the United States and Canada. T h e
Presented at the meeting of the ACS-NCI National National Cancer Institute of Canada and the
Conference on Advances in Cancel Management, Part
11: Detection and Diagnosis, Denver, CO, May 1-3, American Cancer Society sponsored a col-
1975. laborative study of CEA tests employinq the
From the Gastroenteiology Unit, Mayo Clinic and Thomson technique,25 while the Hoffmann-
Mayo Foundation, Rochester, Minnesota. LaRoche Company organized a trial utilizing
Supported by research giant CB 23854 from the
National Cancer Institute, National Institutes of
tlie Hansen technique.22 Through a contract
Health. awarded by the National Cancer Institute, we
Address for reprints: V. L. MI. Go, MD, Mayo Clinic, have carried out a prospective evaluation of
Rochester, M N 55901. CEA test5 in a clinical setting, using reagents
562
10970142, 1976, S1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197601)37:1+<562::AID-CNCR2820370721>3.0.CO;2-0 by Nat Prov Indonesia, Wiley Online Library on [04/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
No. 1 CARCINOEMBRYONIC
ANTIGEN - Go 563
kindly supplied by Dr. Hans Hansen, Hoff- or serum and their ways of separating free
mann-LaRoche Company. Over the last 30 from antibody-bound antigen. Some tech-
months, 6,700 patients have been entered into niques use either serum or plasma and some
the study. From our experience and that of use inta.ct serum o r plasma (direct assay),
others in such studies and in applying the whereas for others the test serum must be ex-
CEA test to b10od3.2"30.31,~~.*3,~~and to gastro- tracted first with perchloric acid (indirect as-
iritestinal1,15,17.",4~and urinary secretions,13.21 say). T h e reliability and comparability of the
I shall review the present status of this test. various methodologies were demonstrated in
a study organized by the National Cancer In-
stitute in which CEA levels of 94 blood speci-
PHYSICOCHEMICAL
PROPERTIES
OF CEA mens ohtained from different patients were
tested simultaneously by different 1a.borato-
Recent progress in elucidation of the physi-
ries, including those of Das, Go, Gold, Han-
cal and chemical properties of purified CEA
sen, LoCerfo, Mach, Martin, Reynoso, Todd,
has been reviewed extensively by Terry et al.38
and Zarncheck:"4 Correlations of 82 to 907;
CEA is a glycoprotein, extracted, and purified
from primary adenocarcinoma of the colon o r were obtained.
from colonic carcinoma metastasized to the
liver. Purified CEA has a molecular weight of CEA LEVELI N HEALTH
CIRCULATING AND
about 200,000, sedimentation coefficient of 7.0 BENIGNDISORDERS
to 8.OS, and beta-globulin electrophoretic mo-
T h e normal values for the different assays
hili ty. Electron microscopy has shown the
vary among laboratories. T h e Thomson assay
molecule to be of uniform size with a complex
and the CEA-Roche assay used the cut-off
secondary structure.6 It is soluble in I hl
point of 2.5 ng/ml; the Egan-Todd assay is
perchloric acid and in half-saturated ammo-
approximately 12.5 ng/ml; and other labora-
nium sulfate.
tories, including Mach and our laboratory,
Chemical analysis of purified CEA shows
use a cut-off point of 5 ng/ml. Therefore, the
approximately 50 to 65y0 carbohydrate, the
CEA result obtained by each laboratory
remainder being protein. T h e carbohydrate
should always be interpreted in comparison
portion of CEA contained fucose, mannose,
with tlie value obtained from normal controls
galactose, N-acetyl-glucosamine, sialic acid, and
tracer of N-acetyl-galactosamine. T h e charge using the same assay procedure.
heterogeneity of various CEA preparations T h e serum or plasma CEA level is influ-
enced by the history of cigarette smoking,
have been attributed, in part, to variations in
sialic acid content of the molecule. Amino tending to he higher in heavy smokers than in
acid sequencing of the protein backbone of nonsmokers.2') Elevated 'CEA levels between
CEA is not yet complete. However, the first 24 2.6 and 10 ng/ml and occasionally as high as
residues from the N-terminal of purified CEA, 10 ng/ml occur in many patients with a va-
obtained from liver metastasis or isolated riety of benign conditions including bron-
from serum of patients with advanced meta- chitis, inflammatory bowel disease, pancrea-
static colonic cancer, are identical.*' titis, cirrhosis, and pulmonary empliysetna.2~~~
x,21.2*.33.37 CEA positivity defined as greater
than 2.5 ng/ml is not helpful in the diagnosis
CE,\ RADIOIMMLINOASSAY METHOD of cancer, particularly if there is a history of
heavy smoking or any of the listed underlying
Several techniques for radioimmunoassay henign diseases.
to measure CEA have been described. The We have found that other factors-sex, age,
m a y measures inhibition of the binding of time of the clay when tlie blood sample was
known amounts of radiolabeled purified CEA drawn, and the presence or absence of family
to the specific antibody. T h e techniques used history of cancer-do not influence the CEA
most often are those originally described by level.";
Thornson et al.,5O by Hansen,31 and by Egan.11
Several modifications of these methods have CEA IN MALIGNANT
DISEASES
been validated.30e34~42 To date, the CEA-Roche
test is the only one approved by the FDA for CEA tests have limited sensitivity and speci-
clinical use. T h e assay techniques differ mostly ficity for cancer. T h e initial studies utilized
in their ways of extracting CEA from plasma cases of frank gastrointestinal cancer, many
10970142, 1976, S1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197601)37:1+<562::AID-CNCR2820370721>3.0.CO;2-0 by Nat Prov Indonesia, Wiley Online Library on [04/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
564 Janirory Supplement 197G
CANCER 1'01. 97
with metastasis; the CEA levels were higher Gerfo et al.,31J2 Reynoso et al.,23s43 Laurence
than 2.5 ng/ml in more than 75% of them. et > I I . , ~ O Mach et al.,3-' and Khoo and Macky.41
Subsequent prospective evaluations of CEA However, a drop of the CEA level to normal
tests in gastrointestinal malignancy, particu- after surgery does not always provide a good
larly in cancer of the colon, have shown that index of completeness of surgical excision, for
the CEA level varies with the stage of the can- in some cases the cancer recurs. I n a small
cer. Large proportions of patients with early number of cases the CEA level has fallen to
surgical and resectable colonic cancer have normal after surgical therapy but risen again
normal concentrations of circulating CEA. As during recurrence, perhaps before there was
the cancer spreads to adjacent organs or me- clinical evidence of recurrence. O u r experi-
tastasi7es distantly, the amount of circulating ence showed that during recurrence after 110-
CEA and the incidence of CEA positivity in- tentially curative resection the level of CEA
crease. Greatly increased serum CEA values depends o n the stage of the recurrent disease.
(> 25 ng/ml) are highly suggestive of meta- T h e CEA level is normal in localized recur-
static cancer, and particularly hepatic metas- rent disease, and a n elevated CEA level sug-
tasis. Similar patterns have been observed in gests regional and distant metastasis. Our data
cancer of the pancreas, stomach, lung, breast, suggest that serial determinations of serum
prostate, and other solid tumors. Therefore, CEA could indicate advances of recurrent can-
the use of CEA test alone for screening pur- cer in long-term follow-up of patients who had
poses is not recommended. At present, CEA undergone curative surgery and who have a
tests are useful as a diagnostic adjunct when normal postoperative CEA. However, i t must
cancer is suspected, but they cannot replace be made clear that i n those cases where CEA
any of the currently standard methods for can- increased, the tumor recurrence was readily
cer detection. A normal CEA level does not detectable by other means.42
preclude the presence of primary, metastatic, Serial CEA assays have been used for moni-
or recurrent cancer. toring cancer chemotherapy in patients with
Comparison of concentrations of circulating cancer of the colon, pancreas, stomach, biliary
CEA and other enzymes such as serum alkaline tract,*4-.J"4G breast,5?48 cervix, body of the
phosphatase, gamma-glutamyl transpeptidase, uterus, ovary,"fi.2' and lung,51 and in patients
lactate dehydrogenase, and other serum en- with neuroblastoma.4~ These studies have
zymes suggest that measurements of CEA and shown a fair correlation between effectiveness
enzyme concentrations were complementary to of cancer chemotherapy and serum CEA con-
each other in patients with primary and meta- centration, and our findings seem to confirm
static m a l i g n a n ~ i e s . l 8 . ~Similar
0 ~ ~ ~ findings were these general results. However, serial determi-
obtained from simultaneous measurements of nations of serum CEA must be interpreted in
CEA and other tumor-associated antigens such the clinical context, for we have noted that
as alpha-fetoprotein. I n our experience, when preterminally the CEA concentration may fall
alpha-fetoprotein and CEA were measured si- rather than rise and that patients whose orig-
multaneously, 54y0 of patients with gastric inal cancer produced no CEA may deteriorate
carcinoma had elevations of one or both, without producing any. Furthermore, various
whereas only 27% had elevated alplia-fetopro- cancer chemotherapy agents may alter the syn-
tein alone and 2 2 7 , had elevated CEA al0ne.3~ thesis and secretion of CEA without affecting
This suggests the possibility that measure- the progression of the neoplasia. It is in this
ments of CEA and other tumor-associated an- area of research that CEA assay as a biologic
tigens such as alpha-fetoprotein, human cho- marker for following cancer chemotherapy
rionic gonadotropin, or Regan isoenzymes may prove fruitful.
and other enzymes might increase significantly
our ability to detect advanced gastrointestinal CEA-LIKEACTIVITY
I N SECRETIONS
cancer.
CEA or CEA-like activities have been de-
CEA AS MARKERFOR CANCER
BIOLOGIC tected by various immunologic tests in saliva,
THERAPY gastrointestinal secretion, feces, urine, bron-
chial washings, and other biologic fluids and
Thomson, Gold et al. first reported five secretions of different organ sy~tems.l,7.1"1~,~~.
cases of colonic cancer with elevated CEA 1 5 ~ 7 . 2 1 . 3 5 . 3 6 ~ 4With
5 use of several intestinal per-
levels that declined to normal in three cases fusion techniques, we recently have quantified
after complete resection of the cancer. Such the secretion of CEA-like activity in the gastro-
a response was confirmed by Dhar et al.,'" L o intestinal tract of healthy human subjects.
10970142, 1976, S1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197601)37:1+<562::AID-CNCR2820370721>3.0.CO;2-0 by Nat Prov Indonesia, Wiley Online Library on [04/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
No. 1 CARCINOEMBRYONIC
ANTIGEN - Go 565
T h e secretory rate was highest in colonic se- end.5' I n pancreatic secretion, we found that
cretion, arid next highest in pancreatico-biliary CEA output does not differentiate patients
secretion.17 T h e CEA-like material extracted with pancreatic disease from healthy persons;
from normal human saliva, normal gastroin- yet one-third of patients with pancreatic can-
testinal secretion, and feces has chromato- cer and 20% of those with chronic pancreatitis
graphic and immunologic properties similar had increased outputs of CEA in response to
to those of purified CEA extracted from liver cholecystokinin stimulation.9 Hall and co-
tissue containing metastatic cancer of the workers found abnormal urinary CEA values
colon. Whether this immunoreactive CEA ma- in two-thirds of their patients with active
terial is chemically the same as purified CEA bladder cancer.tl We have confirmed their ob-
needs further study. servations and further noted that the fre-
It has been suggested that studies of CEA-
quency of abnormal CEA values correlated
like activity in fluid secreted by hollow vis-
with the extent and grade of the tumor. How-
cera such as the gastrointestinal tract, lung,
and urinary bladder might lead to improve- ever, urinary tract infection can produce ab-
ment in early detection of cancer. Winawer normal CEA values in patients without can-
found that the CEA concentration in colonic cer.
lavage specimens from 38 patients ranged These and 0therf5-36,~gvarious preliminary
from 0 to 4450 ng/mg protein.5' Patients with results suggest that measurement of CEA-like
cancer and polyps were at the higher end of activities may have some diagnostic value.
the range, patients with ulcerative colitis in- However, its ultimate clinical application re-
termediate, and normal subjects at the lower mains to be determined.
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Jnnzinry Supplement 1976 Vol. 37
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