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Journal
of Clinical
Endocrinology
and Metabolism
Copyright
0 1996 by The Endocrine
Society
Vol. 81, No. 3
Printed
in U.S.A.
A Direct Relationship
Breast Cancer*
P. P. A. SMYTH,
J. G. GERAGHTY,
Endocrine
University
between
Thyroid
D. F. SMITH,
E. W. M. MCDERMOTT,
AND N. J. O’HIGGINS
Laboratory,
Departments
College, Dublin, Ireland
of Medicine
and Therapeutics
Enlargement
and
M. J. MURRAY,
and Surgery,
St. Vincent’s
Hospital,
ABSTRACT
Despite extensive
study, evidence
to support
a direct relationship
between
diseases of the thyroid
and breast has not been established.
In this study thyroid
volume
was assessed
by ultrasound
in 200
patients
with breast cancer and 354 with benign breast disease. Results were compared
to appropriate
female control groups. Both mean
thyroid
volume
(21.1 2 1.4 mL) and the percentage
of individual
patients
with enlarged
(>18.0
mL) thyroid
glands (41.5%)
were significantly
greater
in the breast cancer group than equivalent
values
(13.2 + 0.5 mL and 10.5%, respectively)
in age-matched
controls
(I’ < 0.01 in both cases). The mean thyroid
volume of 14.5 t 0.34 mL
in patients
with benign breast disease was also significantly
greater
than that of 12.5 + 0.38 mL in younger
controls (P < 0.01). The results
support
a direct
association
between
breast
cancer and increased
thyroid
volume
as mean thyroid
volumes
and the percentage
of individual
patients
with enlarged
thyroid
glands were similar
in those
studied both before (20.8 2 1.3 mL and 43.0%) and after (21.4 2 1.6
mL and 40.0%)
therapies
for breast
cancer.
Although
there is no
evidence
that thyroid
enlargement
represents
a risk factor for breast
cancer, the results emphasize
the importance
ofraising
the consciousness ofthe coincidence
ofboth
disorders.
(J Clin Endocrinol
Metab 81:
937-941,
1996)
S
Selection
INCE THE report of Beatson (1) on the use of oophorectomy and thyroid extract in the treatment of breast
cancer, many studies have shown a range of associations
between the two disorders. Associations of breast cancer
with hypothyroidism (2-5), T, replacement therapy (6), hyperthyroidism (7,8), and thyroiditis (9) have been reported,
whereas no significant relationship has been observed by
others (10-14). Increased breast cancer incidence in areasof
endemic goiter have been reported (15-l@, but no change
occurred when goiter rate decreasedafter iodine prophylaxis
(4, 8). Finally, an increased breast cancer mortality was reported by Goldman et al. (19) in patients who had nontoxic
nodular goiter and were receiving T, suppression therapy.
Thus, the significance of the simultaneous occurrence of thyroid diseaseand breast cancer remains to be elucidated. The
objective of the present study was to investigate whether the
availability of high resolution diagnostic ultrasound could
permit the detection in patients with breast cancer of more
subtle changes in thyroid volume.
Selection
Patients
St. Vincent’s
Subjects
of patients
under
study
were
Hospital
(Dublin,
a specialist
breast
clinic
The control populations
consist of women
participating
in a health
screening
program
carried
out at University
College Dublin,
during
1988/1989.
Those with a history
of breast disease were excluded
from
the study. Age matching
was achieved
by selecting
from the control
populations
only those patients whose ages fell within the age ranges of
patient
groups. Subjects were not matched
for height or body weight.
Both patient and control groups came from the same catchment
area and
represented
a reasonable
cross-section
of an adult female urban/rural
population
of varied socioeconomic
status.
Coincidence
of breast and thyroid
disease
Patients and controls were assessed for both breast and thyroid
disease by the same surgical
team, and any history
of previous
thyroid
disease was recorded.
Where such a history
was present, classification
as hyperthyroidism,
hypothyroidism,
or nontoxic
goiter was made on
the basis of the original
diagnosis.
Breast
cancer
Two hundred
consecutive
patients, aged 28-89 yr (mean 2 SE, 57.2
2 1.4 yr; median, 57 yr) had thyroid
scans over a 5-yr period (19881993).
Histological
classification
of breast cancers was made in the Department
of Pathology,
St. Vincent’s
Hospital
(Dublin,
Ireland).
Information
on
histologically
measured
tumor size made according
to Union Internationale Contre le Cancer criteria was available
for 191 patients; 7 were
classified TO (not palpable),
57 Tl (c2.0 cm), 94 T2 (2.0-5.0 cm), and 33
T3 or T4 (>5.0 cm). One hundred
were studied retrospectively,
in that
they had received
both surgical and medical
therapy
before being subjected to thyroid
ultrasound
scans. The remaining
100 patients, termed
the prospective
group, had thyroid
scans at the time of excision biopsy
before the diagnosis
of breast malignancy.
and Methods
attending
Ireland).
of controls
at
Received July 21,1995. Revision received October
25,1995. Accepted
November
2, 1995.
Address all correspondence
and requests for reprints
to: Dr. P. P. A.
Smyth, Endocrine
Laboratory,
Department
of Medicine
and Therapeutics, Woodview,
University
College Dublin,
Dublin 4, Ireland.
* Presented
in part at the American
Thyroid
Association
Meeting,
Boston,
MA, September
11-15, 1991, and at the European
Thyroid
Association
Clinical
Symposium:
The Female Thyroid
In Health
and
Disease, Dublin, Ireland, June 20-25,1992.
This work was supported
by
the Royal College of Surgeons
in Ireland Research Committee.
Older
controls
Two hundred
0.67 yr; median,
937
nonhospitalized
52 yr) served
women,
as controls
aged 22-84 yr (mean, 53.0 ?
for the breast cancer group.
SMYI’H ET AL.
938
Benign
breast disease (BBD)
Thyroid
This group consisted of 354 patients,
aged 16-50 yr (mean, 37.1 Z 0.5
yr; median,
36 yr), with either clinical
evidence
of fibrocystic
breast
disease or clinical and histological
evidence
of fibroadenoma.
Younger
controls
One hundred
and twenty-four
nonhospitalized
premenopausal
volunteers, aged 16-44 yr (mean, 34.0 f 0.47 yr; median, 34 yr), without
a history
of breast disease served as controls for the BBD group.
Urinary
iodine
studies
Spot urine specimens
were obtained
from 1063 nonhospitalized
patients attending
the breast clinic at St. Vincent’s
Hospital
(Dublin,
Ireland) and from 60 female controls
without
evidence
of breast disease
attending
the health screening
clinic.
Thyroid
ultrasound
scans were performed
using a scanner fitted with
a hand-held
7.5.mHz
linear transducer
(Siemens SL-1, Darmstadt,
Germany).
All scans were performed
by the same observer.
The sonographer was not blinded
as to control and breast disease study groups.
However,
within
the breast cancer group,
100 patients
were studied
prospectively
at the time of excision biopsy when the diagnosis
was
unknown
to all, including
the sonographer.
The coefficient
of variation
for thyroid
volume
measurement
at a volume
of 12.0 mL was 10.0%.
Repeat thyroid
volumes
were judged to be unchanged
if they differed
by 0.5 mL or less. The volume
of each lobe was calculated
according
to
the formula
(W X D X L X 0.479) (20). The upper limit for normal thyroid
volume
in an iodine-sufficient
nonendemic
goitrous
area (18.0 mL for
adult females) (21) was used in this study. Thyroid volumes greater than
18.0 mL were termed
enlarged.
Serum T,, T,, TSH, and PRL were estimated
by immunoassay
using
an IMX analyzer
(Abbott
Laboratories
Diagnostic
Division,
Dublin
Ireland Ltd.).
Urinary
iodine was measured
in spot samples by alkaline
ashing at
approximately
600 C using a muffle
furnace
fitted with a microchip
temperature
control. Iodide was quantified
in the Sandell Kolthoff
re-
action. Results were expressed as micrograms of iodine per L urine.
Statistical
analysis
Results were
[chil’ test.
Prevalence
analyzed
of thyroid
The prevalence
past and present
using
Student’s
t, Wilcoxon’s
rank
sum,
or
Results
disorders
in the study groups of thyroid disorders
are shown in Table 1. There was no sig-
nificant difference in the prevalence of hyperthyroidism and
hypothyroidism between either of the breast diseasegroups
and appropriate control groups. However, the frequency of
nontoxic goiter was greater in both the breast cancer and the
BBD groups
than in the controls
(P < 0.01 and P < 0.025,
respectively).
TABLE
1. Prevalence
of thyroid
disorders
in groups of patients
with breast cancer or BBD compared
to appropriate
age-matched
controls
Group
No.
Hyperthyroidism
Hypothyroidism
Nontoxic
goiter
Breast
cancer
200
7
3
21”
Older
controls
200
4
2
10
a P < 0.01, breast disease us. control
groups.
’ P < 0.025, breast disease us. control
groups.
BBD
Younger
354
10
1
24b
124
1
2
6
controls
JCE & M . 1996
Vol81
. No 3
function
tests
Blood samples were not available from all patients who
had thyroid ultrasound scans.In addition, thyroid function
tests from three subjectswho had uncontrolled thyroid disease (two hypothyroid and one hyperthyroid; all from the
breast cancer group) were excluded from the study. Although as shown in Table 2, there was a remarkable consistency in mean values 2 SE for serum T,, T,, TSH, and PRL
between the two breast diseasestudy groups and controls,
there was a tendency for lower serum T, and higher TSH in
the groups with breast disease.
Thyroid
volume
Breastcancer.The percent frequency distribution of individual thyroid volumes in the 200 patients with breast cancer
compared to that in 200 older controls is shown in Fig. 1. The
distribution of individual thyroid volumes in the breast cancer group covered a broad range, varying from 5.2-96.0 mL.
It can be seenthat in breast cancer patients, thyroid volumes
were skewed to the right, with 41.5% being enlarged (>18.0
mL) compared to only 10.5% in the controls (P < 0.01). The
mean thyroid volume of 21.1 2 1.4 mL (median, 16.7 mL) in
the patients with breast cancer were significantly greater
than that of 13.2 ? 0.5 mL (median, 12.0 mL) in control
patients (P < 0.01). The mean age in the 117 breast cancer
patients with normal thyroid volume was 54.2 ? 1.16 yr
(median, 53.0 yr), whereas that in the 83 patients with thyroid
enlargement was 61.4 5 1.43yr (median, 62yr; P < 0.01).This
was in contrast to findings in the older controls, in whom
mean ages of 52.4 -+ 0.7 yr (median, 52 yr) in those with
normal volumes was not significantly different from that of
55.1 -t 2.2 yr (median, 53.5 yr) in those who had enlarged
thyroids. Classification of patients according to pathologically measured tumor size demonstrated, as shown in Table
3, that on the basisof histological staging, both mean thyroid
volume and percentage of individual patients with enlarged
thyroid volumes increased with tumor size.
BBD. As in the breast cancer group, a wide range of indi-
vidual thyroid volumes (range, 5.8-50.2 mL) was observed
in the 354 patients with BBD. The frequency distribution of
individual thyroid volumes in patients with BBD compared
to that in younger controls is shown in Fig. 2. The mean
thyroid volume of 14.5 2 0.34 mL (median, 13.1 mL) was
significantly greater than that of 12.5 -C0.38mL (median, 11.5
mL) in the younger controls (P < 0.01). Although the number
of individual patients with BBD having enlarged thyroid
volumes (61 of 354,17.2%) was greater than that (14 of 124,
11.3%) in younger controls, the difference was not significant. As with the breast cancer group, the mean age of BBD
patients with normal thyroid volumes (36.0 t 0.60 yr; median, 37 yr) was significantly lower than that of 41 ? 1.2 yr;
median, 43 yr) in patients with enlarged thyroids (P < 0.05).
Such differences were not observed in controls (normal thyroid volume: mean age, 33.4 ? 0.48 yr; median, 33.0 yr;
enlarged thyroid volume: mean age, 36.6 ? 0.21 yr; median,
36.0 yr; P = NS).
THYROID
TABLE
2. Mean
values
Ifr SE for serum
Group
T,, T,, TSH,
NO.
Breast cancer
Older controls
BBD
Younger
controls
190
182
124
95
VOLUME
and PRL
IN BREAST CANCER
in patients
with
breast
T4
T,
(nmol/L)
fnmol/L)
111
116
117
119
k
2
?
t
2.9
2.0
2.4
2.1
2.1
2.3
2.2
2.3
Blood samples were not available
from all patients
who had thyroid
ultrasound
uncontrolled
thyroid
disease (2 hypothyroid
and 1 hyperthyroid
from the breast
?
2
-c
k
cancer
939
or BBD
and control
groups
TSH
(mu/L)
0.05
0.08
0.04
0.05
2.1
1.9
2.4
1.9
?
?
k
?
PrL
(ng/mL)
0.10
0.08
0.09
0.11
5.0
4.7
5.8
5.0
scans and results of thyroid
function
cancer group)
were excluded
from
tests from
the study.
Median
Volume (ml)
t
?
2
2
0.40
0.29
0.30
0.45
patients
with
% Enlarged
> 18.0 ml
60 50 --
q
Control
11.5
n
BBD
13.1
20
25
11.3%
N.S.
% 40
Frequency
-.
17.2%
30 ._
20
10
0
FIG. 1. Percent
frequency
distribution
roid volumes
in breast cancer (Br CA)
TABLE
classified
3. Thyroid
according
Tumor
staging
TO
Tl
T2
T3-T4
of ultrasound-measured
and older control
groups.
Thyroid
vol
(mL)
7
57
94
33
17.6
18.9
20.9
33.4
z
k
2
?
3.0”
1.5
1.6
2.5b
Median
(mL)
Thyroid
vol
>18.0
mL (%I
15.6
16.3
16.8
23.3
217
23157
36/94
21/33”
TO, not palpable;
Tl, <2.0 cm; T2, 2-5 cm; T3-T4,
a Mean
? SE.
b P < 0.01 compared
to TO, Tl, and T2.
‘P < 0.05 compared
to TO, Tl, and T2.
>5.0
(28.5)
(40.3)
(38.2)
(63.6)
Thirty-nine patients with breast cancer were available for
repeat thyroid scans from 18-41 months (median, 30
months) after the original scan. Alterations in thyroid volumes in the 39 patients with breast cancer between the first
and the second scanare shown in Fig. 3. The first and second
scan mean volumes of 22.6 ? 2.8 mL (median, 16.7 mL) and
23.3 2 2.6 mL (median, 18.0 mL), respectively, were not
significantly different.
vs. prospective
10
15
30
35
40
45
50
Thyroid Volume (ml)
distribution
of ultrasound-measured
with BBD and younger
control
groups.
thy-
who had been studied after a variety of therapies for breast
cancer (retrospective group; n = 100). A comparison of the
results obtained is shown in Table 4. This table shows that
both mean thyroid volumes and the percentage of individual
patients with enlarged thyroids were basically identical in
the retrospective and prospective groups.
cm.
Repeat scans
Retrospective
5
FIG. 2. Percent
frequency
roid volumes
in patients
volumes
in 191 breast cancer patients
to pathologically
measured
tumor
size
No.
1
thy-
studies
To exclude the possibility that the increased thyroid volume observed in 41.5% of patients with breast cancer might
arise from therapeutic intervention for breast cancer, thyroid
ultrasound scans were performed at the time of excision
biopsy for discrete breast lumps (i.e. before the diagnosis of
breast malignancy). Patients from this series subsequently
diagnosed clinically and histologically as having breast cancer were termed the prospective group (n = 100). Findings
from this group were compared to those obtained in patients
Urinary
iodine
Urine samples were not available from all of the study
patients and controls. However, the mean urinary iodine
value of 80.0 ? 1.6 pg/L (median, 70) in 1063 patients with
breast disease of all types attending the same breast clinic
was not significantly different from that of 75.0 ? 2.7 Fg/L
(median, 66) in female controls.
Discussion
The present study describesapplication of the highly sensitive technique of diagnostic ultrasound to the investigation
of subtle changes in thyroid volume in patients with breast
disease.Thyroid enlargement has been previously reported
in association with breast cancer, but these reports, which
relied on neck palpation, have emanated from areas of endemic iodine deficiency (15,18) and, indeed, a direct role for
iodine deficiency in promoting breast diseasehas been postulated (22). In this study iodine excretion in patients attending a breast clinic did not differ significantly from controls.
The dietary iodine supply in Ireland, although consistent
with the borderline low levels encountered throughout Europe, does not indicate severe endemicity (23). The finding
that thyroid enlargement was more prevalent in older patients who had either breast cancer or benign breast disease
940
JCE & M . 1996
VolEl*No3
SMYTH ET AL,.
W Initial Volume
H Repeat Volume
< Volume
Decreased >
Patient l-l 5
Volume Unchanged
Patient 16 - 22
>
Volume Increased
Patient 23 - 39
>
3. Changes
in ultrasound-measured thyroid
volume
in 39 patients
with breast cancer who had repeat thyroid scans from 18-41 months
(median,
30 months)
after the original
scan.
FIG.
123456789111111111122222222223333333333
012345678901234567890123456769
Patient
TABLE
4. Comparison
of mean thyroid
volumes
? SE and
percentage
of individual
patients
with enlarged
thyroid
glands in
patients
scanned after (retrospective
group) and before
(prospective
group) commencement
of therapies
for breast cancer
Mean age
2 SE (yr)
Control
Breast cancer
Retrospective
Prospective
200
200
100
100
53.0
57.2
58.0
56.3
t
i
k
i
0.7
1.4
1.5
1.2
Thyroid vol
(ml)
13.2
21.1
20.8
21.4
t
k
2
i
No >18.0 mL
(70)
0.5
1.4
1.3
1.6
21(10.5)
83 (41.5)
43 (43.0)
40 (40.0)
might be interpreted as reflecting improvements in dietary
iodine
intake.
However,
a previous
iodine
deficiency
cannot
provide the sole answer for these age differences in the patient
groups,
as such
differences
were
not
observed
in con-
trols.
Thus, the underlying cause of the finding of enlarged
thyroids in such a high proportion of patients with breast
cancer
(41.5%)
compared
to age-matched
controls
without
evidence of breast disease(8.6%) remains unknown. The fact
that there is a direct association between the two conditions,
rather than thyroid enlargement occurring as a consequence
of various therapies for breast cancer, is supported by the
finding of a concurrence between results obtained in patients
studied retrospectively or prospectively. Repeat thyroid
scansshowed that there were no significant trends in thyroid
enlargement or involution. The largest changes in thyroid
volume (-18.0, +10.8, and +13.6 mL occurred in patients
with significantly enlarged glands (96.0, 45.2, and 33.8 mL,
respectively) and may reflect the difficulty in accurately measuring thyroid volume in such patients (24, 25).
The absence of a trend in alterations in thyroid volume
over the time period investigated suggeststhat thyroid enlargement either preceded or paralleled the breast lesion. The
striking associationbetween thyroid enlargement and breast
cancer leads us to speculate on the possibility of the endocrine and other growth stimuli identified in the thyroid exerting a simultaneous action on the breast (26). How such
stimuli could exert their effect on mammary tissue is unknown, although the recent demonstration of extrathyroidal
loci for the TSH receptor (27-301,in particular in fatty tissue,
may have significance for the breast.
Number
The consequences of thyroid enlargement for the genesis or natural history of breast cancer remain unknown,
although one report (19) showed increased mortality (standardized mortality ratio, 2.8) in breast cancer patients who
had nontoxic nodular goiter and were receiving T, suppression therapy. Although the significance of the association between thyroid enlargement and breast cancer
demonstrated in the present study remains to be elucidated, it may be of value to establish whether the phenomenon exists in populations from different genetic
pools or dietary iodine intakes. Perhaps the most important outcome of the association will be to emphasize the
importance of raising the consciousnessof the coincidence
of both disorders.
Acknowledgments
The authors gratefully
acknowledge
the contribution
in making
this
work
possible
of Nurse F. Hanley-Leahy
for expert
phlebotomy;
Sr.
Josepha, Nurse K. Murray,
and the staff of St. Anthony’s
Rehabilitation
Center;
the staff of the Department
of Surgery,
University
College
Dublin;
and Ms. A. M. Hetherton
for expert technical
assistance.
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