(CANCER RESEARCH 50. 228.1-2289. April 15. 1990| Cancer Mortality in Women with Thyroid Disease1
Marlene B. Goldman,2 Richard R. Monson, and 1aralio Maloof Department of Epidemiology, Harvard School of Public Health, Boston 02115 [M. B. 6"..R. K. M.J, and Thyroid I'nil, Massachusetts Ornerai Hospital, Boston 02114 /F. M.I, Massachusetts
ABSTRACT in a study of American women (4). A mechanism for a causal relationship between the two diseases is not established, al A retrospective follow-up study of 7338 women with either nontoxic though thyroid hormones are known to influence the breast nodular goiter, thyroid adenoma, hyperthyroidism, hypothyroidism, Hashimoto's thyroiditis, or no thyroid disease was conducted. All women either directly or through effects on thyroid-stimulating hor patients at the Massachusetts General Hospital Thyroid Clinic who were mone, prolactin, estrogens, or androgens. Researchers sug seen between 1925 and 1974 and who were treated for a minimum of 1 gested that a deficit of thyroid hormone altered the hormonal year were traced. A total of 2231 women (30.4%) were dead and 2012 milieu in a way that permitted the growth of malignant cells (1, women (27.4%) were alive as of December 31, 1978. Partial follow-up 5, 6). It is just as reasonable to hypothesize, however, that an information was available for the remaining 3095 women (42.2%). The excess of thyroid hormone may promote tumor growth. A average length of follow-up was 15.2 years. When losses to follow-up number of biochemical and clinical studies have been con were withdrawn at the time of their loss, the standardized mortality ratios ducted, but no consensus has been reached as to the role of (SMR) for all causes of death were 1.2 |95% confidence interval (CI), thyroid hormones in the initiation or promotion of cancer. 1.1-1.3) for women with nontoxic nodular goiter, 1.2 (95% CI 1.0-1.3) In addition, two thyroid treatments have been associated with for those with thyroid adenoma, 1.4 (95% CI 1.3-1.5) for women with an increased risk of cancer, "'I therapy for hyperthyroidism hyperthyroidism, 1.5 (95% CI 1.3-1.7) for hypothyroid women, 1.2 (95% CI 0.9-1.5) for those with Hashimoto's thyroiditis, and 1.5 (95% CI 1.4- and thyroid supplements for hypothyroidism. Since 1946, when I3II was introduced, there has been concern that the radiation 1.6) for those without thyroid disease. For deaths from all cancers, the standardized mortality ratios were 1.5 (95% CI 1.2-1.8) for women with may cause cancer. While there have been case reports of leu nontoxic nodular goiter, 1.5 (95% CI 1.1-1.9) for those with thyroid kemia (7-9), thyroid (10-12), breast (13), and colon cancer (14) adenoma, 1.2 (95% CI 1.0-1.4) for women with hyperthyroidism, 1.0 after '"I treatment, epidemiologie studies have not found large (95% CI 0.7-1.4) for the hypothyroid women, 1.2 (95% CI 0.7-2.1) for increases in cancer incidence or mortality among thyroid pa those with Hashimoto's thyroiditis, and 1.3 (95% CI 1.0-1.5) for those tients treated with "'I. Muñozétal.(15)found a slightly higher women without thyroid disease. When specific cancer sites were studied, than expected incidence of cancer in hyperthyroid patients who excess numbers of deaths were observed from breast cancer in women had received radioactive iodine therapy. Hoffman et al. (16), in with nontoxic nodular goiter (SMR = 1.6, 95% CI 1.0-2.6) and from a continuation of the United States Public Health Service lymphatic and hematopoietic cancer in women with nontoxic nodular goiter (SMR = 2.4, 95% CI I.2-4.3) and thyroid adenoma (SMR = 2.7, Cooperative Thyrotoxicosis Therapy Follow-up Study (Mayo 95% CI 1.I-5.2). An increase in thyroid cancer risk was observed in Clinic Center), reported no difference between radioactive io women with thyroid adenoma (SMR = 11.7, 95% CI I.3-42.1) but was dine-treated patients and surgically treated patients for total based on only two deaths. In hyperthyroid women, statistically significant cancer incidence, breast cancer, or leukemia. An elevated rate increases in the number of deaths were observed from pancreatic cancer ratio (rate ratio = 1.8, 95% CI' 1.1-3.2) was observed for (SMR = 2.6, 95% CI 1.4-4.3) and respiratory cancer (SMR = 2.2, 95% cancers of the salivary glands, digestive tract, kidney, and CI 1.3-3.5), but not breast cancer (SMR = 1.3, 95% CI 0.8-1.8). When bladder; these organs are known to concentrate radioactive the data were stratified by the time between the onset of thyroid symp iodine. Goldman et al. (17) found that women who were treated toms and death, a nonsignificant excess number of cancer deaths was with '"I at the Massachusetts General Hospital between 1946 observed in hyperthyroid women who died 20 or more years after their and 1964 had a standardized rate ratio for developing breast symptoms began. The standardized mortality ratio for deaths from breast cancer of 1.9 (95% CI 0.9-4.1), compared with those never cancer was 1.1 (95% CI 0.5-2.3) for all hypothyroid women and 1.0 treated with I3II. The standardized rate ratios were 0.7 for (95% CI 0.4-2.1) for hypothyroid women with a history of thyroid replacement hormone use. deaths due to cancer and 1.0 for incident cases of cancer. After treatment for hyperthyroidism, a majority of patients develop iatrogenic hypothyroidism and may require treatment INTRODUCTION with thyroid supplements. In 1976, Kapdi and Wolfe (18) For the last 30 years investigators have been interested in reported that women who were seen at a mammography screen what relationship, if any, there is between thyroid diseases and ing clinic and who used thyroid supplements were at high risk their treatments and the development of cancer, especially of developing breast cancer. The likelihood that selection bias breast cancer. In the 1950s, clinical investigators reported that, occurred in the design of this study prompted the American while breast cancer seldom occurred in hyperthyroid women, it Thyroid Association to urge the National Cancer Institute to seemed to occur more frequently than expected in hypothyroid support further research on the role of thyroid diseases and women (1, 2). More recently, Itoh and Maruchi (3) suggested their treatments in the etiology of cancer, particularly breast that Japanese women with Hashimoto's thyroiditis had an cancer (19). In 1978, we began a retrospective follow-up study to measure increased incidence of breast cancer, but no increase was noted mortality in women with thyroid disease who were diagnosed Received 5/17/89; revised 12/14/89. at the Massachusetts General Hospital Thyroid Clinic between The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in 1925 and 1974. This paper presents the cancer mortality results accordance with 18 LJ.S.C. Section 1734 solely to indicate this fact. for women with nontoxic nodular goiter, thyroid adenoma, 1Supported by National Cancer Institute Contract NCI-CB-84230. M. B. G. hyperthyroidism, hypothyroidism, or Hashimoto's thyroiditis. was also supported by an award from the Exxon Corporation Fellowship Program in Epidemiology. For comparison, a group of women who were referred to the 2To whom requests for reprints should be addressed, at Department of Epidemiology. Harvard School of Public Health. 677 Huntington Avenue, Bos ' The abbreviations used are: CI, confidence interval; MGH, Massachusetts ton. MA 02115. General Hospital: SMR. standardized mortality ratio. 2283
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Thyroid Clinic for examination but who were found not to have whichever came first. Since very few women reached age 80 or 90 prior thyroid disease were also included. to the closing date. Assumptions 3 and 4 had little effect. Assuming the losses to be alive until the closing date inflated the number of woman-years. The most reasonable estimates were obtained when the SUBJECTS AND METHODS losses were withdrawn at their date of loss. Definition of Period of Observation. Woman-years of follow-up were Population accrued starting from the first anniversary of the date of diagnosis of thyroid disease at MGH. The observation period ended at the common The study population was 7338 women with nontoxic nodular goiter, thyroid adenoma, hyperthyroidism, hypothyroidism, Hashimoto's thy- closing date of the study (December 31, 1978), at the date a woman was last known to be alive, or at her date of death, whichever occurred roiditis, or no thyroid disease who were first seen at the MGH Thyroid first. Women who were lost to follow-up were withdrawn at their date Clinic between January 1, 1925, and December 31, 1974; who were Massachusetts residents; and who were followed by the Hospital for at of loss. least 1 year. These women were identified from a roster of all patients Statistical Analysis that has been kept since the Clinic opened in 1920. Observed numbers of deaths were compared with those that were Diagnosis Confirmation and Medical Record Review expected based on race-, sex-, age-, calendar time-, and cause-specific The diagnosis of thyroid disease was confirmed by a review of the mortality rates using the USDR computer program (21). This program calculated the number of woman-years of follow-up and the number of MGH medical record. Patients who were referred for a thyroid workup but who were found not to have thyroid disease are included in the "no deaths that would be expected based on United States or on Massachu thyroid disease" category. The patients were categorized according to setts death rates for white women. The number of deaths observed in their first thyroid diagnosis at MGH. This means that women are the study population was compared with the expected number generated included in the "hyperthyroidism" category if they were diagnosed as by the program. The expected numbers were calculated by allocating the woman- hyperthyroid, even if they later developed iatrogenic hypothyroidism. Patients identified as "hypothyroid" are those with idiopathic hypothy years of observation of the thyroid patients to 5-year age and calendar roidism. For each patient, a medical history that included information time categories and multiplying by the corresponding death rates. The on the date of onset of thyroid symptoms, the type of thyroid treatment, results were summed over all ages and years to obtain the total expected the date of diagnosis and type of cancer (if any), smoking history, and numbers. Ratios of observed to expected numbers of deaths were reproductive history was abstracted. The patient's vital status, date she expressed as standardized mortality ratios. Confidence intervals were was last seen at MGH, her date of death if deceased, and other pertinent calculated under the assumption that the observed numbers of deaths follow-up information were also recorded. were distributed as Poisson variables (22).
Follow-up Procedures RESULTS Ascertainment of Deaths. For all women, a search of the Massachu setts death certificates was conducted. Deaths reported in the MGH The number of women, number of woman-years of follow- medical record were confirmed upon location of the death certificates. up, and vital status of the population as of December 31, 1978, The underlying cause of death was coded according to the Eighth by thyroid diagnosis, is presented in Table 1. The 7338 women Revision of the International Classification of Diseases (20). Twenty were observed for 111,654.6 woman-years, an average length decedents whose death certificates were unavailable were assumed to of 15.2 years. A total of 57.8% of the women were located have died of unknown cause on the date of death reported in the through December 31, 1978. Of these, 2231 women (30.4%) medical record. were dead and 2012 (27.4%) were alive. The 3095 women Tracing Procedures. Because of the time involved in locating women who were last seen many years ago, live follow-up tracing was restricted (42.2%) who could not be confirmed alive as of December 31, to the 3592 women who were not known to be dead and whose last 1978, and for whom no death certificate could be found, were visit to MGH was more recent than 1960. These women were traced considered lost on the date they were last known to be alive. using the Massachusetts Residents Lists, the Registry of Motor Vehi Among the losses, a minimum of 10 years of follow-up was cles drivers' license records, birth and marriage records, and telephone recorded for 40.8% and a minimum of 15 years of follow-up books. For the 1988 women who were last seen at MGH before 1961 for 26.7% of the women. and for whom no death certificate could be found, live follow-up tracing To evaluate the uncertainty presented by the women who was limited to the information recorded in the medical record. were lost to follow-up, we compared the hyperthyroid women Losses to Follow-up. Women who could not be confirmed alive as of in the present study (Mortality Study) to a second, similar December 31, 1978, and for whom no death certificate could be found, population for whom follow-up was virtually complete (Thy- were considered lost on the date they were last reported to be alive. To rotoxicosis Therapy Study). We had recently studied 1762 be eligible for this study, a woman must have been followed by MGH for at least 1 year after her thyroid diagnosis. This restriction eliminated hyperthyroid women who were treated at the MGH Thyroid the least stable group of women, i.e., those most likely to be located Unit between January 1, 1946, and December 31, 1964 (17). only if they died. Many of these women had been seen in the Clinic These women were part of the US Public Health Service Co just once and would be lost to follow-up unless a death certificate was operative Thyrotoxicosis Therapy Follow-up Study (23, 24). A found. death certificate was located or telephone contact was made In addition to the entry restriction, we tested several withdrawal with 92% of the 1762 women. For the remaining 8%, a mini assumptions for the women who were lost to follow-up prior to the mum of 10 years of follow-up was recorded for 44%. They were closing date of the study. Four different assumptions were used: As observed for 30,324.3 woman-years, an average length of fol sumption 1, women were withdrawn at their date of loss. This gave the low-up of 17.2 years. There were 734 women who were also in minimum number of woman-years of follow-up and the lowest expected the Mortality Study. number of deaths; Assumption 2, women were assumed to be alive until the common closing date. This gave the maximum number of woman- We compared the results for hyperthyroid women in both studies (Table 2). Women who were lost to follow-up were years and the highest expected number of deaths; Assumption 3, women were withdrawn either when they reached 80 years of age or at the withdrawn at their date of loss. The standardized mortality common closing date, whichever came first; Assumption 4, women ratios were both 1.4 for deaths from circulatory diseases, the were withdrawn either at age 90 years or at the common closing date, most common cause of death, and 0.9 and 1.1 for deaths from 2284
Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1990 American Association for Cancer Research. CANCER MORTALITY AFTER THYROID DISEASE Table 1 Number of women, number of woman-years, average age al entry into the study, average year of entry; and vital status, by thyroid diagnosis (%)Alive23.327.533.726.245.619.727.4Dead30.523.934.335.418.928.830.4Lost46.248.632.038.535.551.542.2status of of age at yr of diagnosisNontoxicThyroid women1.2349282.3007103181.8487,338No.woman-yr17,313.414.459.737,171.310.049.13.691.028.970.1111.654.6Av.entry(yr)46.640.143.446.844.639.9Av.entry1953.01950.11951.31951.91962.11949.7Vital goiterThyroidnodular adenomaHypcrthyroidismHypothyroidismHashimoto's
thyroiditisNo thyroid diseaseNo.
Table 2 Observed numbers of deaths, SMR,°and 95% CI, by cause of death and study, for hyperthyroid women diagnosed between 1946 and I96411
StudyCause Thyrotoxicosis Therapy StudySMR1.41.11.21.499146.11955.916,375.695% (ICD-8r)All of death CI1.2-1.40.7-1.10.8-1.91.3-1.6Observed3405212209MortalityCI1.3-1.60.8-1.40.6-2.21.3-1.7 causesAll 209)Breastcancers (140- (174)Circulatorycancer (390-458)No.system diseases ofwomenAv. (yr)Av.age at entry yr ofentryNo. of woman-yrObserved5608324359SMR1.30.91.31.41.76246.41957.230.324.395% °Observed/expected; expected numbers were based on age- and calendar time-specific mortality rales for United States white women. * Women who were followed for at least 1 year at MGH Thyroid Unit between 1946 and 1964; those lost to follow-up were withdrawn at their date of loss. Fifty- four women in the Thyrotoxicosis Therapy Study and 30 women in the Mortality Study with cancer diagnosed prior to 1946 were excluded. c ICD-8, International Classification of Diseases. Eighth Revision (20). all cancers. The similarity of the standardized mortality ratios lymphatic and hematopoietic tissues (SMR = 2.7). indicated to us that withdrawing the losses at their date of loss Among the 231 women (24.9%) who were current or former for the analysis of the Mortality Study data was reasonable. smokers, 39 deaths from all causes were observed (27.3 ex The observed numbers of deaths and standardized mortality pected, SMR = 1.4, 95% CI 1.0-2.0). There were 16 observed ratios for deaths from all causes, all cancers, and selected cancer cancer deaths while 7.6 were expected (SMR = 2.1, 95% CI sites for each thyroid diagnosis are presented in Table 3. 1.2-3.4). The standardized mortality ratio for cancers of the respiratory system was 5.6 (4 observed deaths/0.7 expected, Nontoxic Nodular Goiter 95% CI 1.5-14.3) in smokers and 2.3(5 observed/2.1 expected, For the 1234 women with nontoxic nodular goiter, the stand 95% CI 0.8-5.5) in nonsmokers. ardized mortality ratio for deaths from all causes was 1.2 (95% CI 1.1-1.3). There were significantly more deaths from cancer Hyperthyroidism (SMR = 1.5) than were expected. Increased numbers of deaths For the 2300 women with hyperthyroidism, the standardized were observed from cancers of the respiratory system (SMR = mortality ratio was 1.4 for all causes of death and 1.2 for all 2.3) and lymphatic and hematopoietic tissues (SMR = 2.4). A cancers. Twenty-seven deaths from breast cancer were observed SMR of 1.6 was observed for deaths from breast cancer. while 21.6 were expected (SMR = 1.3). Excess numbers of Among the 277 women (22.5%) who reported that they were deaths were observed from pancreatic cancer (SMR = 2.6) and current or former smokers, 66 deaths from all causes were respiratory cancer (SMR = 2.2). Fifteen of the 17 respiratory observed while 45.0 were expected (SMR = 1.5, 95% CI 1.1- cancer deaths were from lung cancer (SMR = 2.0). 1.9). A SMR of 1.2 (95% Cl 1.0-1.3) was observed for those For the 681 women (29.6%) who reported that they were with no mention of smoking in their medical record. Among current or former smokers, significant increases in the number the smokers, a significant increase in the number of deaths of deaths were observed for deaths from all causes (SMR = 1.6, from cancer (21 observed/10.0 expected, SMR = 2.1, 95% CI 95% CI 1.4-1.9) and from cancer (SMR = 1.5, 95% CI 1.1- 1.3-3.2) was observed. The standardized mortality ratio for 2.1). The standardized mortality ratio was 1.8 (95% CI 0.2- cancer deaths among nonsmokers was 1.3 (95% CI 1.0-1.7). 6.4) for pancreatic cancer deaths, 2.6 (95% CI 1.0-5.8) for When specific cancer sites were looked at among the smokers, respiratory cancer deaths, and 1.9 (95% CI 0.9-3.4) for breast the standardized mortality ratio was 16.1 for buccal cavity and cancer deaths. pharyngeal cancer deaths (2 observed/0.1 expected, 95% CI Treatment with Radioactive Iodine. Among the 873 women 1.8-58.1), 6.2 for respiratory cancer deaths (5 observed/0.8 who were treated with radioactive iodine between 1946 and expected, 95% CI 2.0-14.5), 2.4 for breast cancer deaths (5 1975, the standardized mortality ratios were 1.4 (95% CI 1.2- observed/2.1 expected, 95% CI 0.8-5.7), and 3.7 (3 observed/ 1.6) for all causes of death, 1.5 (95% CI 1.3-1.7) for all 0.8 expected, 95% CI 0.7-10.7) for lymphatic and hemato circulatory disease deaths, and 1.1 (95% CI 0.8-1.4) for all poietic cancer deaths. cancer deaths. The standardized mortality ratio was 2.2 (95% CI 0.7-5.2) for pancreatic cancer deaths, 1.7 (95% CI 0.6-3.8) Thyroid Adenoma for respiratory cancer deaths, and 1.7 (95% CI 0.9-2.8) for The standardized mortality ratio for deaths from all causes breast cancer deaths. for the 928 women with thyroid adenoma was 1.2 (95% CI 1.0- Thyroid Replacement Hormone Use. latrogenic hypothyroid- 1.3). A significant increase in the number of deaths due to ¡smmay occur 10 years or more after treatment for hyperthy cancer (SMR = 1.5) was observed. There were also more deaths roidism, due to the ablative nature of the therapy. There were than expected from cancers of the large intestine (SMR = 2.0), 1050 women (45.7%) with an initial diagnosis of hyperthyroid respiratory system (SMR = 3.2), thyroid (SMR = 11.7), and ism who later reported treatment with thyroid replacement 2285
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o¿o77 r- os ON M o. vi ^77• ;1B«fl - . •¿ O •¿ Ov fS —¿ r-O —¿ —¿ —¿ ^*I*J *> t ^ïii H r* H o o ^3 ^ —¿ iiiON(-- i i 7 7 i o*OS2C«•oyÕ.ouÈSl/ìiuSÕOuSairOOd OO «N ^ O O O •¿ — dfNfNd d ~ d d ^(N^\cOO^— rjvifs'o——¿ OCfN Os' —¿ O —¿ d— ^t —¿ —¿ XIII scSeS•ss lili^dddddddddViOOXVl II J?-13E: O_; —¿ fNON —¿ 00 Q1%!•c'C6?S•ksqg"Si:g•«'~g-number--JÃ^wfN.J —¿ ^O*N äjS1*iSiuHisease-o'5.Cc*.—¿ d —¿ d !2 r-OfSÕN22 ÕN ^t fS ro CN rN 1£ 2^ sU —¿ S •¿ ï OauS.a•3•o'|.¿oZ^5I—'Q0SJ=X•J-.3'~ç.e'1KX.—•5îA1X1o5nS777ï Si 27 S i 3 i S^'77j^ 5£1 _:_'_:c!Ööö21^^2233232 —¿ —¿ •¿ ö IJ~£ Sv:15-1ÕNo^o-o^^r-r^-ovr~ 1% &S o¿ 1S —¿ — j^Oö °E10 r.j— n1 viII ^.' fi ró fi fi ^' *O iN -»t »r,o*v¡T3>1OCWÃŒ9tesSVIpCio£~~XÃIli«*— 1 1 1 . J. ^-*.r> ! |¿ —¿ _' 0 0 0 0 —¿ ' 0 —¿ *J co»•D3'5>.HS'Ij"3T3Oe•aoCZi g•o rs(NON—¿ ' —¿ ' o (N d ~ fì —¿ --(N --irtCO w— Ci"3 ^«•a .£sCi« OfNOOrN r- fNsOr~-i —¿ -J O -- —¿ • OOO--"r~ fì (N 00 fi ^ ON •¿ §ö oo—¿ UOtfvi fN —¿ g"Sg- otu^ ^: r^ „¿ •m =:Z ö ööö (M•oc-—.—r^9 je.—.¡2 B OBJB -^ u *•u 3¿w •¿ 1-^ r, —¿ 4 UH 4 0J•e*£seGwO*-gi'S&o£3sm 11 .111s^ •¿ ^WO^i 4j m >,^' —¿ cis °"5"aj'5 it/)OS;Oc5""i o ^^ .H •¿ —¿ - ' w -—¿ •¿ oi ^ ^'•—c5 P"S~""SB 8 èaP®1*"*§|.Sa5*3£ïj&| fi viwt--;;o-"^ ||--Q fix » II x x tig(j x £ §i<< aäcQH-J Z'S£1i 2286 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1990 American Association for Cancer Research. CANCER MORTALITY AFTER THYROID DISEASE hormone. For these women, the standardized mortality ratios OO7^ fi Vi fi were 1.2(95% CI 1.0-1.3) for all causes of death and 1.1 (95% —¿ K51/3•oETfi"TT T "! CI 0.9-1.4) for all cancer deaths. For specific cancer sites, the 00•^O *t fl —¿ standardized mortality ratios were 2.2 (95% CI 0.8-4.8) for stomach cancer, 2.3 (95% CI 0.9-5.1) for pancreatic cancer, «0,•g§SC1^S|ÕÕCs111iS)*N•fN«fN *O fN O --o « r-i p-i fN 1.2 (95% CI 0.4-2.8) for respiratory cancer, and 1.4 (95% CI 0.8-2.3) for breast cancer deaths. ^o t r- v, i Time since Onset of Thyroid Symptoms. For the hyperthyroid t- —¿ vi women, the largest thyroid diagnosis group, the standardized 1OJsP0"- mortality ratios and observed numbers of deaths for all causes "ÃŒfNr-i^^ai fN'vi fi of death were stratified by the length of time between the onset «i&>2 -^fIIIrs —¿ —¿ " 1-T 1 O—? -T t t of thyroid symptoms and death (Table 4). The standardized o--*' o —¿ ' d mortality ratio for all causes of death increased from 1.2 for those with an interval of less than 10 years between onset and death to 1.8 for those women who died 40 years or more after i/i•oH1o— ^i fi the onset of their thyroid symptoms. A small increase in the number of cancer deaths was observed in women who died 20 —¿ sOfi fi fN fN years or more after their symptoms began. There were more Ofi deaths than expected from pancreatic, respiratory, and breast O- 00 VI O V. cancer. For pancreatic and respiratory cancer deaths, the excess «fiIII » l—¿ oO ^ —¿ r-fi CI 0.9-1.5). Thirteen cancer deaths were observed while 10.6 O1-0—¿ r- fi fN 0XJ5 '^~ were expected (SMR = 1.2). An excess number of deaths due fNv, to stomach cancer (SMR = 5.8) was observed but was based on *2 5,O only three deaths. fi«f, r- o fN —¿ time-specific ofdeathaH•c1G"ÄKm1^••f.«r^À« f*ÃŒ ^ *f nt'—eralHospital: VI— ' ' f- fl No Thyroid Disease ' d odd There were 1848 women who were examined in the Thyroid SC/3T3EüoIe„C/3|-O0$£"ö—¿ do—¿ — —¿ —¿ ¿~OVS?_S^a. Clinic but found not to have thyroid disease. For these women, Clog^¡ the standardized mortality ratio for deaths due to all causes was *2fNS~ 1.5 (95% CI 1.4-1.6). Excess numbers of deaths due to liver fi""fN-T "—'u c•0 (SMR = 2.5) and lymphatic and hematopoietic (SMR = 2.4) 3 -S cancers were observed. Elevated numbers of deaths due to M (j"Jä fN¿™r- —¿ oq ÕN «¿° respiratory cancer (5 observed deaths/1 expected, SMR = 4.9, T *? i i â„¢¿ 95% CI 1.6-11.3) and liver cancer (4 observed deaths/0.3 ooo r- ^ fi w"a4» —¿ doddfN expected, SMR = 13.0, 95% CI 3.5-33.2) occurred in the 413 *^UJ• •¿ rfi-ll!11 women in this category who reported that they smoked. r-4 CT« r~- —¿ & —¿ i--OVi O fN fN 1ÃŽE3 Thyroid Supplements and Breast Cancer Risk ViVi.. .. ^ (*^ Among the 5038 women with a diagnosis of nontoxic nodular fiv—i goiter, thyroid adenoma, idiopathic hypothyroidism, Hashi 1filed/expected. moto's thyroiditis, or no thyroid disease, 2113 women (41.9%) C•^f0s«.'SIwOlCol'Z>£^7iE? reported the use of thyroid replacement hormone. The stand iwhoweref ardized mortality ratio for breast cancer was 1.5 (25 observed/ Internatiom%îè 17 expected deaths, 95% CI 1.0-2.2) among hormone users '•*c «^ ^ —¿ Q 2 ° ^0 u NO t and 1.2 (31 observed/25.4 expected deaths, 95% CI 0.8-1.7) —¿ •¿ • j^— 4i —¿ O CIII *—' U ^^ ^* 1 W for the 2925 nonusers. The excess number of breast cancer I~ÖVI deaths occurred in the 479 women with nontoxic nodular goiter (38.8% of the 1234 women with nontoxic nodular goiter) who III< o'f^« were treated with thyroid replacement hormone. The SMR for <ú°'si^u'S£•d < ^ breast cancer for these women was 2.8 (11 observed/3.9 ex- 2287 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1990 American Association for Cancer Research. CANCER MORTALITY AFTER THYROID DISEASE pected deaths, 95% CI 1.4-5.1) compared to 1.0 (7 observed/ adenoma and hyperthyroidism, but the confidence intervals 7.3 expected deaths, 95% CI 0.4-2.0) for women with nontoxic included unity. No increase in breast cancer risk was observed nodular goiter who were not treated with thyroid replacement in hyperthyroid women who were treated with '-"I. hormone. For the 1634 women with diagnoses other than We analyzed the data separately for patients with nontoxic nontoxic nodular goiter who used thyroid supplements, the nodular goiter, thyroid adenoma, idiopathic hypothyroidism, SMR for breast cancer was 1.1 (95% CI 0.6-1.8). A total of Hashimoto's thyroiditis, or no thyroid disease whose medical 684 of the 710 women (96.3%) with a diagnosis of idiopathic record reported that they used thyroid supplements. In addition, hypothyroidism reported use of thyroid supplements. In these we studied the women with an initial diagnosis of hyperthyroid women the SMR for breast cancer was 1.0 (6 observed/6.2 ism who developed iatrogenic hypothyroidism due to the abla expected deaths, 95% CI 0.4-2.1). tive nature of their treatment. Iatrogenic hypothyroidism is a common occurrence 10 years or more after treatment for hy perthyroidism and may occur earlier in radioactive iodine- DISCUSSION treated individuals than in patients treated by surgery or drugs. A number of studies have been conducted (1-18, 23, 24), but- Forty-six percent of the women who were initially diagnosed any role for thyroid diseases, or their treatments, in the etiology as hyperthyroid and 96% of the women with idiopathic hypo of cancer remains unclear. In this paper, we present the results thyroidism reported the use of supplements, but no increase in of our investigation into the relationship between benign thy breast cancer risk was noted in these women. The only group roid disease and subsequent death from cancer in women pa with a significant increase in the number of breast cancer deaths tients seen at the MGH Thyroid Clinic between 1925 and 1974. were the nontoxic nodular goiter patients who reported using A standardized mortality ratio for all causes of death of 1.2 or thyroid supplements. This finding was unanticipated and re greater was observed in each category of thyroid disease studied. quires replication in an independent dataset. Statistically significant increases in the risk of death from all Kapdi and Wolfe (18) first suggested that either hypothyroid cancers were observed in women with nontoxic nodular goiter, ism or the use of thyroid replacement hormone increased a woman's breast cancer risk. They interviewed 5505 women who thyroid adenoma, hyperthyroidism, and no thyroid disease. While the 7338 women were observed for a reasonably long were referred to a mammography screening clinic and con time, an average of 15.2 years, a limitation of this study is the cluded that women who were receiving thyroid supplements large number of women who were lost to follow-up. To quantify were 60% more likely to develop breast cancer than those who the uncertainty presented by the losses, we constructed six never used thyroid supplements (age-adjusted rate ratio = 1.6, analysis categories based on various entry criteria and with 95% CI 1.2-2.1). Referral for mammography was likely to have drawal assumptions and calculated a range of values for each been selective in this population, however. The high proportion standardized mortality ratio. When we restricted the study of breast cancer cases among the women screened (6.9%) sug population to women with at least 1 year of follow-up at MGH gests that these women sought a mammogram because they and withdrew the losses at their date of loss, our results were were motivated by health concerns. In addition, the proportion very similar to those of the Thyrotoxicosis Therapy Study, of thyroid hormone users among subjects without breast cancer which had a location rate of 92%. The presence of bias due to was 10.9% indicating that users were taking the medicine for loss to follow-up cannot be ruled out, but the similarity of the purposes other than hypothyroidism, which is a relatively un results of the two studies indicates that bias is not a likely common condition. The use of thyroid supplements in the explanation for the results that we observed. absence of hypothyroidism reflects a preoccupation with health Vena et al. (25) have recently published a thoughtful analysis that may have influenced the likelihood of referral to the and discussion of the issues involved in assessing and quanti mammography clinic. fying the presence of loss to follow-up bias. They point out that Our essentially negative results are consistent with those of if subjects who are lost to follow-up are treated as alive until two recent studies. In 1980, Shapiro et al. (26) reported the the close of the study, mortality will be underestimated since rate of thyroid hormone use in 679 breast cancer patients all of the observed deaths have not been identified and the compared with that in 1765 patients hospitalized for other expected numbers are maximized. Treating the losses as lost diseases and found no evidence of an association between the on the date of last contact provides an unbiased estimate of the diagnosis of breast cancer and use of thyroid supplements (rate mortality among those whose vital status is known. ratio = 1.0, 95% CI 0.7-1.3). Similarly, Hoffman et al. (27) A few comments about the clinical interpretation of the reported that, 1 year or more after a diagnosis of hypothyroid thyroid diagnoses are in order. This study spans 50 years in the ism, 47 cases of breast cancer were observed in 1665 women history of the MGH Thyroid Clinic. The medical procedures while 52.9 cases were expected (standardized incidence ratio = and laboratory tests that were available to aid in diagnosis 0.9, 95% CI 0.6-1.2). underwent many changes over that time. We have categorized Several studies have reported an increased risk of myelopro- the patients as the examining physicians did, since these labels liferative and lymphoproliferative cancers in patients with reflect the treatment practices in use at the time of diagnosis. chronic thyroiditis (28-30). We observed a >2-fold increase in By doing so we also maintain consistency between diagnoses, risk of death from these cancers in women with nontoxic at any given time period, and minimize the introduction of nodular goiter, thyroid adenoma, and no thyroid disease, but no increase in the women with Hashimoto's thyroiditis. Ap misclassification. Clinicians today will realize that it is likely that a subset of the women who were diagnosed as hypothyroid proximately one-half of the deaths observed in these categories would be diagnosed as having Hashimoto's thyroiditis today. were due to leukemia and the remainder were due to Hodgkin's Similarly, some of the women with nontoxic nodular goiter disease and other lymphomas. would currently be diagnosed as having Hashimoto's thyroidi An excess number of pancreatic cancer deaths among women tis. with hyperthyroidism appeared among those with 20 years or With regard to breast cancer, 30% increases in the number more between the onset of thyroid symptoms and death. Since of breast cancer deaths were observed in women with thyroid diabetes is known to be a risk factor for pancreatic cancer and 2288 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1990 American Association for Cancer Research. CANCER MORTALITY AFTER THYROID DISEASE to occur more frequently than expected among patients with following radioiodine therapy for carcinoma thyroid. Br. J. Radiol.. 50: 61- Graves' disease, a possible connection between the etiologies of 64, 1977. 10. Araki. M., and Oshiro, K. Papillary adenocarcinoma of the thyroid devel the two autoimmune diseases, Graves' disease and diabetes, oping after treatment of hyperthyroidism with I3I-I. Gann, 61: 267-269, 1970. and pancreatic cancer is intriguing. In 1982, Haines et al. (31) 11. Kreps. E. M., Kreps. S. M., and Kreps, S. 1. Treatment of hyperthyroidism reported in a case-control study of pancreatic cancer that 3 of with sodium iodide I 131. Carcinoma of the thyroid after 20 years. JAMA, 226:774-775, 1973. 60 female cases but only 1 of 120 control women had a history 12. McDougall. I. R. Thyroid cancer after iodine-131 therapy. JAMA. 227:438. of hyperthyroidism. 1974. A significant increase in the number of deaths from all 13. Donovan, J. W., and Adelstein, A. M. Multiple-cause analysis of deaths of patients treated with radio-iodine. Br. J. Prev. Soc. Med., 28: 69, 1974. cancers was observed in the women who were seen in the Clinic 14. Warner. T. F. C. S.. and Peralta. J. Multifocal adenocarcinoma of the but who did not have thyroid disease. Risks were more than jejunum. Cancer (Phila.), 44: 1142-1145, 1979. 15. Muñoz,J. M.. Gorman. C. A., Elveback, L. R.. and Wentz. J. R. Incidence doubled for deaths from liver cancer and lymphatic and hema- of malignant neoplasms of all types in patients with Graves' disease. Arch. topoietic cancers. These results suggest that these women were Intern. Med.. 138:944-947, 1978. ill and had been referred to the Thyroid Clinic for evaluation 16. Hoffman, D. A.. McConahey. W. M.. Fraumcni, J. F., Jr.. and Kurland, L. T. Cancer incidence following treatment of hyperthyroidism. Int. J. Epide- but were, in fact, suffering from nonthyroid diseases. miol., / 7:218-224, 1982. In summary, women with the thyroid diagnoses included in 17. Goldman, M. B., Maloof, F., Monson, R. R.. Aschengrau. A.. Cooper, D. this study were not at an increased risk of death from breast S., and Ridgway. E. C. Radioactive iodine therapy and breast cancer: a follow-up study of hyperthyroid women. Am. J. Epidemiol.. 727: 969-980, cancer with the exception of those with nontoxic nodular goiter 1988. who used thyroid supplements. A significant increase in the 18. Kapdi, C. C., and Wolfe, J. N. Breast cancer. Relationship to thyroid supplements for hypolhyroidism. JAMA, 236: 1124-1127, 1976. number of deaths from lymphatic and hematopoietic cancers 19. Gorman, C. A.. Becker, D. V., Greenspan, F. S., Levy. R. P., Oppenheimer, was observed in women with nontoxic nodular goiter and J. H., Rivlin. R. S., Robbins, J.. and VanderLaan. W. P. American Thyroid thyroid adenoma. Statistically significant excess numbers of Association Statement. Breast cancer and thyroid hormone therapy. Ann. Intern. Med.. 86: 502-503, 1977. deaths due to pancreatic and respiratory cancers were observed 20. World Health Organization. Manual of the International Statistical Classi in hyperthyroid women. The excess of pancreatic cancer deaths fication of Diseases. Injuries, and Causes of Death. WHO, Geneva, 8th first appeared 20 years after the onset of thyroid symptoms and Revision, 1967. 21. Monson, R. R. Analysis of relative survival and proportional mortality. was present at the end of 40 years or more of observation. Comput. Biomed. Res.. 7: 325-332. 1974. 22. Rothman, K. J., and Boice, J. D. Epidemiologie Analysis with a Program mable Calculator, p. 29. Boston: Epidemiology Resources, Inc.. 1982. ACKNOWLEDGMENTS 23. Saenger, E. L.. Thoma, G. E., and Tompkins. E. A. Incidence of leukemia following treatment of hyperthyroidism. Preliminary report of the Coopera tive Thyrotoxicosis Therapy Follow-up Study. JAMA. 205: 855-862. 1968. We gratefully acknowledge the assistance of Pamela Boardman, 24. Dobyns, B. M., Sheline, G. E.. Workman, J. B., Tompkins, E. A., Mc Mark Josefski, Doris Rosoff. and Kenneth Schoendorf. Conahey, W. M.. and Becker. D. V. Malignant and benign neoplasms of the thyroid in patients treated for hyperthyroidism: a report of the Cooperative Thyrotoxicosis Therapy Follow-up Study. J. Clin. Endocrinol. Metab., 38: REFERENCES 976-988, 1974. 25. Vena, J. E., Sultz, H. A., Carlo, G. L., Fiedler, R. C., and Barnes. R. E. Sources of bias in retrospective cohort mortality studies: a note on treatment 1. Loeser, A. A. A new therapy for prevention of post-operative recurrences in of subjects lost to follow-up. J. Occup. Med.. 29: 256-261, 1987. genital and breast cancer. A six-years study of prophylactic thyroid treatment. 26. Shapiro, S., Slone, D.. Kaufman, D. W., Rosenberg. L., Miettinen, O. S., Br. Med. J., 2: 1380-1383. 1954. Stolley. P. D.. Knapp. R. C., Leavitt. T.. Watring, W. G., Rosenshein, N. B., 2. Ellerker. A. G. Thyroid disorders and breast cancer. A causal connection? and Schottenfeld. D. Use of thyroid supplements in relation to the risk of Med. Press. 235: 280-282, 1956. breast cancer. JAMA, 244: 1685-1687, 1980. 3. Itoh, K.. and Maruchi. N. Breast cancer in patients with Hashimoto's 27. Hoffman, D. A., McConahey, W. M., Brinton, L. A., and Fraumeni, J. F., thyroiditis. Lancet, 2: 1119-1121, 1975. 4. Kurland. L. T.. and Annegers. J. F. Breast cancer and Hashimoto's thyroid Jr., Breast cancer in hypothyroid women using thyroid supplements. JAMA, 257:616-619. 1984. itis. Lancet. 7:808, 1976. 28. Holm. L. E., Blongren. H., and Lowhagen, T. Cancer risks in patients with 5. Edelstyn, G. A., Lyons, A. R., and Welbourn. R. B. Thyroid function in chronic lymphocytic thyroiditis. N. Engl. J. Med., 312:601-604. 1985. patients with mammary cancer. Lancet, /: 670-671, 1958. 29. Kato, I.. Tajima, K.. Suchi, T., Aozasa, K., Matsuzuka. F., Kuma, K., and 6. Backwinkel, K., and Jackson, A. S. Some features of breast cancer and Tominaga, S. Chronic thyroiditis as a risk factor of B-cell lymphoma in the thyroid deficiency. Cancer (Phila.), 17: 1174-1176, 1964. thyroid gland. Jpn. J. Cancer Res.. 76: 1085-1090. 1985. 7. McCormack, K. R.. and Sheline. G. E. Leukemia after radioiodine therapy 30. Fukuda. A., Hirohata, T., Noguchi. S.. Ikeda. M.. Matsuo, K., and Yoshida. for hyperthyroidism. Calif. Med., 98: 207-209. 1963. A. Risks for malignancies in patients with chronic thyroiditis: a long-term 8. Kennedy, W. M., and Fish, R. G. Acute granulocytic leukemia after radio follow-up study. Jpn. J. Cancer Res., 78: 1329-1334, 1987. active-iodine therapy for hyperthyroidism. N. Engl. J. Med., 260: 76-77. 31. Haines, A. P.. Moss, A. R., Whittemore, A., and Quivey, J. A case-control 1959. study of pancreatic carcinoma. J. Cancer Res. Clin. Oncol., 70.}: 93-97. 9. Bundi, R. S., Scott, J. S., and Hainan, K. E. Chronic myeloid leukemia 1982. 2289 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1990 American Association for Cancer Research. Cancer Mortality in Women with Thyroid Disease Marlene B. Goldman, Richard R. Monson and Farahe Maloof Cancer Res 1990;50:2283-2289. Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/50/8/2283 E-mail alerts Sign up to receive free email-alerts related to this article or journal. Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected]. Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/50/8/2283. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site. 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