Hyperparathyroidism after radioactive iodine therapy

The American Journal of Surgery 194 (2007) 323–327

Clinical surgery–American

Hyperparathyroidism after radioactive iodine therapy Shanthi M. Colaço, B.S., Ming Si, M.D., Emily Reiff, B.S., Orlo H. Clark, M.D.* Department of Surgery, University of California San Francisco and UCSF/Mt Zion Medical Center, 1600 Divisadero Street, #C347, San Francisco, CA 94143-1674, USA Manuscript received February 7, 2007; revised manuscript April 16, 2007

Abstract Background: Radioactive iodine (RAI) treatment has been suggested to cause primary hyperparathyroidism (HPT). We describe a series of patients with HPT and a history of RAI exposure. Methods: Patient demographic and clinical information was evaluated, including the latency time to the development of HPT after RAI exposure. Results: We treated 11 patients with HPT and a history of RAI exposure. RAI treatment was administered for benign thyroid disease in 9 (82%) cases. Thirty-six cases of HPT after RAI exposure in the English literature were compiled for further analysis. In this collective experience, the average latency time to the development of HPT after RAI treatment was 13.5 ⫾ 9.1 years and was found to be inversely correlated with age at RAI exposure. Conclusions: Patients who undergo RAI treatment are at risk of developing HPT, and this risk appears to increase in elderly patients. Serum calcium surveillance is recommended for patients who have undergone RAI treatment. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Primary hyperparathyroidism; Radioactive iodine

The causal effect of localized external-beam ionizing radiation exposure and subsequent development of primary hyperparathyroidism (HPT) has been extensively described and studied since it was first suggested by a case report in 1975 [1–17]. The treatment of thyroid disease with iodine 131 (131I) and its possible effect on the subsequent development of HPT was noted almost a decade later [7,18,19]. Several case series describing patients with HPT and a history of 131I treatment followed these initial observations [20 –25]. The authors of some of these reports noted that younger patients may have increased susceptibility to 131I and advised periodic calcium surveillance in patients with a history of 131I exposure [19,22,24]. The safety of 131I therapy for benign thyroid disease in young patients has been shown, and some clinicians have advocated its use in this patient population [26 –29]. However, previous studies fail to document or address the development of HPT in these young patients. This has motivated the retrospective review of our own experience of patients with a history of 131I treatment referred to us for surgical management of HPT. We also performed an exten-

* Corresponding author. Tel: ⫹1-415-885-7616; fax: ⫹1-415-8857617. E-mail address: [email protected]

sive review of the medical literature and analyzed the resultant collective experience. Materials and Methods We conducted a retrospective analysis of patients undergoing parathyroidectomy for primary HPT at the University of California San Francisco (UCSF) Medical Center from 1996 to 2004. In these patients, the diagnosis of primary HPT was established by an elevated serum parathyroid hormone in the setting of hypercalcemia. Each patient completed a standard questionnaire at the initial preoperative visit and again postoperatively. Demographic and clinical information collected with the questionnaire included age at the time of treatment for HPT, sex, symptoms commonly associated with thyroid and parathyroid disorders, history of thyroid disease treated with RAI therapy, dose of radioiodine received, and age at the time of RAI therapy. We reviewed the medical records of the hyperparathyroid patients who reported a history of RAI treatment for any reason. The operative notes and pathology reports provided information regarding the number and location of the abnormal parathyroid glands and coexistent thyroid pathology. Patients with 1 enlarged parathyroid gland were considered to have a parathyroid adenoma, whereas patients with 2 enlarged parathyroid glands were considered to have a double adenoma. Parathyroid hyperplasia was diagnosed

0002-9610/07/$ – see front matter © 2007 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2007.04.005

324

S.M. Colaço et al. / The American Journal of Surgery 194 (2007) 323–327

when all glands were abnormal, although the size was variable. Next, we performed a comprehensive literature search to identify the previously reported cases of patients who developed functional parathyroid adenomas after receiving RAI treatment for any reason. To our knowledge, there have been 36 cases reported to date in the English-language literature. Information from these cases regarding the age and sex of patients presenting with primary HPT, age at the time of radioiodine treatment, and the reason for RAI treatment were recorded and combined with the data obtained from our patient series. In this collective experience, analysis was performed for 3 groups of patients: (1) all patients, (2) patients who were treated with RAI for benign thyroid disease, and (3) patients who were treated with RAI for malignant thyroid disease. The age distribution and the mean age at the time of RAI treatment were calculated. The latency period was defined as the time (in years) between RAI treatment and the diagnosis of primary HPT. If the patient received multiple courses of RAI, the year of the earliest treatment was used to calculate the latency period. When appropriate, variables were compared between groups 2 and 3 by using the 2-sided Student t test or analysis of variance. The association between age at the time of RAI treatment and the latency period was explored by scatterplot, nonparametric, and parametric correlation analyses and linear regression analysis. A P value of ⬍.05 was considered significant for all analyses. Statistical analysis was performed by using SPSS for Windows (version 12.0; SPSS, Inc, Chicago, IL). Results Eleven patients were identified in the UCSF clinical database who underwent surgical treatment for primary HPT after being treated with RAI for any reason. The demographic characteristics of these patients are presented in Table 1. Nine of the 11 patients were women (82%), and 2 were men (18%). The parathyroid resections were performed in patients who were 48 to 84 years of age (mean age, 63.3 ⫾ 10.6 years). This was 2 to 35 years after their earliest treatment with RAI or a mean latency period of 16.0 ⫾ 12.0 years. Nine of the 11 patients were treated with RAI for benign thyroid disease (82%). Eight of these patients received RAI therapy for Graves’ disease, and 1 received RAI therapy for multinodular goiter. The remaining 2 of the 11 patients were treated with RAI after undergoing a total thyroidectomy for papillary thyroid carcinoma (18%). An additional 36 patients who received RAI therapy and subsequently underwent surgical treatment for primary HPT were identified in the English-language literature. The available demographic characteristics of these patients are presented in Table 1. Female sex predominated similarly to the UCSF cohort of patients. Out of 27 patients, there were 26 women (96.3%) and 1 man (3.7%). The parathyroid resections were performed in patients who were 26 to 80 years of age (mean age 59.0 ⫾ 13.8 years). This was 3 to 30 years after their earliest treatment with RAI or a mean latency period of 12.7 ⫾ 8.3 years. The reason for receiving RAI therapy was available for 35 patients, and, like the UCSF

cohort, the majority of the patients were treated for benign thyroid disease. Of the 30 patients (85.7%) treated for benign thyroid disease, 17 received RAI therapy for Graves’ disease, 5 for toxic multinodular goiter, and 8 for hyperthyroidism of an unknown origin. The remaining 5 out of 35 patients (14.3%) were treated with RAI for thyroid carcinoma. Combining the data obtained from the literature with the data obtained from our patient series resulted in a total of 47 patients; however, patient characteristics were not available for all 47 patients. Thirty-four of the 38 patients were women (89.5%) and 4 were men (10.5%). The parathyroid resections were performed in patients who were 35 to 85 years of age (mean age 59.4 ⫾ 13.5 years; n ⫽ 38). Postsurgical pathological analysis revealed 38 single adenomas (32 benign and 6 malignant), 2 double adenomas, and 4 cases of parathyroid hyperplasia (n ⫽ 43). The mean age of the patients at the time of RAI therapy was 45.5 ⫾ 17.5 years (n ⫽ 35), resulting in a mean latency period of 13.5 ⫾ 9.1 years (n⫽37) before the onset of primary HPT. A statistically significant association was found between the age of the patient at the time of RAI therapy and the latency period before the development of primary HPT (Kendall’s correlation coefficient ⫽ ⫺0.473, P ⬍ .0001; Spearman’s rho ⫽ ⫺0.648, P ⬍ .0001). Linear regression showed a negative correlation between these 2 variables (slope ⫽ ⫺0.361, R2 ⫽ 0.4406, P ⬍ .0001). As age at the time of RAI treatment increased, the latency period decreased (Fig. 1). The effects of the amount of RAI on the development of HPT could not be determined because the RAI dosage was not known for most patients. We thus assumed that patients treated for benign disease received a lower dose of RAI than those treated for malignant thyroid disease. In patients with a history of RAI treatment for benign thyroid disease (including Graves’ disease, a toxic multinodular goiter, and hyperthyroidism), surgical treatment for primary HPT occurred at a mean age of 58.9 ⫾ 12.8 years (n ⫽ 31). The mean latency period between RAI therapy and theonset of primary HPT in this group of patients was 12.9 ⫾ 8.8 years (n ⫽ 30). In patients with a history of RAI treatment for thyroid malignancy (mostly papillary carcinoma), surgical treatment for primary HPT occurred at a slightly older mean age of 61.4 ⫾ 17.0 years (n ⫽ 7). The mean latency period between RAI therapy and the onset of primary HPT in these patients when compared with those patients treated for benign thyroid disease was also increased at a mean of 16.3 ⫾ 10.5 years (n ⫽ 7). However, the differences in age at the time of parathyroidectomy and latency period between patients who were treated with RAI for benign versus malignant thyroid disease were not significant as determined by analysis of variance (P ⫽ .665 and .379, respectively). Comments It is not surprising that many patients diagnosed with primary HPT have been previously exposed to localized external-beam ionizing radiation. External ionizing radiation has been shown to cause parathyroid adenomas in numerous cases since the first published case report in 1975

S.M. Colaço et al. / The American Journal of Surgery 194 (2007) 323–327

325

Table 1 Patients with RAI treatment and subsequent primary HPT Case

Study

Sex

Thyroid disease

Age at RAI

Age at HPT

Latency time

Parathyroid disease

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Present Present Present Present Present Present Present Present Present Present Present Christmas [30] Christmas [30] Esselstyn [19] Esselstyn [19] Esselstyn [19] Esselstyn [19] Bondeson [22] Bondeson [22] Bondeson [22] Bondeson [22] Bondeson [22] Bondeson [22] Bondeson [22] Bondeson [22] Bondeson [22] Bondeson [22] Rosen [21] Rosen [21] Rosen [21] Rosen [21] Rosen [21] Rosen [21] Rosen [21] Rosen [21] Cundiff [24] Netelenbos [18] Netelenbos [18] Acar [25] Prinz [7]

M F F F F F F F M F F ? ? F F F F F F M F F F F F F F F F F F ? ? F F F F F F F

Graves’ disease Graves’ disease Graves’ disease Graves’ disease Graves’ disease Graves’ disease Graves’ disease Multinodular goiter Papillary thyroid ca Papillary thyroid ca Graves’ disease Hyperthyroidism Hyperthyroidism Graves’ disease Graves’ disease Graves’ disease Graves’ disease Graves’ disease Carcinoma Carcinoma Graves’ disease Graves’ disease Graves’ disease Graves’ disease Graves’ disease Carcinoma Graves’ disease Thyroid nodule, Hurthle cell Toxic goiter Hyperthyroidism Toxic goiter Hyperthyroidism Hyperthyroidism Follicular carcinoma Hyperthyroidism hyperthyroidism Toxic nodular goiter Toxic nodular goiter Toxic nodular goiter Thyroid cancer

54 ? 38 51 ? 40 54 40 82 28 ? 62 57 11 32 63 8 73 22 39 34 34 51 45 35 52 44 60 20 51 57 ? ? 63 47 67 69 57 64 30

58 75 58 66 60 57 57 75 84 58 48 65 61 33 57 69 36 78 35 56 55 42 65 50 38 79 58 63 50 64 67 ? ? 68 56 73 80 77 69 50

4 ? 20 15 ? 17 3 35 2 30 ? 3 4 22 25 6 28 5 13 17 21 8 14 5 3 27 14 3 30 13 10 10 10 5 9 6 11 20 5 20

Adenoma Adenoma Adenoma Double adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Hyperplasia Adenoma Adenoma Adenoma Double adenoma Adenoma Adenoma Adenoma Hyperplasia Hyperplasia Adenoma Adenoma ? Adenoma Adenoma Adenoma Adenoma Hyperplasia Adenoma Adenoma Adenoma Adenoma Adenoma ? ? Adenoma Adenoma

F ⫽ female; M ⫽ male

[1–17]. The relationship between RAI therapy and the subsequent development of primary HPT, however, is not as clearly defined. The incidence of parathyroid adenomas in patients who have been exposed to RAI is unclear. To date, there have been 36 documented cases of patients with a history of RAI treatment that later presented with primary HPT [7,18 –22,24,25,30]. Combining the 11 patients reported in our series resulted in a total of 47 patients who were treated for HPT after receiving RAI therapy for any reason. We had sufficient clinical data on 40 of these patients to perform our analyses. Characteristics of our patients are in concordance with previously reported case series. Specifically, we also described a high female predominance and a wide range in both the age distribution of patients presenting with HPT and the latency period from RAI treatment to the development of HPT.

RAI concentrates in functioning thyroid tissue, providing an effective treatment for hyperthyroidism and susceptible thyroid tumors while causing minimal damage to the adjacent tissue. The treatment results predominantly in betaradiation, with an average distance penetration of .5 mm (maximum of 2 mm) [19,31]. Triggs and Williams [32] reported a 61% incidence of parathyroid tumors in adult rats given RAI in the first 2 days of life, which was supported by the findings of Wynford-Thomas et al [33]. These authors suggest that a similar high incidence of HPT does not exist in humans because rat parathyroids are partially embedded in the thyroid tissue resulting in greater radiation exposure during RAI therapy. It can be speculated that patients who develop parathyroid adenomas or hyperplasia after RAI may have intrathyroidal parathyroid glands, thus giving them greater radiation exposure. The observation that 2 patients in our series and 2 patients described by Bondeson

326

S.M. Colaço et al. / The American Journal of Surgery 194 (2007) 323–327

40 y = -0.3618x + 30.403

35

2

R = 0.4406

Latency (years)

30 25 20 15 10 5 0 0

20

40

60

80

100

Age at RAI treatment (years)

Fig. 1. Scatterplot and linear regression of age at RAI exposure and the latency time to the development of HPT. Data from patients described in the literature and in this case series were included for analysis. There is a significant inverse relationship between age at RAI exposure and the latency time to the development of HPT. These results suggest that parathyroid glands in older patients may be more sensitive to the effects of RAI.

et al [22] had parathyroid adenomas adjacent to RAI-treated thyroid remnants further supports this hypothesis. Evidence from rodent experiments suggests that age affects the susceptibility of parathyroid glands to RAI. As mentioned earlier, Triggs and Williams [32] determined a high frequency of parathyroid adenomas in rats after RAI therapy within 2 days of life. However, in a separate study, rats given similar doses of RAI at 2 to 4 months of age did not show any increase of parathyroid hyperplasia or adenomas when compared with untreated control animals [34]. We are not aware of any studies that evaluate the effects of RAI on parathyroid adenoma formation in older animals. Age at the time of exposure to radioactive therapy is hypothesized to be an important factor for determining the risk and timing of subsequent development of primary HPT in the clinical setting [22]. Previously reported case series of patients developing primary HPT after treatment with RAI have suggested that younger patients (less than 35 years old) are more susceptible to RAI [19,22]. However, the only prospective study evaluating the risk of HPT development after treatment with RAI using a relatively young cohort of patients found no increase in the incidence of HPT after 16 years [35]. Furthermore, our analyses show that as patient age at the time of RAI therapy increases, there is a statistically significant decrease in the latency period before the development of primary HPT. These results suggest that the parathyroid glands in older patients are more susceptible to the neoplastic effects of RAI. The finding of a shortened latency time to the development of parathyroid adenomas after RAI in older patients is of interest but is opposite of what is found for the development of thyroid cancers after radiation exposure [36]. Recently, Hamilton et al [37] reported the results of their study on patients exposed to RAI from the Hanford Nuclear Site. Of 3,440 patients eligible for evaluation, .35% had confirmed primary HPT. These investigators could not find any relationship between the model estimated RAI exposure level and the development of HPT. They concluded that

RAI exposure in their study population did not increase the risk of primary HPT and that the effects of dose and condition of RAI exposure on the risk of HPT are yet to be defined. The increased susceptibility of most tissues other than thyroid to the neoplastic effects of radiation exposure as age increases may be explained by the subsequent genomic instability [38], with subsequent loss of apoptotic mechanisms, deficient tumor suppressor function, and activation of oncogenes. Overexpression of cyclin D1/PRAD1 and mutation/deletion of the MEN1 tumor suppressor gene are genetic alterations found in a substantial fraction of parathyroid adenomas [39]. In addition, parathyroid carcinomas frequently have mutations in the HRPT2 gene, which has been implicated in a type of familial HPT, HPT-jaw tumor syndrome, which carries an increased risk of parathyroid cancer [40]. It remains to be determined whether RAI affects these genes or induces alterations in others. An inherent assumption made in our correlation analyses of the data is that a substantial fraction of cases of RAIinduced HPT was reported in the literature or that those reported were a representative cohort of the total population of patients with RAI-induced HPT. Furthermore, benign thyroid disease may be linked independently to HPT. Indeed, the most rigorous study would require a prospective monitoring of the development of HPT in patients treated with RAI, including those treated for benign thyroid disease. The establishment of such an RAI patient registry would also allow a more precise investigation of the effects of RAI dosage on the development of HPT. Until such a registry exists with prospective evaluation for parathyroid adenoma formation/HPT in these patients, the effects of RAI on the development of HPT in humans can only be assessed in case series such as that described here. Other investigators have proposed routine serum calcium measurements after RAI [19,21,22,24]. We also support routine serum calcium measurement after RAI therapy and further propose that these measurements should be more frequent if the patient sustained RAI exposure at an older age. In conclusion, we have shown that a number of our patients with HPT undergoing parathyroidectomy have a history of RAI exposure. The latency time to the development of HPT after RAI treatment decreases as the age of RAI exposure increases, suggesting that older patients are more sensitive to the neoplastic effects of RAI. We believe that this is yet another reason that surgical treatment of benign thyroid disease in the elderly maybe superior to RAI ablation. Elderly patients who have undergone RAI treatment should have serum calcium surveillance at 2- to 3-year intervals. Acknowledgments Supported in part by the Friends of Endocrine Surgery, the Helen and Sanford Diller Foundation, the Jerold Heller Family Foundation, and the Bell Charitable Foundation. References [1] Rosen IB, Strawbridge HG, Bain J. A case of hyperparathyroidism associated with radiation to the head and neck area. Cancer 1975; 36:1111– 4.

S.M. Colaço et al. / The American Journal of Surgery 194 (2007) 323–327 [2] Tisell LE, Carlsson S, Lindberg S, Ragnhult I. Autonomous hyperparathyroidism: a possible late complication of neck radiotherapy. Acta Chir Scand 1976;142:367–3. [3] Paloyan E, Lawrence AM, Prinz RA, et al. Radiation-associated hyperparathyroidism. Lancet 1977;1:949. [4] Tisell LE, Carlsson S, Fjalling M, et al. Hyperparathyroidism subsequent to neck irradiation. Risk factors. Cancer 1985;56:1529 –33. [5] Hedman I, Hansson G, Lundberg LM, Tisell LE. A clinical evaluation of radiation-induced hyperparathyroidism based on 148 surgically treated patients. World J Surg 1984;8:96 –105. [6] Karstrup S, Hegedus L, Sehested M. Hyperparathyroidism after neck irradiation for Hodgkin’s disease. Acta Med Scand 1984;215:287– 8. [7] Prinz RA, Barbato AL, Braithwaite SS, et al. Prior irradiation and the development of coexistent differentiated thyroid cancer and hyperparathyroidism. Cancer 1982;49:874 –7. [8] Prinz RA, Paloyan E, Lawrence AM, et al. Unexpected parathyroid disease discovered at thyroidectomy in irradiated patients. Am J Surg 1981;142:355–7. [9] Fiorica V, Males JL. Hyperparathyroidism after radiation of the head and neck: a case report and review of the literature. Am J Med Sci 1979;278:223– 8. [10] Taylor DA, Palmer FJ, Sawyers TM. Neck radiation and hyperparathyroidism. Ann Intern Med 1978;89:1012–3. [11] Christensson T. Hyperparathyroidism and radiation therapy. Ann Intern Med 1978;89:216 –7. [12] Tisell LE, Hansson G, Lindberg S, Ragnhult I. Occurrence of previous neck radiotherapy among patients with associated non-medullary thyroid carcinoma and parathyroid adenoma or hyperplasia. Acta Chir Scand 1978;144:7–11. [13] Prinz RA, Paloyan E, Lawrence AM, et al. Radiation-associated hyperparathyroidism: a new syndrome? Surgery 1977;82:296 –302. [14] Tisell LE, Hansson G, Lindberg S, Ragnhult I. Hyperparathyroidism in persons treated with X-rays for tuberculous cervical adenitis. Cancer 1977;40:846 –54. [15] Tezelman S, Rodriguez JM, Shen W, et al. Primary hyperparathyroidism in patients who have received radiation therapy and in patients who have not received radiation therapy. J Am Coll Surg 1995;180:81–7. [16] Schneider AB, Gierlowski TC, Shore-Freedman E, et al. Doseresponse relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab 1995;80:254 –7. [17] Parfitt AM, Braunstein GD, Katz A. Radiation-associated hyperparathyroidism: comparison of adenoma growth rates, inferred from weight and duration of latency, with prevalence of mitosis. J Clin Endocrinol Metab 1993;77:1318 –22. [18] Netelenbos JC, Lips P. Hyperparathyroidism after radioactive iodine therapy. Arch Intern Med 1981;141:1555– 6. [19] Esselstyn CB Jr, Schumacher OP, Eversman J, et al. Hyperparathyroidism after radioactive iodine therapy for Graves disease. Surgery 1982;92:811–3. [20] Kawamura J, Tobisu K, Sanada S, et al. [Hyperparathyroidism after radioactive iodine therapy for Graves’ disease: a case report]. Hinyokika Kiyo 1983;29:1513–9.

327

[21] Rosen IB, Palmer JA, Rowen J, Luk SC. Induction of hyperparathyroidism by radioactive iodine. Am J Surg 1984;148:441–5. [22] Bondeson AG, Bondeson L, Thompson NW. Hyperparathyroidism after treatment with radioactive iodine: not only a coincidence? Surgery 1989;106:1025–7. [23] Pauwels EK, Smit JW, Slats A, et al. Health effects of therapeutic use of 131I in hyperthyroidism. Q J Nucl Med 2000;44:333–9. [24] Cundiff JG, Portugal L, Sarne DH. Parathyroid adenoma after radioactive iodine therapy for multinodular goiter. Am J Otolaryngol 2001;22:374 –5. [25] Acar T, Gomceli I, Aydin R. Primary hyperparathyroidism due to giant adenoma after treatment with radioactive iodine. N Z Med J 2003;116:U441. [26] Foley TP Jr, Charron M. Radioiodine treatment of juvenile Graves disease. Exp Clin Endocrinol Diabetes 1997;105(suppl 4):61–5. [27] Rivkees SA. The use of radioactive iodine in the management of hyperthyroidism in children. Curr Drug Targets Immune Endocr Metabol Disord 2001;1:255– 64. [28] Read CH Jr, Tansey MJ, Menda Y. A 36-year retrospective analysis of the efficacy and safety of radioactive iodine in treating young Graves’ patients. J Clin Endocrinol Metab 2004;89:4229 –33. [29] Metso S, Jaatinen P, Huhtala H, et al. Long-term follow-up study of radioiodine treatment of hyperthyroidism. Clin Endocrinol (Oxf) 2004;61:641– 8. [30] Christmas TJ, Chapple CR, Noble JG, et al. Hyperparathyroidism after neck irradiation. Br J Surg 1988;75:873– 4. [31] Berger MJ. Distribution of absorbed dose around point sources of electrons and beta particles in water and other media. J Nucl Med 1971;(suppl 5):5–23. [32] Triggs SM, Williams ED. Irradiation of the thyroid as a cause of parathyroid adenoma. Lancet 1977;1:593– 4. [33] Wynford-Thomas V, Wynford-Thomas D, Williams ED. Experimental induction of parathyroid adenomas in the rat. J Natl Cancer Inst 1983;70:127–34. [34] Lindsay S, Potter GD, Chaikoff IL. Radioiodine-induced thyroid carcinomas in female rats. Induction by low doses of radiation. Arch Pathol 1963;75:20 – 4. [35] Fjalling M, Dackenberg A, Hedman I, Tisell LE. An evaluation of the risk of developing hyperparathyroidism after 131I treatment for thyrotoxicosis. Acta Chir Scand 1983;149:681– 6. [36] Kikuchi S, Perrier ND, Ituarte P, et al. Latency period of thyroid neoplasia after radiation exposure. Ann Surg 2004;239:536 – 43. [37] Hamilton TE, Davis S, Onstad L, Kopecky KJ. Hyperparathyroidism in persons exposed to iodine-131 from the Hanford Nuclear Site. J Clin Endocrinol Metab 2005;90:6545– 8. [38] Suzuki K, Ojima M, Kodama S, Watanabe M. Radiation-induced DNA damage and delayed induced genomic instability. Oncogene 2003;22:6988 –93. [39] Carling T. Molecular pathology of parathyroid tumors. Trends Endocrinol Metab 2001;12:53– 8. [40] Shattuck TM, Valimaki S, Obara T, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 2003;349:1722–9.