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2073
Lymphocyte Subpopulations in Patients with Multiple
Primary Tumors
Eliezer Robinson, M.D.1
Ruth Segal, B.Sc.1
Lily Struminger, M.Sc.1
David Faraggi, Ph.D.1
Ruchama El’ad-Yarum,
Tamar Mekori, Ph.D.1
BACKGROUND. Cancer patients with single tumors live longer today due to earlier
2
B.Sc.
1
Northern Israel Oncology Center, Rambam Medical Center and Faculty of Medicine, TechnionIsrael Institute of Technology, Haifa, Israel.
2
University of Haifa, Haifa, Israel.
detection and improved treatment methods. For this reason, the authors see more
patients who develop a second primary tumor. The etiology of the second tumor
can be the same as the first, whether treatment-induced or unknown. The prognoses of these patients usually depend on the behavior of the second tumor.
METHODS. The authors investigated the lymphocyte subset in 88 of the more than
750 patients listed in the tumor registry at their treatment center who had at least
one carcinoma of the breast or colon and a second primary of the same or another
site. Mononuclear cells were obtained from heparinized blood by the standard
fractionation Hypaque gradient centrifugation technique. Helper and suppressor
cells were identified by using three murine monoclonal antibodies: CD3 for mature
T lymphocytes, CD4 for helper inducer cells, and CD8 for suppressor cytotoxic
cells. T-cell subset distribution was evaluated with flow cytometry.
RESULTS. Most values of CD3, CD4, and CD4/CD8 were lower in patients than in
healthy controls. The values of CD4 and CD4/CD8 were lower in patients who had
a second tumor in the colon rather than in the breast.
CONCLUSIONS. As tumors in patients with a second primary sometimes recur or the
patient develops a third primary, the authors are prospectively following their
patients to see whether those with immunosuppression have a greater tendency to
develop recurrent disease or a third primary. Cancer 1999;85:2073– 6.
© 1999 American Cancer Society.
KEYWORDS: lymphocyte subsets, lymphocyte subpopulation, multiple primary tumors, second primary tumor.
C
The authors thank Mrs. M. Perlmutter for her
assistance in the preparation of this article.
Address for reprints: Eliezer Robinson, M.D.,
Northern Israel Oncology Center, Rambam Medical
Center, P.O. Box 3595, Haifa 31034, Israel.
Received February 1, 1999; accepted February 4,
1999.
© 1999 American Cancer Society
ancer patients with single tumors live longer today due to earlier
detection and improved treatment methods. For this reason, we
see more patients who develop a second primary tumor. The etiology
of the second tumor can be the same as the first, whether treatmentinduced or unknown. The prognosis of these patients usually depends
on the behavior of the second tumor. Many authors, including us,
have reported on the immune status of cancer patients and its relation to the prognosis.1–3 We have a multiple primary tumor registry at
our treatment center that contains over 750 patients. In this study, we
investigated the lymphocyte subset in 88 of these patients with at
least 1 breast or colon carcinoma and a second primary at the same
or another site.
PATIENTS AND METHODS
Patient Characteristics
Fifty-two patients with breast carcinoma and 36 with colon carcinoma who had a metachronous second primary solid tumor, according to the definition of Warren and Gates, at the same site or at
2074
CANCER May 1, 1999 / Volume 85 / Number 9
another site were included in this study. Twenty-one
patients had breast carcinoma as a first primary tumor
and another tumor as a second primary (br1x). Fourteen patients had the first tumor at any site and breast
carcinoma as the second one (x1br). Twenty-nine
patients had bilateral breast tumors (br1br) and 16
had a single breast tumor (br). The mean age (6
standard deviation) of the healthy controls was 39.8 6
10 years, of the patients with single breast carcinoma
60.8 6 19 years, and of the patients with multiple
primaries 67.0 6 9 years. Twelve patients had colon
carcinoma and a second primary tumor at another site
(col1x). In 19 patients, colon carcinoma was the second tumor (x1col), and 5 patients had two primaries
in the colon (col1col). (Eight patients had br1col and
four had col1br; these were included in the abovenoted numbers.) Ten men and 20 women served as
controls. All patients registered in the tumor registry at
least 1 year before the diagnosis of the second tumor
were included. Patients were diagnosed at least 1 year
before the test was performed. Most patients had had
prior chemotherapy and/or radiotherapy. Blood was
taken after informed consent was obtained.
TABLE 1
Comparison of T-Cell Subsets in Cancer Patients and Healthy
Controls
Group
No. of patients
Mean 6 SD
Median
CD3
Healthy controls
At least one breast tumor
At least one colon tumor
30
52
34
70.03 6 14.61
60.78 6 18.67
59.80 6 18.95
CD4
Healthy controls
At least one breast tumor
At least one colon tumor
30
52
36
51 6 13.53
51.46c
44.83 6 20.14
41.76d
35.43 6 13.79
38.00c,d
CD4/CD8
Healthy controls
At least one breast tumor
At least one colon tumor
30
52
36
1.41 6 0.61
1.17 6 0.7
0.91 6 0.46
73.82a,b
61.45a
65.18b
1.42e,f
0.99e
0.80f
The groups with the same indices indicate that they differ significantly (a 5 0.05).
a
P 5 0.0214.
b
P 5 0.0242.
c
P 5 0.0001.
d
P 5 0.0407.
e
P 5 0.0222.
f
P 5 0.0001.
Methods
Twenty mL of heparinized blood was drawn from each
donor. The test was carried out as described by Reinherz et al.4 Mononuclear cells were obtained by the
standard fractionation Hypaque gradient centrifugation technique. Helper and suppressor cells were
identified by using three murine monoclonal antibodies (Ortho Pharmaceuticals, Raritan, NJ): CD3 for mature T lymphocytes; CD4 for helper inducer cells, and
CD8 for suppressor cytotoxic (method described previously5). The appropriate monoclonal antibody was
added to aliquots of 1–2 3 106 cells and the cells were
stained by an immune fluorescent technique using a
fluorescein-labeled goat antimouse: immunoglobulin
(Ig)G fluorescein isothiocyanate– conjugated goat antimouse IgG antibody (Tago Inc., Burlingame, CA).5
T-cell subsets distribution was evaluated using the
flow cytometer (FacScan, Becton-Dickinson, San
Jose, CA).
Statistical Evaluation
The Wilcoxon test was used to evaluate the differences
between pairs of means. For a comparison of three or
more means, the Kruskal–Wallis test was used.6
RESULTS
The T-cell subsets for healthy controls and patients
are shown in Table 1. The values of CD3 were statistically significantly lower in patients as compared with
healthy controls (P 5 0.01).
CD4 was found to be significantly higher in patients with at least one breast carcinoma than in patients with at least one colon carcinoma (44.83 6 20.14
vs. 35.43 6 13.79; P , 0.0407) (Table 1). CD4 was also
significantly higher in the x1br group than in the
x1col group (44.15 6 12.68 vs. 34.40 6 14.19; P ,
0.0432) (Table 2). In the group with bilateral breast
tumors, CD4 was significantly higher as compared
with the patients with two primaries in the colon
(47.71 6 21.10 vs. 28.24 6 17.15; P , 0.0239). CD4 was
significantly lower in these patients than in controls
(P 5 0.004) (Table 2).
The CD4/CD8 ratio was lowest in patients with at
least one colon carcinoma and statistically significantly higher in patients with at least one breast carcinoma, but still significantly lower than in healthy
controls (Table 1). It was found to be significantly
higher in x1br as compared with x1col (1.14 6 0.39
vs. 0.88 6 0.48; P , 0.0376). It was significantly lower
in patients with br1x as compared with normal controls (P 5 0.0014) or patients with a single breast
carcinoma (P 5 0.0046). The CD4/CD8 values of patients with x1br were significantly higher than those
with br1x (P 5 0.0450). The values obtained for patients with x1col or col1col were significantly lower
when compared with those for controls (P 5 0.0004
and 0.0077) (Table 2). The ratio of CD4/CD8 was
higher in br1br groups than in those with two primaries in the colon (1.3 6 0.75 vs. 0.72 6 0.26), but the
Lymphocyte Subpopulations/Robinson et al.
2075
TABLE 2
The Values of CD4, CD8, and CD4/CD8 Ratio in Patients with Breast Carcinoma, Patients with Colon Carcinoma, and Healthy Controls
CD4
CD8
CD4/CD8
Group
No.
Mean 6 SD
Median
Mean 6 SD
Median
Mean 6 SD
Median
Healthy controls
Single breast
Breast 1 x
x 1 breast
Bilateral breast
Colon 1 x
x 1 colon
Colon 1 colon
30
16
21
14
29
12
19
5
51.00 6 13.53
45.84 6 16.04
39.33 6 20.01
44.15 6 12.68
47.71 6 21.10
40.04 6 10.95
34.40 6 14.19
28.24 6 17.15
51.46e
44.90
36.00
43.50a
40.98b
47.70
31.80a,c
26.12b
40.20 6 16.03
33.75 6 13.95
45.34 6 21.98
40.57 6 11.77
39.95 6 15.74
45.21 6 18.64
42.27 6 16.76
39.73 6 21.54
36.24
36.00
37.40
40.89
39.40
39.91
37.88
29.90
1.41 6 0.61
1.41 6 0.62
1.00 6 0.70
1.14 6 0.39
1.30 6 0.75
1.03 6 0.50
0.88 6 0.48
0.72 6 0.26
1.42f,h,i
1.20d
0.80d,e,f
1.11e,g
1.06
0.96
0.80g,h
0.73i
SD: standard deviation.
The groups with the same indices indicate that they differ significantly [a 5 0.05].
a
P 5 0.0432.
b
P 5 0.0239.
c
P 5 0.0004.
d
P 5 0.0046.
e
P 5 0.0450.
f
P 5 0.0014.
g
P 5 0.0376.
h
P 5 0.0004.
i
P 5 0.0077.
difference was not statistically significant (P , 0.09)
due to the small size of the group in col1col (5 patients only). No significant difference was found when
comparing br1x with those with col1x (Table 2).
There was no significant difference in the CD8 cell
subset among patients with multiple primary tumors
and between each group of patients and healthy controls.
DISCUSSION
One hundred four patients with breast or colon carcinoma were included in the study, 88 of whom had 2
metachronous primary tumors (1 of which was in the
breast or colon) and 16 of whom had single breast (SB)
carcinomas. Studying all patients together, we found
that the CD3, CD4, and CD4/CD8 ratios were significantly lower in patients than in healthy controls (HC).
We could not rule out the possibility that the difference between normal controls and patients was due
to the younger age of the patients. When the patients were divided into seven subgroups according to
the site of the tumor, a significant difference was
found in CD4 between col1x and controls. In the
CD4/CD8 ratios, the following six significant differences were found: HC.br1x; SB.br1x; x1br.br1x;
x1br.x1col; HC.x1col; HC.col1col.
Reviewing the literature, we found few studies on
lymphocyte subsets in patients with single tumors.
The mean CD4/CD8 mean helper suppressor ratio
was significantly lower in patients with metastatic
breast carcinoma as compared with that observed either in controls or in patients without metastasis. The
results of this study suggest that a decrease in CD4/
CD8 ratios in patients with metastatic disease is due to
a decrease in T helper cells.7 In breast carcinoma
patients without relapse, increased CD4/CD8 ratios
were found as compared with patients who had a
relapse.8 Patients without axillary lymph node involvement had a higher CD4/CD8 ratio than patients with
axillary metastases.9 Patients with metastatic cancer
treated with a cancer vaccine (ASI) showed an increase in CD4 cells on improved survival.10 Breast
carcinoma patients treated with tamoxifen showed an
increase in CD4/CD8 lymphocyte subsets as compared with a control group not receiving this treatment. It seems that tamoxifen helps in the recovery of
lymphocyte populations decreased by radiotherapy.11
In patients with breast carcinoma who had lymph
node involvement or distant metastases, the average
CD4/CD8 values were lower than in patients without
metastases (difference not significant).12 In a proportion of patients with renal cell carcinoma, interferon
seemed to influence the host immune system, resulting in increased CD4/CD8 ratios concomitant with
tumor regression.13 In patients with cervical carcinoma, it was found that low CD4 cell counts and
CD4/CD8 ratios were characteristic of patients who
2076
CANCER May 1, 1999 / Volume 85 / Number 9
had recurrent disease as compared with those who did
not.14
We did not find any references to the lymphocyte
subsets in patients with multiple primary tumors, but
it is clear that these patients have an immune suppression similar to that of patients with single tumors,
and of an even greater degree. It seems also that, in
patients who have colon carcinoma as a second tumor, the immunosuppression is greater than in patients with breast carcinoma as a second primary. The
CD4/CD8 was also higher in patients with a second
primary in the breast and the first elsewhere as compared with the reverse. This was also in accordance
with the better prognosis of the first group. Of course,
we could not rule out the possibility that this was due
to other causes.
As tumors in patients with a second primary
sometimes recur or the patient develops a third primary, we are prospectively following the patients to
see whether those with immunosuppression have a
greater tendency to develop recurrent disease or a
third primary.
In conclusion, lymphocyte subsets were studied
in 88 patients with two metachronous tumors and
compared with those of healthy controls and patients
with a single breast carcinoma. Most values of CD3,
CD4, and CD4/CD8 were lower in patients than in
healthy controls. The values of CD4 and CD4/CD8
were lower in patients who had a second tumor in the
colon rather than in the breast.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
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