Long-Term Prognosis of Thyroid Nodule Cases Compared with ...

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The Journal of Clinical Endocrinology & Metabolism 90(9):5009 –5014 Copyright © 2005 by The Endocrine Society doi: 10.1210/jc.2005-0268

Long-Term Prognosis of Thyroid Nodule Cases Compared with Nodule-Free Controls in Atomic Bomb Survivors Misa Imaizumi, Toshiro Usa, Tan Tominaga, Masazumi Akahoshi, Kiyoto Ashizawa, Shinichiro Ichimaru, Eiji Nakashima, Reiko Ishii, Eri Ejima, Ayumi Hida, Midori Soda, Renju Maeda, Shigenobu Nagataki, and Katsumi Eguchi Departments of Clinical Studies (M.I., M.A., K.A., S.I., A.H., M.S., R.M.) and Statistics (E.N.), Radiation Effects Research Foundation, Nagasaki 850-0013, Japan; First Department of Internal Medicine (M.I., T.U., R.I., E.E., K.E.), Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan; Department of Internal Medicine (T.T.), Sasebo Chuo Hospital, Nagasaki 857-1195, Japan; and Japan Radioisotope Association (S.N.), Tokyo 113-8941, Japan Context: Radiation exposure is associated with development of thyroid nodules. The long-term risk of thyroid cancer development in irradiated people with thyroid nodules, however, has not been clarified. Objective: The objective of this study was to assess the long-term risk of cancer development in irradiated individuals with thyroid nodules. Design, Setting, and Participants: This prospective study comprised 2637 atomic bomb survivors (mean age, 59 yr; 1071 men and 1566 women) who participated in the baseline thyroid study of the Nagasaki Radiation Effects Research Foundation from 1984 through 1987. The participants were divided into three groups at baseline by ultrasound findings: 82 cases of solid thyroid nodules other than cancer, 121 cases of thyroid cysts, and 2434 thyroid nodule-free controls. Both the solid nodule and the cyst groups included postoperative cases. In the solid nodule group, 68 cases had ultrasound-detected solid nodules, including 31 cases diagnosed as benign by cytological or histological examination. They were followed for an average of 13.3 yr.

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T IS WIDELY known that individuals exposed to radiation are at high risk for development of thyroid nodules and cancers (1– 4). Especially in atomic bomb survivors, it has been reported that thyroid nodule and cancer prevalence increased with radiation dose (5, 6). Ultrasonography is widely recognized as useful in the detection of thyroid nodules, and this technology has been commonly used in numerous studies of irradiated individuals (7, 8). Most thyroid nodules detected by ultrasonography are reported to be benign (9, 10). However, whether patients with benign thyroid nodules have increased risk of developing thyroid cancer is uncertain. Many case-control studies of thyroid cancer showed more preexisting benign thyroid nodules and goiter in cancer patients than in control subjects (11–19). These case-control studies, however, had

First Published Online June 7, 2005 Abbreviations: CI, Confidence interval; DS86, Dosimetry System 1986; HR, hazard ratio; RERF, Radiation Effects Research Foundation; Tg-Ab, antithyroglobulin antibody. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

Main Outcome Measure: Incident thyroid cancer was measured during an average 13.3-yr follow-up period. Results: During the follow-up period, six thyroid cancer cases (7.3%) were found in the solid nodule group, seven cases in the controls (0.3%), and one case (0.8%) in the cyst group. In 31 cases with solid nodules diagnosed as benign, three cases (9.7%) developed thyroid cancer. The hazard ratio (HR) for cancer development was significantly high at 23.6 [95% confidence interval (CI), 7.6 –72.8] in the solid nodule group (HR, 40.2; 95% CI, 9.4 –173.0 in 31 people with solid nodules diagnosed as benign) but not in the cyst group (HR, 2.7; 95% CI, 0.3–22.2), after controlling for age and sex. Sex, age, TSH level, thyroglobulin level, radiation dose, nodule volume, and increase in nodule volume did not predict cancer development in the solid nodule group. Conclusions: Risk of thyroid cancer development is high in atomic bomb survivors with solid thyroid nodules, suggesting the need for careful observation of irradiated individuals with such nodules. (J Clin Endocrinol Metab 90: 5009 –5014, 2005)

potential bias because most data came from retrospective histories obtained from cases of cancer and controls. On the other hand, prospective studies on outcomes of patients with benign thyroid nodules have seldom been conducted (20, 21). For irradiated individuals, who are at higher risk for both thyroid nodules and cancer than the general population, outcomes of thyroid nodules should be clarified to attain adequate follow-up. We conducted a thyroid disease study between 1984 and 1987 on 2856 atomic bomb survivors, identifying subjects with solid nodules or cysts (7). In the present study, we followed the solid thyroid nodule and cyst cases, as well as controls without thyroid nodules, for an average of 13 yr and investigated the risk for thyroid cancer development. We also studied possible clinical risk factors for thyroid cancer in people with thyroid nodules. Subjects and Methods Subjects and baseline measurements A total of 7564 subjects (3374 men and 4190 women) have undergone biennial examinations in Nagasaki since 1958 in the follow-up of atomic bomb survivors by the Radiation Effects Research Foundation (RERF;

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J Clin Endocrinol Metab, September 2005, 90(9):5009 –5014

formerly the Atomic Bomb Casualty Commission). A detailed description of this program has been published elsewhere (Atomic Bomb Casualty Commission and RERF, Research Plan for RERF Research Protocol 2-75, 1975). At the baseline period, between October 1984 and April 1987, 2856 subjects (1119 men, 1737 women, mean age 58.5 yr) agreed to participate in the thyroid disease screening. The detailed procedures of this study were described in a prior publication (7). In brief, trained nurses recorded information on history of thyroid disease and treatment. A fasting blood sample was drawn for measurements of TSH, thyroglobulin, and antithyroglobulin antibody (Tg-Ab). Subjects were described as positive for Tg-Ab if a positive result was obtained at a dilution in excess of 1/100. A high-resolution arch-automatic scanning ultrasonographic instrument (Aloka SSD-270, Aloka ASU-46, 7.5 MHX annular array probe, immersion-in-water method, mechanical scanning, Aloka Co., Ltd., Tokyo, Japan) was used to scan the thyroid in the range of 50 ⫻ 140 mm in all participants. An automatic camera connected to the ultrasonographic system provided cross-sectional serial images measuring 1–5 mm wide (usually 5 mm). At least two experts examined the images. The cross-sectional thyroid nodule images, if any nodules existed, were traced for volume measurement by a digitizer attached to the automatic analyzer (22). Subjects with solid thyroid nodules were referred to Nagasaki University Hospital for further examination. The following people were excluded from analysis in this study: individuals with a history of thyroid cancer (n ⫽ 21), those with a history of unknown thyroid diseases or a history of surgery or radiation therapy for unknown thyroid diseases (n ⫽ 61), and those suspected but not confirmed to have thyroid nodules by at least two experts (n ⫽ 137). There exists the possibility that people undergoing surgery for thyroid nodules may still have a higher risk for development of thyroid cancer in their residual thyroid glands than people without a history of thyroid nodule operation. Therefore, patients with either a history of surgery for solid thyroid nodules or a presence of solid thyroid nodules detected by ultrasonography (greater than 5 mm in diameter) were classified as the solid nodule group (n ⫽ 82). Patients with either a history of surgery for thyroid cyst or a presence of thyroid cyst detected by ultrasonography (greater than 5 mm in diameter) without a history or a presence of solid nodules were classified as the cyst group (n ⫽ 121). A cystic nodule with solid component was classified as a solid nodule. People without either solid nodules or cysts were considered to be the control group (n ⫽ 2434). Our study, therefore, involved a total of 2637 subjects (mean age 59 yr, 1071 men and 1566 women). Table 1 shows the classification of subjects in the solid nodule group and the cyst group. In the solid nodule group, 19 people were postoperative cases. Among them, solid nodules were detected in residual thyroids in five cases by ultrasonography. Sixtyeight people, including five postoperative cases, had solid nodules detected by ultrasonography in the baseline thyroid study. Thirty-seven cases with palpable solid nodules were evaluated by fine needle aspiration biopsy because the high-resolution ultrasound used in the baseline study recorded the images of the thyroid automatically, and a

Imaizumi et al. • Prognosis of Thyroid Nodules after Radiation Exposure

high-resolution-ultrasound-guided aspiration biopsy was not available in our institute at the baseline period. Among them, one case was diagnosed as follicular adenoma by histological examination. Table 2 shows the volume of aspirated and nonaspirated solid nodules. Cytological diagnosis was classified into the following categories: benign lesion, indeterminate (the presence of atypical follicular cells), suspicious for malignancy, and malignant. None of the solid nodule cases belonged to the suspicious for malignancy or malignant groups. The nonpalpable solid nodule cases (n ⫽ 31) were not evaluated either by histological or cytological examination. Aspiration biopsy was not performed for cyst cases because it is thought that cystic thyroid nodules are less malignant than solid nodules (23), and cyst cases in our study are considered to have a lower possibility of malignancy because we defined cyst as cyst without solid component. The Dosimetry System 1986 (DS86) (24) was used in estimating the thyroid radiation doses of individual subjects. Subjects that were exposed in utero (n ⫽ 74), those not in city at the time of the bombings (n ⫽ 178), and those with unknown radiation dose (n ⫽ 573) were excluded from analyses using thyroid radiation dose. This study was reviewed and approved by an institutional ethical committee at RERF, the Human Investigation Committee, and written informed consent was obtained from all subjects participating in the second thyroid study (see below).

Follow-up procedure Cohort members of RERF’s program have undergone biennial general health examinations at Nagasaki RERF, as described above. Therefore, all participants in this study visited RERF biennially for general health examination including thyroid palpation after the baseline examination. When abnormalities were found in the thyroid palpation, thyroid ultrasonography was performed, and the subjects were referred to Nagasaki University hospital for further examination. When thyroid surgery was performed, surgical and pathological reports were reviewed by thyroid experts. Nagasaki Prefectural Cancer Registry (25) gave us permission to use its collected case information. Incident thyroid cancer cases were also ascertained through records linked to Nagasaki Prefectural Cancer Registry and the second thyroid study described below. Follow-up began on the date of the baseline thyroid study (October 1984 to April 1987) and ended on the date of diagnosis of thyroid cancer, the date of migration or death, December 1998 for nonparticipants in the second thyroid study, or the examination date of the second thyroid study, whichever came first. We performed the second thyroid study between March 2000 and February 2003. Among the 2637 participants of the baseline thyroid study, 636 people had died or dropped out of our program because of migration by the time of the second thyroid study. A total of 2001 people were eligible for participation in the second thyroid study, but 607 people were unavailable or refused to participate. As a result, 1394 participants (70%) of the 2001 people [1272 of 1836 (69%) in the control group, 68 of 94 (72%) in the cyst group, and 54 of 71 (76%) in the solid

TABLE 1. Classification of subjects in solid nodule and cyst groups at baseline thyroid study (1984 –1987) Groups (n)

Cyst (121) Postoperative Ultrasound-detected Solid nodule (82) Postoperative Ultrasound-detected

No. of subjects

Histological or cytological diagnosis

No. of subjects

2

Cysta

2

120 (including 1 postoperative cyst case)

N.D.a

120

19

Follicular adenomaa Adenomatous goitera

16 3

68 (including 5 postoperative nodule cases)

Follicular adenomaa Benignb Indeterminateb Inadequate sampleb N.D.b

1 30 4 2 31

N.D., Histological or cytological examinations were not conducted. Thirty-seven of ultrasound-detected solid nodule cases including one follicular adenoma case were examined by aspiration biopsy. a Histological diagnosis. b Cytological diagnosis.


TABLE 2. Nodule volume of solid nodule cases Nodule volume

No. of aspirated nodule cases

No. of nonaspirated nodule cases

4 32 1 37

9 21 1 31

⬍1 cm3 (0.4 – 0.9 cm3) ⱖ1 cm3 (1.0 –20.1 cm3) Unknown Total

“Unknown” indicates that thyroid nodule volume could not be measured because of a large calcified lesion.

nodule group] participated in the second thyroid study. There was no significant difference in participation rates between the three groups (P ⬎ 0.1). All participants of the second thyroid study underwent ultrasonographic thyroid examination by the ALOKA, 7.5-MHz linear electronic scanning probe. Two radiological technicians recorded ultrasonographic images, and two thyroid experts confirmed the diagnoses. When solid nodules measuring more than 1 cm in diameter were detected by ultrasonography, cytological examination was conducted by ultrasound-guided fine needle aspiration biopsy. We detected new thyroid nodules with a diameter greater than 1 cm in 51 subjects of the control group, 10 subjects of the cyst group, and eight subjects of the solid nodule group. Most people (40 of 51 of the control group, eight of 10 of the cyst group, and five of eight of the solid nodule group) were examined by aspiration biopsy, except those who refused the examination or were unavailable due to other diseases. Subjects who were known to have solid nodules in the baseline study were also examined with a high-resolution, arch-automatic scanning ultrasonographic instrument, the same equipment used in the baseline thyroid study to measure nodule volume. The cross-sectional thyroid nodule images were traced for volume measurement in the same manner as in the baseline examination. Nobody in the solid nodule group was on thyroid hormone replacement for TSH suppression after the baseline study.

Statistical analysis The Statistical Analysis System package for personal computers was used for statistical analysis. Analyses of covariance, ␹2, and Wilcoxon Rank Sum test were used to evaluate differences in baseline characteristics. Kaplan-Meier analysis was performed to assess cancer-free survival among the three groups using the log-rank test. Cox proportional hazards regression analysis was used to estimate the hazard ratio (HR) of cancer development in subjects with solid nodules or cysts using controls as a reference group, after adjustment for age, sex, and/or thyroid radiation dose. In the analysis of people who participated in both the baseline and the second thyroid studies, the logistic model was used to estimate the odds ratio of cancer development in subjects with solid nodule using controls as a reference group. For each covariate, the estimate of HR with 95% confidence interval (CI) was determined. All significance tests were two-sided, and P values of less than 0.05 were considered significant.


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Results Baseline characteristics (Table 3)

Age of the cyst and solid nodule groups did not differ from that of the control group (P ⫽ 0.18 and 0.13). More women were observed in the cyst and solid nodule groups compared with the control group (P ⬍ 0.01). TSH levels did not differ among the three groups. Thyroglobulin levels were significantly elevated in the cyst group and the solid nodule group in the analysis of individuals negative for Tg-Ab (2482 cases). Thyroid radiation doses were significantly higher in the cyst and solid nodule groups than in the control group (P ⬍ 0.05). Development of thyroid cancer

Table 4 shows the clinical and pathological findings in cancer cases detected during the follow-up period. During the average 13.3 ⫾ 3.6 yr of the follow-up, 14 cancer cases were found among all subjects (0.6%). Three cancer cases (cases 2, 3, and 6) were newly detected in the second thyroid study, and other cases were ascertained through biennial examinations in RERF or the Nagasaki Prefectural Cancer Registry. Six cases (7.3%) were found in the solid nodule group, seven cases in the controls (0.3%), and one case (0.8%) in the cyst group (Table 5). Even in 31 cases with solid nodules diagnosed as benign by cytological or histological examination in the baseline thyroid study, three cases (cases 9, 12, and 13) developed thyroid cancer (9.7%). One case with an inadequate aspiration biopsy sample in the baseline study was found to have thyroid cancer at 6 yr after the baseline study (case 14). All six cancer cases in the solid nodule group developed from ultrasound-detected solid nodule cases but not from postoperative nodule cases in the baseline thyroid study. Subsequently, six of 68 ultrasound-detected solid nodule cases (8.8%) developed thyroid cancers, and five of them (cases 9 –13) including three cases initially diagnosed as benign (case 9, 12, and 13), developed from the same nodules detected by ultrasonography in the baseline thyroid study. In one case in the solid nodule group (case 14) and one cyst group case (case 8), cancers were found in locations other than the nodules detected by ultrasonography in the baseline thyroid study. The latency period of thyroid cancer development from the baseline thyroid study varied from 2.0 –13.8 yr in the solid nodule group and from 2.0 –16.4 yr in the control group. Age at diagnosis was younger in the solid nodule group (from 46.4 – 69.6 yr old, 60.1 ⫾ 8.8) than in the

TABLE 3. Baseline characteristics

No. Age [mean ⫾ SD (yr)] Women (%) TSH [mean ⫾ SD (mIU/liter)]b Thyroglobulin [mean ⫾ SD (ng/ml)]c Thyroid radiation dose [mean ⫾ SD (Sv)]d

Control

Cyst (P)a

Solid nodule (P)a

2434 59 ⫾ 10 57.5 3.5 ⫾ 6.7 26.3 ⫾ 39.4 0.43 ⫾ 0.65

121 60 ⫾ 10 (0.13) 79.3 (⬍0.01) 4.1 ⫾ 10.9 (0.34) 39.4 ⫾ 51.9 (0.02) 0.57 ⫾ 0.73 (0.02)

82 57 ⫾ 9 (0.18) 86.6 (⬍0.01) 4.4 ⫾ 11.5 (0.16) 56.7 ⫾ 77.2 (⬍0.01) 1.12 ⫾ 1.20 (⬍0.01)

All data were from examinations at the time of thyroid disease screening conducted between October 1984 and April 1987. a P values in cyst and solid nodule were analyzed in comparison to control. b Adjusted for age and sex. c Analyzed in 2482 of Tg-Ab-negative subjects. Thyroglobulin is converted from ng/ml to ␮g/liter. d Analyzed in 1812 subjects (1676 in the control group, 81 in the cyst group, and 55 in the solid nodule group) except those who were in utero (n ⫽ 74) and not in city (n ⫽ 178) at the time of the atomic bombings, and subjects with unknown radiation dose by DS86 (n ⫽ 573).

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TABLE 4. Characteristics of thyroid cancer cases found during follow-up period Case no.

Group

Thyroid Sex radiation dose (Sv)

Cytological result at baseline

Age at Latency diagnosis (yr) (yr)

1 2 3 4 5

Control Control Control Control Control

F F F F F

0 0.28 1.39 0.36 0.33

81.6 77.3 70.0 83.1 59.2

5.8 16.4 16.1 2.0 12.0

6 7

Control Control

F M

0.02 1.48

60.3 58.1

16.0 2.3

8

Cyst

F

NICb

N.D.

59.0

5.8

9 10 11

Solid nodule Solid nodule Solid nodule

F F F

0.09 1.68 0

Benign N.D. N.D.

62.6 68.4 69.6

3.9 13.8 11.8

12

Solid nodule

F

3.73

Benign

59.3

11.1

13

Solid nodule

F

1.61

Benign

54.5

2.0

14

Solid nodule

M

2.07

Inadequate

46.4

6.0

Opportunity of discovery

Autopsy 2nd study 2nd study Autopsy Follow-up examination in RERF 2nd study Operation for parathyroid adenoma Awareness of neck nodule Hoarseness Nodule growth Hospital visit for other reason Hospital visit for other reason Operation for parathyroid adenoma Hoarseness

Histological type of thyroid carcinoma

Tumor size

Papillary Papillary Papillary Papillary Follicular

1 cm 1.3 cm 3.6 cm Unknowna 2.5 cm

No No No No Yes

No No Yes No Yes (⫹lung)

Papillary Papillary

1.2 cm ⬍1 cm

No No

No Yes

Papillary

Unknowna Unknowna Unknowna

Papillary Papillary Papillary

Unknowna Yes 1.4 cm No 1.6 cm Yes

Yes Yes No

Follicular

Unknowna No

No

Papillary

0.5 cm

No

No

Papillary

2.1 cm

Yes

Yes

Local invasion

Cervical metastasis

N.D., Histological or cytological examinations were not conducted; F, female; M, male. a Information was not available because of insufficient Cancer Registry data or because surgical records could not be obtained. b Subject was not in city (NIC) at the time of the atomic bombings.

control group (from 58.1– 83.1 yr old, 69.9 ⫾ 10.9). All the cancer cases underwent surgery, and diagnosis was confirmed histologically. Most cancer cases were found in women and diagnosed as papillary carcinoma. In the analysis by the Kaplan-Meier method, thyroid cancer-free survival was lower in the solid nodule group than in the control (P ⬍ 0.01) and cyst (P ⫽ 0.01) groups (Fig. 1). No difference was observed between the cyst and control groups (P ⫽ 0.25) (Fig. 1). The risk of cancer development was significantly higher in the solid nodule group (HR, 23.6; 95% CI, 7.6 –72.8; P ⬍ 0.01) compared with the control group but not in the cyst group (HR, 2.7; 95% CI, 0.3–22.2; P ⫽ 0.36), after controlling for age and sex (Table 5). After controlling for thyroid radiation dose, age, and sex, the risk of cancer development was still significantly higher in the solid nodule group (Table 5). In 31 cases with solid nodules diagnosed as benign by aspiration biopsy in the baseline thyroid study, the risk of cancer development was also high (HR, 40.2; 95% CI, 9.4 –173.0; P ⬍ 0.01), after controlling for age and sex. In the logistic analysis in people who participated in both the baseline and the second thyroid studies, the solid nodule group had a higher risk for cancer development compared with the control

group after controlling for age and sex (five of 54 vs. four of 1272; odds ratio, 31.3; 95% CI, 7.5–125.0; P ⬍ 0.01). Clinical risk factors for thyroid cancer (Table 6)

Clinical risk factors were evaluated in the solid nodule group. Neither age nor sex was associated with cancer development. The risk of thyroglobulin (more than 30 ng/ml) was suggestive (HR, 7.3; 95% CI, 0.8 – 65.2; P ⫽ 0.08). Thyroid radiation dose was not associated with cancer development when analysis was limited to the solid nodule group (P ⫽ 0.79), although it was significantly associated with cancer development in the analysis including all subjects irrespec-

TABLE 5. Relative risk for cancer Cancer case (%) Hazard ratio (95% CI)

Control (n ⫽ 2434) Cyst (n ⫽ 121) Solid nodule (n ⫽ 82) a

7 (0.3%) 1 (0.8%) 6 (7.3%)

1.00 2.7 (0.3–22.2)a 23.6 (7.6 –72.8)a 19.8 (4.9 – 61.1)b

P

0.36a ⬍0.01a ⬍0.01b

Adjusted for age and sex. Adjusted for age, sex, and thyroid radiation dose. Analyzed in 1812 subjects except those who were in utero (n ⫽ 74) and not in city (n ⫽ 178) at the time of the atomic bombings, and subjects with unknown radiation dose by DS86 (n ⫽ 573). b

FIG. 1. Thyroid cancer-free survival. Kaplan-Meier plots showing thyroid cancer-free survival. The thyroid cancer-free survival was lower in the solid nodule group than in the control (P ⬍ 0.01) and cyst groups (P ⫽ 0.01). No difference was observed between the cyst group and the control group (P ⫽ 0.25).


TABLE 6. Risk factors for thyroid cancer in solid nodule group (n ⫽ 82)

Age (1 yr) Women Tg ⱖ30 ng/mla,b TSH (1-mIU/liter)a Thyroid radiation dose (1 Sv)a,c Nodule volume (1 cm3)a,d

Hazard ratio (95% CI)

P

0.93 (0.84 –1.03) 0.81 (0.09 – 6.96) 7.27 (0.81– 65.20) 0.84 (0.46 –1.53) 1.10 (0.56 –2.13) 0.82 (0.48 –1.40)

0.17 0.85 0.08 0.56 0.79 0.47

a

Adjusted for age and sex. Analyzed in 66 Tg-Ab-negative subjects. c Analyzed in 55 subjects except subjects who were in utero (n ⫽ 1) and not in city (n ⫽ 6) at the time of the atomic bombings and subjects with unknown radiation dose in DS86 (n ⫽ 20). d Analyzed in 68 ultrasound-detected nodule cases. b

tive of the baseline groups (HR, 2.1; 95% CI, 1.3–3.6; P ⫽ 0.0029). TSH level and nodule volume were not associated with cancer development (P ⫽ 0.56 and 0.47, respectively). Furthermore, among the 68 solid nodule cases detected by ultrasonography in the baseline thyroid study, we compared nodule volume in 29 cases between the baseline and the second thyroid study. An increase in nodule volume greater than 20% was observed in 17 subjects (58.6%), although none of these subjects developed thyroid cancer. The volume was unchanged (⫺20% to ⫹20%) in 10 subjects (34.5%) and decreased greater than 20% in two subjects (6.9%). Only one case with volume almost unchanged (change was ⫺2.8%) developed thyroid cancer. This finding indicates that volume increase was not associated with thyroid cancer development in this study. Discussion

We are now able to detect many thyroid incidentalomas in regular medical check-ups with thyroid ultrasonography. Therefore, attention has been focused on the management of these nodules (26 –31), especially in irradiated individuals, who are at high risk for development of thyroid nodules and cancers. Our study is the first to show the high risk for thyroid cancer in atomic bomb survivors with solid thyroid nodules compared with nodule-free survivors in a long-term follow-up study. This result will contribute to clinical guidelines for the management of thyroid nodules in individuals irradiated by radiation therapy, nuclear plant accidents, or nuclear weapons. We observed that 7.3% of subjects in the solid nodule group and 9.7% of benign solid nodule cases confirmed cytologically or histologically developed thyroid cancer during an average 13.3-yr follow-up period. Although we realize that aspiration biopsy always has the uncertainty of falsenegatives, we think that thyroid cancers detected in the follow-up period could represent not only false-negative cytology but also new malignant foci associated with preexisting benign thyroid diseases or progression of occult malignant foci, although it is generally believed that papillary carcinoma is not derived from adenomas (32). Whatever the reason for the development of cancer from solid nodules diagnosed as benign, the present results suggest the importance of careful follow-up of solid nodule cases among atomic bomb survivors. The rate of cancer development in this study seems very


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high. One possible explanation for the high rate is that all our participants were atomic bomb survivors. Thyroid cancer incidence has been reported to increase by radiation dose (6, 33, 34), and this was the same in the present analysis for all subjects irrespective of their baseline status. In this study, however, we found that radiation dose was higher in the solid nodule group than in the control group, but we observed no radiation dose dependency in cancer development among the subjects with solid nodules (Table 6). This may be because the analysis was of a small number, 82 cases, of solid nodule subjects whose radiation doses were already high. Therefore, the effect of radiation on cancer development cannot be completely denied in explaining the higher rate of cancer development in solid nodule cases. On the other hand, our results showing that controls without thyroid nodule in the baseline thyroid study were at low risk for cancer development compared with solid nodule cases might be related to the low radiation dose of this group (Table 3). Further study with a larger number of subjects is thus required to clarify the relationship between radiation dose and cancer development many years after radiation exposure. Several reports exist for establishing guidelines of thyroid nodule follow-up in irradiated individuals. Tan and Gharib (31) recommended annual follow-up by means of palpation of irradiated patients with small benign thyroid nodules diagnosed by aspiration biopsy. Schneider et al. (35) recommended follow-up with thyroid ultrasonography at intervals determined by the clinical findings if risk factors such as radiation exposure and aging are sufficient enough to warrant imaging. From our study results, we believe that irradiated individuals with thyroid nodules should be followed carefully not only by ultrasonography but also by biopsy, irrespective of age, sex, thyroglobulin level, TSH level, thyroid radiation dose, or nodule volume, because none of these factors predicted the development of cancer. Nodule volume change also failed to predict cancer development. This result is consistent with a previous report finding that an increase in nodule volume alone is not a reliable predictor of malignancy (20, 36, 37). How often should subjects with thyroid nodule be examined? Thyroid nodules, even thyroid cancer, usually grow very slowly, and the shortest latency period from the diagnosis of solid nodule to the diagnosis of cancer was 2 yr, suggesting that follow-up examinations should be conducted at least biennially. In the present study, controls without thyroid nodule in the baseline thyroid study were at low risk for cancer development compared with solid nodule cases. However, this does not necessarily imply that follow-up is unnecessary in control cases because irradiation predicted incident thyroid cancer in the analysis for all subjects irrespective of baseline status (control, cyst, and solid nodule cases) even roughly 40 yr after atomic bomb exposure. We acknowledge, however, a potential limitation of our study. Although all subjects were examined biennially by thyroid palpation at RERF, the subjects with solid nodules might have been more motivated to undergo additional thyroid examination by their personal physician during the follow-up period compared with the nodule-free controls. Thus, the subjects with solid nodules may have had a greater and earlier chance of being diagnosed with thyroid cancer than the nodule-free controls, and it is possible that the HR

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for development of thyroid cancer was overestimated. To decrease this bias, we performed the second thyroid study using thyroid ultrasonography not only for subjects with solid nodules but also for the nodule-free controls and by so doing detected three new cancer cases in the controls. Participation rates for the second thyroid study were almost identical among the three groups. In the analysis of people who participated in both the baseline and the second thyroid studies, a significant increased odds ratio for development of cancer was observed in the solid nodule group. Therefore, we think that the motivation bias did not affect the overall conclusion. However, because the number of cancer cases in the follow-up period was small in all groups, further studies with a larger population are necessary. In conclusion, we showed increased cancer risk in atomic bomb survivor subjects with solid thyroid nodules compared with nodule-free controls. We recommend at least biennial follow-up for irradiated people with thyroid nodules even if the nodules are diagnosed as benign. Because we could not find significant predictable clinical risk factors, further studies are required for detecting pathological or genetic risk factors. Acknowledgments We thank Ms. Kaoru Yoshida for general assistance. Received February 9, 2005. Accepted May 31, 2005. Address all correspondence and requests for reprints to: Misa Imaizumi, M.D., Radiation Effects Research Foundation, 1-8-6 Nakagawa, Nagasaki 850-0013, Japan. E-mail: [email protected]. This work was supported by RERF Research Protocol 02-99. RERF (Hiroshima and Nagasaki, Japan) is a private, nonprofit foundation funded by the Japanese Ministry of Health, Labor and Welfare and by the U.S. Department of Energy, with the latter funding provided through the National Academy of Sciences.

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