0021.972x196/$03.00/0 Vol. 81, No.

3
Journal of Clinical Endocrinology and Metabolism Printed in U.S.A.
Copyright 0 1996 by The Endocrine Society

A Direct Relationship between Thyroid Enlargement and

Breast Cancer*
P. P. A. SMYTH, D. F. SMITH, E. W. M. MCDERMOTT, M. J. MURRAY,
J. G. GERAGHTY, AND N. J. O’HIGGINS

Endocrine Laboratory, Departments of Medicine and Therapeutics and Surgery, St. Vincent’s Hospital,
University College, Dublin, Ireland

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ABSTRACT in patients with benign breast disease was also significantly greater
Despite extensive study, evidence to support a direct relationship than that of 12.5 + 0.38 mL in younger controls (P < 0.01). The results
between diseases of the thyroid and breast has not been established. support a direct association between breast cancer and increased
In this study thyroid volume was assessed by ultrasound in 200 thyroid volume as mean thyroid volumes and the percentage of in-
patients with breast cancer and 354 with benign breast disease. Re- dividual patients with enlarged thyroid glands were similar in those
sults were compared to appropriate female control groups. Both mean studied both before (20.8 2 1.3 mL and 43.0%) and after (21.4 2 1.6
thyroid volume (21.1 2 1.4 mL) and the percentage of individual mL and 40.0%) therapies for breast cancer. Although there is no
patients with enlarged (>18.0 mL) thyroid glands (41.5%) were sig- evidence that thyroid enlargement represents a risk factor for breast
nificantly greater in the breast cancer group than equivalent values cancer, the results emphasize the importance ofraising the conscious-
(13.2 + 0.5 mL and 10.5%, respectively) in age-matched controls ness ofthe coincidence ofboth disorders. (J Clin Endocrinol Metab 81:
(I’ < 0.01 in both cases). The mean thyroid volume of 14.5 t 0.34 mL 937-941, 1996)

S INCE THE report of Beatson (1) on the use of oophorec-

tomy and thyroid extract in the treatment of breast
cancer, many studies have shown a range of associations
Selection

screening
of controls
The control populations
program carried
consist of women
out at University
participating
College Dublin,
in a health
during
between the two disorders. Associations of breast cancer 1988/1989. Those with a history of breast disease were excluded from
with hypothyroidism (2-5), T, replacement therapy (6), hy- the study. Age matching was achieved by selecting from the control
perthyroidism (7,8), and thyroiditis (9) have been reported, populations only those patients whose ages fell within the age ranges of
patient groups. Subjects were not matched for height or body weight.
whereas no significant relationship has been observed by
Both patient and control groups came from the same catchment area and
others (10-14). Increased breast cancer incidence in areasof represented a reasonable cross-section of an adult female urban/rural
endemic goiter have been reported (15-l@, but no change population of varied socioeconomic status.
occurred when goiter rate decreasedafter iodine prophylaxis
(4, 8). Finally, an increased breast cancer mortality was re-
ported by Goldman et al. (19) in patients who had nontoxic Coincidence of breast and thyroid disease
nodular goiter and were receiving T, suppression therapy. Patients and controls were assessed for both breast and thyroid dis-
Thus, the significance of the simultaneous occurrence of thy- ease by the same surgical team, and any history of previous thyroid
roid diseaseand breast cancer remains to be elucidated. The disease was recorded. Where such a history was present, classification
as hyperthyroidism, hypothyroidism, or nontoxic goiter was made on
objective of the present study was to investigate whether the
the basis of the original diagnosis.
availability of high resolution diagnostic ultrasound could
permit the detection in patients with breast cancer of more
subtle changes in thyroid volume. Breast cancer
Two hundred consecutive patients, aged 28-89 yr (mean 2 SE, 57.2
Subjects and Methods 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
Selection of patients of Pathology, St. Vincent’s Hospital (Dublin, Ireland). Information on
Patients under study were attending a specialist breast clinic at histologically measured tumor size made according to Union Interna-
St. Vincent’s Hospital (Dublin, Ireland). tionale 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
Received July 21,1995. Revision received October 25,1995. Accepted they had received both surgical and medical therapy before being sub-
November 2, 1995. jected to thyroid ultrasound scans. The remaining 100 patients, termed
Address all correspondence and requests for reprints to: Dr. P. P. A. the prospective group, had thyroid scans at the time of excision biopsy
Smyth, Endocrine Laboratory, Department of Medicine and Therapeu- before the diagnosis of breast malignancy.
tics, 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 Older controls
Association Clinical Symposium: The Female Thyroid In Health and
Disease, Dublin, Ireland, June 20-25,1992. This work was supported by Two hundred nonhospitalized women, aged 22-84 yr (mean, 53.0 ?
the Royal College of Surgeons in Ireland Research Committee. 0.67 yr; median, 52 yr) served as controls for the breast cancer group.

937
938 SMYI’H ET AL. JCE & M . 1996
Vol81 . No 3

Benign breast disease (BBD) Thyroid function tests

This group consisted of 354 patients, aged 16-50 yr (mean, 37.1 Z 0.5 Blood samples were not available from all patients who
yr; median, 36 yr), with either clinical evidence of fibrocystic breast had thyroid ultrasound scans.In addition, thyroid function
disease or clinical and histological evidence of fibroadenoma.
tests from three subjectswho had uncontrolled thyroid dis-
ease (two hypothyroid and one hyperthyroid; all from the
Younger controls
breast cancer group) were excluded from the study. Al-
One hundred and twenty-four nonhospitalized premenopausal vol- though as shown in Table 2, there was a remarkable consis-
unteers, 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.
tency in mean values 2 SE for serum T,, T,, TSH, and PRL
between the two breast diseasestudy groups and controls,
Urinary iodine studies there was a tendency for lower serum T, and higher TSH in
the groups with breast disease.
Spot urine specimens were obtained from 1063 nonhospitalized pa-

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tients attending the breast clinic at St. Vincent’s Hospital (Dublin, Ire-
land) and from 60 female controls without evidence of breast disease Thyroid volume
attending the health screening clinic.
Thyroid ultrasound scans were performed using a scanner fitted with Breastcancer.The percent frequency distribution of individ-
a hand-held 7.5.mHz linear transducer (Siemens SL-1, Darmstadt, Ger-
many). All scans were performed by the same observer. The sonogra- ual thyroid volumes in the 200 patients with breast cancer
pher was not blinded as to control and breast disease study groups. compared to that in 200 older controls is shown in Fig. 1. The
However, within the breast cancer group, 100 patients were studied distribution of individual thyroid volumes in the breast can-
prospectively at the time of excision biopsy when the diagnosis was cer group covered a broad range, varying from 5.2-96.0 mL.
unknown to all, including the sonographer. The coefficient of variation
for thyroid volume measurement at a volume of 12.0 mL was 10.0%. It can be seenthat in breast cancer patients, thyroid volumes
Repeat thyroid volumes were judged to be unchanged if they differed were skewed to the right, with 41.5% being enlarged (>18.0
by 0.5 mL or less. The volume of each lobe was calculated according to mL) compared to only 10.5% in the controls (P < 0.01). The
the formula (W X D X L X 0.479) (20). The upper limit for normal thyroid mean thyroid volume of 21.1 2 1.4 mL (median, 16.7 mL) in
volume in an iodine-sufficient nonendemic goitrous area (18.0 mL for
adult females) (21) was used in this study. Thyroid volumes greater than the patients with breast cancer were significantly greater
18.0 mL were termed enlarged. than that of 13.2 ? 0.5 mL (median, 12.0 mL) in control
Serum T,, T,, TSH, and PRL were estimated by immunoassay using patients (P < 0.01). The mean age in the 117 breast cancer
an IMX analyzer (Abbott Laboratories Diagnostic Division, Dublin patients with normal thyroid volume was 54.2 ? 1.16 yr
Ireland Ltd.).
Urinary iodine was measured in spot samples by alkaline ashing at (median, 53.0 yr), whereas that in the 83 patients with thyroid
approximately 600 C using a muffle furnace fitted with a microchip enlargement was 61.4 5 1.43yr (median, 62yr; P < 0.01).This
temperature control. Iodide was quantified in the Sandell Kolthoff re- was in contrast to findings in the older controls, in whom
action. Results were expressed as micrograms of iodine per L urine. mean ages of 52.4 -+ 0.7 yr (median, 52 yr) in those with
normal volumes was not significantly different from that of
Statistical analysis 55.1 -t 2.2 yr (median, 53.5 yr) in those who had enlarged
Results were analyzed using Student’s t, Wilcoxon’s rank sum, or thyroids. Classification of patients according to pathologi-
[chil’ test. cally measured tumor size demonstrated, as shown in Table
3, that on the basisof histological staging, both mean thyroid
Results volume and percentage of individual patients with enlarged
Prevalence of thyroid disorders thyroid volumes increased with tumor size.
The prevalence in the study groups of thyroid disorders
past and present are shown in Table 1. There was no sig- BBD. As in the breast cancer group, a wide range of indi-
nificant difference in the prevalence of hyperthyroidism and vidual thyroid volumes (range, 5.8-50.2 mL) was observed
hypothyroidism between either of the breast diseasegroups in the 354 patients with BBD. The frequency distribution of
and appropriate control groups. However, the frequency of individual thyroid volumes in patients with BBD compared
nontoxic goiter was greater in both the breast cancer and the to that in younger controls is shown in Fig. 2. The mean
BBD groups than in the controls (P < 0.01 and P < 0.025, thyroid volume of 14.5 2 0.34 mL (median, 13.1 mL) was
respectively). 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
TABLE 1. Prevalence of thyroid disorders in groups of patients
with breast cancer or BBD compared to appropriate age-matched
volumes (61 of 354,17.2%) was greater than that (14 of 124,
controls 11.3%) in younger controls, the difference was not signifi-
cant. As with the breast cancer group, the mean age of BBD
Breast Older Younger patients with normal thyroid volumes (36.0 t 0.60 yr; me-
Group BBD
cancer controls controls
dian, 37 yr) was significantly lower than that of 41 ? 1.2 yr;
No. 200 200 354 124
Hyperthyroidism 7 4 10 1
median, 43 yr) in patients with enlarged thyroids (P < 0.05).
Hypothyroidism 3 2 1 2 Such differences were not observed in controls (normal thy-
Nontoxic goiter 21” 10 24b 6 roid volume: mean age, 33.4 ? 0.48 yr; median, 33.0 yr;
a P < 0.01, breast disease us. control groups. enlarged thyroid volume: mean age, 36.6 ? 0.21 yr; median,
’ P < 0.025, breast disease us. control groups. 36.0 yr; P = NS).
 THYROID VOLUME IN BREAST CANCER 939

TABLE 2. Mean values Ifr SE for serum T,, T,, TSH, and PRL in patients with breast cancer or BBD and control groups

T4 T, TSH PrL
Group NO. (nmol/L) fnmol/L) (mu/L) (ng/mL)
Breast cancer 190 111 k 2.9 2.1 ? 0.05 2.1 ? 0.10 5.0 t 0.40
Older controls 182 116 2 2.0 2.3 2 0.08 1.9 ? 0.08 4.7 ? 0.29
BBD 124 117 ? 2.4 2.2 -c 0.04 2.4 k 0.09 5.8 2 0.30
Younger controls 95 119 t 2.1 2.3 k 0.05 1.9 ? 0.11 5.0 2 0.45
Blood samples were not available from all patients who had thyroid ultrasound scans and results of thyroid function tests from patients with
uncontrolled thyroid disease (2 hypothyroid and 1 hyperthyroid from the breast cancer group) were excluded from the study.

Median % Enlarged
Volume (ml) > 18.0 ml
60 -

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50 -- q Control 11.5 11.3%

N.S.
% 40 -.
Frequency
n BBD 13.1 17.2%
30 ._

20

10

0
1 5 10 15 20 25 30 35 40 45 50
FIG. 1. Percent frequency distribution of ultrasound-measured thy- Thyroid Volume (ml)
roid volumes in breast cancer (Br CA) and older control groups.
FIG. 2. Percent frequency distribution of ultrasound-measured thy-
TABLE 3. Thyroid volumes in 191 breast cancer patients roid volumes in patients with BBD and younger control groups.
classified according to pathologically measured tumor size

Tumor Thyroid vol Median Thyroid vol

who had been studied after a variety of therapies for breast
No. cancer (retrospective group; n = 100). A comparison of the
staging (mL) (mL) >18.0 mL (%I
TO 7 17.6 z 3.0” 15.6 217 (28.5) results obtained is shown in Table 4. This table shows that
Tl 57 18.9 k 1.5 16.3 23157 (40.3) both mean thyroid volumes and the percentage of individual
T2 94 20.9 2 1.6 16.8 36/94 (38.2) patients with enlarged thyroids were basically identical in
T3-T4 33 33.4 ? 2.5b 23.3 21/33” (63.6) the retrospective and prospective groups.
TO, not palpable; Tl, <2.0 cm; T2, 2-5 cm; T3-T4, >5.0 cm.
a Mean ? SE. Urinary iodine
b P < 0.01 compared to TO, Tl, and T2.
‘P < 0.05 compared to TO, Tl, and T2. 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
Repeat scans breast disease of all types attending the same breast clinic
Thirty-nine patients with breast cancer were available for was not significantly different from that of 75.0 ? 2.7 Fg/L
repeat thyroid scans from 18-41 months (median, 30 (median, 66) in female controls.
months) after the original scan. Alterations in thyroid vol-
umes in the 39 patients with breast cancer between the first Discussion
and the second scanare shown in Fig. 3. The first and second The present study describesapplication of the highly sen-
scan mean volumes of 22.6 ? 2.8 mL (median, 16.7 mL) and sitive technique of diagnostic ultrasound to the investigation
23.3 2 2.6 mL (median, 18.0 mL), respectively, were not of subtle changes in thyroid volume in patients with breast
significantly different. disease.Thyroid enlargement has been previously reported
in association with breast cancer, but these reports, which
Retrospective vs. prospective studies relied on neck palpation, have emanated from areas of en-
To exclude the possibility that the increased thyroid vol- demic iodine deficiency (15,18) and, indeed, a direct role for
ume observed in 41.5% of patients with breast cancer might iodine deficiency in promoting breast diseasehas been pos-
arise from therapeutic intervention for breast cancer, thyroid tulated (22). In this study iodine excretion in patients attend-
ultrasound scans were performed at the time of excision ing a breast clinic did not differ significantly from controls.
biopsy for discrete breast lumps (i.e. before the diagnosis of The dietary iodine supply in Ireland, although consistent
breast malignancy). Patients from this series subsequently with the borderline low levels encountered throughout Eu-
diagnosed clinically and histologically as having breast can- rope, does not indicate severe endemicity (23). The finding
cer were termed the prospective group (n = 100). Findings that thyroid enlargement was more prevalent in older pa-
from this group were compared to those obtained in patients tients who had either breast cancer or benign breast disease
 JCE & M . 1996
940 SMYTH ET AL,. VolEl*No3

W Initial Volume

H Repeat Volume

< Volume Decreased > Volume Unchanged > Volume Increased >
Patient l-l 5 Patient 16 - 22 Patient 23 - 39

FIG. 3. Changes in ultrasound-mea-

sured thyroid volume in 39 patients
with breast cancer who had repeat thy-
roid scans from 18-41 months (median,
30 months) after the original scan.

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123456789111111111122222222223333333333
012345678901234567890123456769
Patient Number

TABLE 4. Comparison of mean thyroid volumes ? SE and The consequences of thyroid enlargement for the gen-
percentage of individual patients with enlarged thyroid glands in esis or natural history of breast cancer remain unknown,
patients scanned after (retrospective group) and before
(prospective group) commencement of therapies for breast cancer
although one report (19) showed increased mortality (stan-
dardized mortality ratio, 2.8) in breast cancer patients who
Mean age Thyroid vol No >18.0 mL had nontoxic nodular goiter and were receiving T, sup-
2 SE (yr) (ml) (70) pression therapy. Although the significance of the asso-
Control 200 53.0 t 0.7 13.2 t 0.5 21(10.5) ciation between thyroid enlargement and breast cancer
Breast cancer 200 57.2 i 1.4 21.1 k 1.4 83 (41.5) demonstrated in the present study remains to be eluci-
Retrospective 100 58.0 k 1.5 20.8 2 1.3 43 (43.0)
Prospective 100 56.3 i 1.2 21.4 i 1.6 40 (40.0) dated, it may be of value to establish whether the phe-
nomenon exists in populations from different genetic
might be interpreted as reflecting improvements in dietary pools or dietary iodine intakes. Perhaps the most impor-
iodine intake. However, a previous iodine deficiency cannot tant outcome of the association will be to emphasize the
provide the sole answer for these age differences in the pa- importance of raising the consciousnessof the coincidence
tient groups, as such differences were not observed in con- of both disorders.
trols.
Thus, the underlying cause of the finding of enlarged Acknowledgments
thyroids in such a high proportion of patients with breast The authors gratefully acknowledge the contribution in making this
cancer (41.5%) compared to age-matched controls without work possible of Nurse F. Hanley-Leahy for expert phlebotomy; Sr.
evidence of breast disease(8.6%) remains unknown. The fact Josepha, Nurse K. Murray, and the staff of St. Anthony’s Rehabilitation
Center; the staff of the Department of Surgery, University College
that there is a direct association between the two conditions, Dublin; and Ms. A. M. Hetherton for expert technical assistance.
rather than thyroid enlargement occurring as a consequence
of various therapies for breast cancer, is supported by the References
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