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0021.972x196/$03.00/0 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. References GT. 1896 On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet. 2104-107. Loeser AA. 1954 A new therapy for prevention of post-operative recurrences in genital and breast cancer: a six-years study of prophylactic thyroid treatment. Br Med J. 2:1380-1383. Stoll BA. 1965 Breast cancer and hypothyroidism. Cancer. 18~1431-1436. Backwinkel K, Jackson A. 1964 Some features of breast cancer and thyroid deficiency. Cancer. 17~1174-1176. Takatani 0, Okumoto T, Kosano H, et al. 1989 Relationship between the levels of serum thyroid hormones or estrogen status and the risk of breast cancer genesis in Japanese women. Cancer Res. 9:3109-3112. 1. Beatson 2. 3. 4. 5. to thyroid supplements 6. Kapdi CC, Wolfe J. 1976 Breast cancer: relationship for hypothyroidism. JAMA. 236:1124-1127. HJ, Benua RS, Rawson RW. 1966 Neoplastic disease and thyrotox7. Wanebo icosis. Cancer. 19:1523-1526. 8. Moossa AR, Price Evans DA, Brewer AC. 1973 Thyroid status and breast cancer; reappraisal of an old relationship. Ann R Co11 Surg Lond. 53:178-188. 9. Itoh K, Mamchi N. 1975 Breast cancer in patients with Hashimoto’s thyroiditis. Lancet. 2:1119-1121. 10. German CA, Becker D, Greenspan FS, et al. 1977 American Thyroid Association statement: breast cancer and thyroid hormone therapy. Ann Intern Med. 86~502-503. 11. Wallace RB, Sherman BM, Bean JA, Leeper J. 1978 Thyroid hormone use in patients with breast cancer: absence of an association. JAMA. 239:958. THYROID VOLUME 12. Brinton LA, Hoffman DA, Hoover R, rraumeni JF. 1984 Relationship of thyroid disease and use of thyroid supplements to breast cancer risk. J Chronic Dis. 37~877-883. 13. Kalache A, Vessey P, McPherson K. 1982 Thyroid disease and breast cancer: findings in a large case-control study. Br J Surg. 69:434-435. 14. Hedley AJ, Jones SI, Spiegelhalter DJ, et al. 1981 Breast cancer in thyroid disease: fact or fallacy. Lancet. 1:131-133. 15. Spencer JGC. 1954 The influence of the thyroid in malignant disease. Br J Cancer. 8:393-411. 16. Bogardus GM, Finley JW. 1961 Breast cancer and thyroid disease. Surgery. 49461-468. 17. Eskin BA. 1970 Iodine metabolism and breast cancer. Tram NY Acad Sci. 11:911-947. 18. Adamopoulos DA, Vassilarus S, Kapolla N, Papadiamantis J, Georgiakodis F, Michalkis A. 1986 Thyroid disease in patients with benign and malignant mastopathy. Cancer. 57~1255128. 19. Goldman MB, Monson RR, Maloof F. 1990 Cancer mortality in women with thyroid disease. Cancer Res. 50:2283-2289. 20. Bnmn J, Block U, Ruf G, Bos I, Kunze WP, Scriba PC. 1981 Volumetric der Schilddriisenlappen mittels Real-time-Sonographie. Dtsch Med Wschr. 106: 1338-1340. 21. Gutekunst R, Becker W, Hehrmann R, Olbricht Th, Pfannenstiel P. 1988 Ultraschalldiagnostik der Schilddmse. Dtsch Med Wschr. 113:1109-1112. 22. Ghent WR, Eskin BA. 1986 Iodine deficiency breast syndrome. In: Medeiros- IN BREAST 23. 24. 25. 26. 27. 28. 29. 30. CANCER 941 Neto G, Gaitan E, eds. Frontiers in thyroidology. New York: Plenum Press; vol 2:1021-1031. Hetherton AM, Smyth PPA. 1993 Status of iodine deficiency in Ireland. In: Delange F, Dunn JT, Glinoer D, eds. Iodine deficiency in Europe: a continuing concern. New York: Plenum Press; 317-322. Berghout A, Wiersinga WM, Smits NJ, Touber JL. 1988 The value of thyroid volume measured by ultrasonography in the diagnosis of goitre. Clin Endocrinol (0x0. 28:409-414. Gutekunst R, Martin-Teichert H. 1993 Requirements for goitre surveys and the determination of goitre size. In: Delange F, Dunnand JT, Glinoer D, eds. Iodine deficiency in Europe, a continuing concern. New York: Plenum Press; 109-118. Dumont JE, Maenhaut C, Pirson I, Baptist M, Roger PP. 1991 Growth factors controlling the thyroid gland. Baillieres Clin Endocrinol Metab. 5727-753. Roselli-Rehfuss L, Robbins LS, Cone Rd. 1992 Thyrotropin receptor messenger ribonucleic acid is expressed in most brown and white adipose tissue in the guinea pig. Endocrinology. 130:1857-1861. Paschke R, Metcalfe A, Alcalde L, Vassart G, We&man A. 1994 Presence of nonfunctional transcripts in retroocular and other tissues. J Clin Endocrinol Metab. 79:1234-1238. Davies TF. 1994 The thyrotrophin receptors spread themselves around. J Clin Endocrinol Metab. 791232-1233. Endo T, Onaya T. 1994 Thyrotropin receptor is expressed in non-thyroid tissues. Nippon Rinsho. 52969-973.