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20. Potter J.D. Hypothyroidism and reproductive failure. Surg. Gynecol. Obstet. 150: 251, 1980.

21. Davis L.E., Leveno K.J., Cunningham G.F. Hypothyroidism complicating pregnancy. Obstet. Gynecol. 72: 108, 1988.

22. Mandell S.J., Reed Larsen P., Seely EW., Brent GA Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N. Engl. J. Med. 323: 91, 1990.

23. Girling J.C., de Swiet M. Thyroxine dosage during pregnancy in women with primary hypothyroidism. Br. J. Obstet. Gynaecol. 99: 368, 1992.

25. Lazarus J.H., Othman S. Thyroid disease in relation to pregnancy. Clin. Endocrinol. 34: 91, 1991.

Thyroid Disease and Breast Cancer P.P.A. Smyth Endocrine Laboratory, Dept. of Medicine &Therapeutics, University College, Dublin, and The Breast Institute, St Vincent's Hospital, Dublin, Ireland. Key-words: Thyroid volume. thyroid ultrasound. breast cancer. gOiter, breast and thyroid.

Correspondence: Dr. P.PA Smyth, Endocrine Laboratory, Department of Medicine. Woodview, University College Dublin, Dublin 4, Ireland.

ABSTRACT. A review of the literature on the rela­tionship between thyroid disorders and breast can­cer does not provide conclusive evidence for the establishment of a causal relationship as breast cancer has been associated with hypothyroidism, hyperthyroidism and nontoxic goiter. Most reports on the association of thyroid enlargement and breast cancer have emanated from areas of en­demic iodine deficiency and these reports have re­lied on neck palpation. The contribution of the pre­sent study is in the application of the highly sensi­tive technique of diagnostic ultrasound to the in­vestigation of subtle changes in thyroid volume and anatomy in patients with breast cancer. The mean thyroid volume of 20.4±1.0 ml in 184 breast cancer patients was significantly greater than that of 12.9±1.2 ml in age-matched controls (p<0.01). Also the number of individual patients with breast can-

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cer having enlarged thyroid glands (73/184; 39.7%) was significantly greater than the corresponding number (13/150; 8.6%) in the control group (p<0.001). There was a direct correlation between thyroid enlargement and breast tumour staging. Both mean thyroid volume and % of enlarged thy­roids were identical in groups of patients scanned after (Retrospective Group) and before (Prospective Group) various therapies for breast cancer, thus ex­cluding therapeutic intervention as a cause for thy­roid enlargement. The results indicate a direct rela­tionship between the two disorders perhaps involv­ing a common growth stimulus and emphasise the importance of raising the consciousness of the co­incidence of both disorders.

INTRODUCTION

The coincidence of the simultaneous occurrence of diseases of the thyroid and breast has long been a subject of conjecture. This coincidence can be ex­plained in part by the fact that the two disorders pre­dominantly affect women of a similar age. Since the report of Beatson (1) on the use of oopherectomy and thyroid extract in the treatment of breast can­cer, many studies have shown a range of associa­tions between the two disorders. Although evidence of extremes of thyroid dysfunction increasing breast cancer risks is difficult to obtain, the impression per­sists of some link between the two. The thyroid dis­order most frequently implicated as a predisposing fact for breast cancer has been hypothyroidism or the use of L-T4 replacement therapy (2-6). An as­sociation between L-T4 replacement and breast cancer was subsequently refuted (7-9). Some re­ports showed an association between breast cancer and hyperthyroidism (10,11) but others (12,13) showed no evidence of such association. A retro­spective study of 2,500 patients with a variety of thy­roid disorders (14) showed no significant associa­tion with breast cancer and these findings were sup­ported by other workers (9, 15, 16). An increased prevalence of thyroid antibodies was observed in patients with breast cancer (17) but another study (16) showed no change in deaths from breast can­cer in patients who were antibody positive. The obvious possibility of a link between radioactive iodine 131 1 therapy for hyperthyroidism and in­creased risk for breast cancer was studied by Hoffman et al. (18, 19) who found no difference in breast cancer incidence when treatment with 131 1

was compared to surgery. Similarly, no increase in neoplasms was reported following either thera­peutic or diagnostic doses of 131 1 for hyperthy­roidism (20-22). The association between breast

cancer and non-toxic goiter has been extensively studied. Increased breast cancer in areas of en­demic goiter has been reported (23-26) but no change in breast cancer incidence occurred when goiter rate decreased following iodine prophylaxis (4, 11). Finally, an increased breast cancer mortal­ity was reported by Goldman (16) in patients who had non-toxic nodular goiter. Thus, the significance of the simultaneous occurrence of thyroid disease and breast cancer remains to be elucidated. The objective of the present study was to investigate if the availability of high resolution diagnostic ultra­sound could permit the detection in patients with breast cancer of more subtle changes in thyroid volume or morphology.

PATIENTS AND METHODS Patients and controls

Patients under study were attending a specialist breast clinic, The Breast Institute, St.Vincent's Hospital, Dublin.

Breast cancer. One-hundred and eighty-four con­secutive patients aged 28-89 years (mean 57.5± 13.6 years) had clinical and histological ev­idence of breast cancer. Ninety-one were stud­ied retrospectively in that they had received both surgical and medical therapy before being sub­jected to thyroid ultrasound scans. The remain­ing 93 patients, termed the prospective group, had thyroid scans at the time of excision biopsy, before the diagnosis of breast malignancy. Patients were investigated for both breast and thyroid disease and any history of previous thy­roid disease recorded.

Age matched controls. One-hundred and fifty non­hospitalized females aged 22-84 years (mean 51.0±8A years) served as controls.

Thyroid ultrasound scans

Thyroid ultrasound scans were performed using a scanner fitted with a hand held 7.5mHz linear trans­ducer (Siemens SL-1, Darmstadt, Germany). The presence of solid nodules was recorded if they

Thyroid disease and breast cancer

Table 1 - Prevalence of thyroid disorders in breast cancer and age matched control populations.

Group Breast Cancer Control

Number of patients 184 150

Hyperthyroidism 6 3

Hypothyroidism 2 2

Nontoxic Goiter 18' 9

·p<O.01

were >5.0 mm diameter. Mixed echogenic patterns of >5.0 mm were also recorded as solid nodules. Only true thyroid cysts without evidence of internal echoes were so recorded. Thyroid volume was measured using transverse scans to obtain the width (W) and depth (D) of each lobe and longitu­dinal (L) scans to measure length. Volume of each lobe was calculated according to the formula (WxDxLxOA79) (27). The upper limit for normal thyroid volume in an iodine sufficient non-endemic goitrous area (18.0 ml. for adult females) (28) was used in this study. Thyroid volumes> 18.0 mi. were termed en­larged.

Statistical analysis

Results were analysed using Student's t-test for un­paired samples or the Chi-square test.

RESULTS Prevalence of thyroid disorders

The prevalence in the study groups of thyroid dis­orders past and present is shown in Table 1. There was no significant difference in the preva­lence of hyperthyroidism and hypothyroidism be­tween the breast cancer and control groups. However, the frequency of non-toxic goiter was greater in the breast cancer group than in con­trols (p<0.025).

Laboratory investigations

When investigations on patients with overt thyroid dysfunction were discarded, there was a remark-

Table 2 - Mean valueS±SE for serum T4, T3, TSH and PRL in breast cancer patients and control groups; N= number of patients.

N AGE T4 T3 TSH PRl (Years) (nmol/l) (nmol/l) (mUll) (ng/ml)

Breast Cancer 184 57.5± 1.0 106±2.0 2.1±0.03 2.2±0.1 5.0±OA

Control 150 51.0±0.6 116±2.0 2.2±0.04 1.9±0.08 4.5±0.29

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** 40 MEAN 40

• VOLUME

i 30 Wi! % >18.0 ml 30 ~

i e :I Q

~ 20 * p>O.OI 20 ~ :9 * ** p>O.OI " e ~ ~

..c:: 10 Eo-<

10

0 0

CONTROL BREAST CANCER

Fig. 1 - Thyroid volumes (mean±SE) and % of individual with enlarged thyroids (> 18.0 ml) in breast cancer and age-matched control groups.

able consistency in mean values±SE for serum T4, T3, TSH and PRL between the two groups as shown in Table 2.

Ultrasound scanning abnormalities

Normal echogenicity was observed in 89 patients but ultrasound scanning abnormalities, solid nod­ules or cysts, were present in 74 (40.2%) and 21 (11.4%) respectively. Thyroid scanning abnormal­ities (nodules and cysts) were detected in 51.6% of patients with breast cancer compared to 10.7% of controls and this difference was highly signifi­cant (p<0.001).

Thyroid volume

The distribution of individual thyroid volumes in the breast cancer group covered a broad range vary­ing from 5.2 to 96.0 ml. Mean thyroid volumes and the percentage of individual patients having signif­icant thyroid enlargement (volume> 18.0 ml) are shown in Figure 1. It can be seen that the mean vol­ume of 20.4± 1.0 ml in the patients with breast can­cer was significantly greater than that of 12.9± 1.2 ml in age matched controls (p< 0.01). Also the

number of individual patients with breast cancer having enlarged thyroid glands (73/184; 39.7%) was significantly greater than the corresponding number (13/150; 8.6%) in the control group (p<0.001 ).

Clinical correlations

Table 3 shows the results of attempts to relate en­larged thyroid volumes in patients with breast can­cer to a number of other indices including tumor size, ovarian status and the influence of the anti­estrogen Tamoxifen. Data from the 173 patients shown in Table 3 in whom results of accurate stag­ing were available, show that mean thyroid volume increased with increasing tumor size (T3> T2, > T1) and this reached significance at T3 (p<0.05). Even more significant was the number of individual pa­tients within each tumor staging group who had en­larged thyroids which reached a maximum in pa­tients with breast tumors graded T3 or greater in whom 52.2% had enlarged thyroid volumes (p<0.02 compared to T1). When patients were di­vided on the basis of ovarian status, 62 were pre­menopausal and 122 postmenopausal . Both mean thyroid volumes and the percentage of patients having enlarged thyroid glands were significantly greater in the postmenopausal group (p<0.01 in each case). Finally the effect of Tamoxifen therapy was investigated in 98 patients, 50 of whom had been on long term therapy and 48 age matched breast cancer patients who had received no Tamoxifen. The respective mean thyroid volume and percentage enlarged thyroid volumes were not significantly different.

Retrospective vs prospective studies

To exclude the possibility that the enlarged thyroid volume observed in 39.7% of patients with breast cancer might arise from therapeutic intervention for breast cancer, sequential patients attending the breast clinic had thyroid ultrasound scans per­formed. This was done at the time of excision biop­sy for discrete breast lumps (i.e. before the diag­nosis of breast malignancy) . Patients from this se-

Table 3 - Relationship of thyroid volume to clinical indices in breast cancer patients. T1- T3 represent breast tumor staging.

Breast Tumour Ovarian Status Tamoxifen (Staging) Premenopausal Postmenopausal Yes No

T1 T2 T3

Number of patients 40 87 46 62 122 48 50

Thyroid volume (Mean±SE) 17.9±1.7 19.6±1.5 22.8±2.0 17.2±0.4 22.5± 1.5 20.4± 1.8 19.2±2.0

% of volumes> 18.0 ml 27.5 358 52.2 28.3 47.2 38.2 32.0

398

Thyroid disease and breast cancer

Table 4 - Comparison of mean thyroid volumestSE and % with enlarged thyroids in patients scanned following (Retrospective Group) and before (Prospective Group) commencement of therapies for breast cancer.

Group Number of patients Age Yrs

Control 150 51 .0±0.68

Breast Cancer 184 57.4±0.97

Retrospective 93 58.1±1.46

Prospective 91 56.7±1.26

ries subsequently diagnosed clinically and histo­logically as having breast cancer were therefore termed the Prospective Group (n=91) . Findings from this group were compared to those obtained in patients who had been studied after a variety of therapies for breast cancer (Retrospective Group, n=93). A comparison of results obtained is shown in Table 4. This table shows that both mean thyroid volumes and the percentage of individual patients having enlarged thyroids were basically identical between the Retrospective and Prospective Groups indicating that thyroid gland enlargement appeared to be independent of therapeutic intervention for breast cancer.

DISCUSSION

A review of the literature on the relationship be­tween thyroid disorders and breast cancer does not provide conclusive evidence for the establish­ment of a causal relationship. 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 (23-26) and indeed a di­rect role for iodine deficiency in promoting breast disease has been postulated (29, 30) . The contri­bution of the present study is in the application of the highly sensitive technique of diagnostic ultra­sound to the investigation of subtle changes in thy­roid volume and anatomy in patients with breast cancer. The underlying cause of the finding of en­larged thyroids in such a high proportion of these patients (39.7%) compared to age-matched con­trols without evidence of breast disease (S.6%) re­mains unknown. The finding of a significant direct correlation between thyroid enlargement and breast tumour size suggests the presence of a common growth stimulus with increasing potency reflected by gland size in both organs. The finding of signif­icantly greater thyroid volume and % thyroid en­largement in postmenopausal compared to pre­menopausal breast cancer patients probably re-

399

Thyroid Volume Mean±SE N (%) of volumes >18.0 ml

12.9±1.2 13 (8.6)

20.4±1.0 73 (39.7)

200±1.2 39(41.9)

20.6±1.6 36 (39.6)

flects the improvement in dietary iodine intake in the younger population (31) . However, 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 strongly supported by the finding of a re­markable concurrence between results obtained in patients studied retrospectively or prospectively . Thus we are lead to speculate on the possibility of the endocrine, paracrine or autocrine growth stim­uli identified in the thyroid (29) also exerting an ac­tion on the breast. The consequences of thyroid enlargement for the genesis or natural history of breast cancer remain unknown although one report (16) showed in­creased mortality (Standardised Mortality Rate:SMR=2.S) in breast cancer patients who had non-toxic nodular goiter and were receiving L-T4 suppression therapy. Perhaps the most important outcome of the demonstrated association between thyroid enlargement and breast cancer will be to emphasise the importance of raising the con­sciousness of the coincidence of both disorders.

ACKNOWLEDGMENTS

The author gratefully acknowledges the contribution of the fol­lowing in making this work possible: Professor N.J. O'Higgins, Senior Oncology Nurse M.J. Murray and the the medical, nurs­ing and clerical staff of the Breast Institute, St. Anthony's Rehabilitation Center; the staff of the Endocrine Laboratory, UCD Woodview, in particular the expert technical assistance of Mr. D.F. Smith and Ms. A.M. Hetherton, and the financial support of the Royal Col lege of Surgeons in Ireland.

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