- Email: [email protected]
Prior Head and Neck Radiation Exposure Is Not a Contraindication to Minimally Invasive Parathyroidectomy
Prior Head and Neck Radiation Exposure Is Not a Contraindication to Minimally Invasive Parathyroidectomy Reza Rahbari, MD, Ileana G Sansano, MPH, Dina M Elaraj, MD, Quan-Yang Duh, MD, FACS, Orlo H Clark, MD, FACS, Electron Kebebew, MD, FACS Most patients with primary hyperparathyroidism can have a minimally invasive parathyroidectomy based on localization studies showing single-gland disease. In patients with a history of head and neck irradiation, due to the increased risk of multigland disease and risk of concurrent thyroid cancer, minimally invasive parathyroidectomy is considered by some to be a contraindication. We postulated that previous history of head and neck irradiation should not be a contraindication for minimally invasive parathyroidectomy and tested this hypothesis in a prospective cohort of patients undergoing parathyroidectomy for primary hyperparathyroidism. STUDY DESIGN: We performed a retrospective analysis of a prospective database of 491 consecutive parathyroidectomies performed between May 2005 and May 2007 at a tertiary referral medical center. RESULTS: Fifty-two (12.6%) patients had a history of head and neck irradiation and 360 (87.4%) had no exposure to radiation. The 2 groups had no significant difference in terms of gender or ethnicity. The radiation group was older, with an average age of 65.1 years versus 58.1 years (p ⬍ 0.0009). There was no significant difference in concurrent benign thyroid neoplasm, thyroid cancer, and type of parathyroid disease (single vs multigland) in the 2 groups. There was no significant difference in the operative approach used between the 2 groups (focused vs unilateral or bilateral). CONCLUSIONS: Head and neck irradiation should not be a contraindication for minimally invasive parathyroidectomy in patients with primary hyperparathyroidism in the setting of preoperative localization studies showing single-gland disease and no concurrent thyroid neoplasm. Furthermore, history of head and neck irradiation is associated with a later age of presentation for parathyroidectomy. (J Am Coll Surg 2010;210:942–948. © 2010 by the American College of Surgeons) BACKGROUND:
In the past, radiation has been used for a wide array of medical problems ranging from benign to malignant disorders. It has been used for conditions such as acne, skin rashes, lymphadenopathy, and enlarged tonsils. In 1975, the first case of primary hyperparathyroidism associated with radiation was reported by Rosen and colleagues.1 The case involved a 57-year-old woman who had received radiation 40 years earlier for facial hirsutism. Multiple series
followed, showing an association between radiation exposure to the head and neck and primary hyperparathyroidism.2-8 In addition, radiation-induced formation of parathyroid adenoma was shown in animal models.9-11 Some early series showed a history of radiation in up to 30% of patients with primary hyperparathyroidism, with more recent series showing a history of head and neck irradiation in anywhere from 1% to 14% of patients with primary hyperparathyroidism.3,7,8 In addition, studies in atomic bomb survivors in Japan showed that even lower doses of radiation exposure than those used in radiotherapy can be associated with hyperparathyroidism.12 Although head and neck radiation for benign disease is no longer used, there are still multiple medical diagnostic and therapeutic procedures associated with significant radiation exposure to the head and neck.2,7,13,14 The continued use of radiation combined with a long latency period before primary hyperparathyroidism
Disclosure Information: Nothing to disclose. Received December 22, 2009; Revised February 13, 2010; Accepted February 15, 2010. From the Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD (Rahbari, Kebebew) and the Departments of Surgery, University of California San Francisco, CA (Sansano, Duh, Clark) and Northwestern University Feinberg School of Medicine, Chicago, IL (Elaraj). Correspondence address: Electron Kebebew, MD, National Cancer Institute, Surgery Branch, CRC, Room 4-5952, 10 Center Dr, MSC 1201, Bethesda, MD 20892-1201. email: [email protected]
© 2010 by the American College of Surgeons Published by Elsevier Inc.
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develops keeps radiation-associated primary hyperparathyroidism and its treatment a relevant concern. Over the last decade, with the advances in localization techniques for parathyroid tumors, the surgical approach to primary hyperparathyroidism has changed from bilateral neck exploration to a focused or minimally invasive approach in most patients with evidence of single-gland disease.15-17 Because most patients with primary hyperparathyroidism have single-gland disease, a minimally invasive approach based on localizing studies showing single-gland parathyroid disease is feasible in up to two-thirds of cases.18 In patients with a history of head and neck irradiation, due to the risk of multigland disease and coexisting thyroid cancer, minimally invasive parathyroidectomy for primary hyperparathyroidism is considered by some surgeons to be contraindicated.19-21 However, in the era of improved localizing studies, which include ultrasonographic evaluation of the thyroid gland, there are limited contemporary data addressing the question of whether a history of head and neck irradiation should be an absolute contraindication for minimally invasive parathyroidectomy.13 We postulated that previous history of head and neck irradiation should not be a contraindication for minimally invasive parathyroidectomy, and we tested this hypothesis in a prospective cohort of patients undergoing parathyroidectomy for primary hyperparathyroidism.
METHODS Study cohort
We did a retrospective analysis of a prospective database of 491 consecutive parathyroidectomies performed at the University of California, San Francisco Medical Centers between May 2005 and May 2007. We reviewed the database, which included demographics, clinical history (history of exposure to head and neck radiation and personal history of thyroid disease or thyroid cancer), radiographic data (high-resolution neck ultrasound and technetium TC 99m sestamibi scan), operative notes, pathology reports, and postoperative clinical follow-ups. Remote history of thyroid cancer was defined as diagnosis of thyroid cancer before presentation of primary hyperparathyroidism. Remote history of benign thyroid neoplasm was defined as diagnosis of benign neoplasm before presentation. Concurrent thyroid cancer was defined as presentation with thyroid cancer at the time of diagnosis of primary hyperparathyroidism, and concurrent benign thyroid neoplasm was defined as diagnosis of benign thyroid neoplasm at the time of diagnosis of primary hyperparathyroidism. All patients with a history of radiation exposure to the head and neck who had a thyroid nodule (benign or malignant
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on fine needle aspiration biopsy) had a total thyroidectomy because of the risk of thyroid cancer.22 Radiation exposure was defined as a history of therapeutic irradiation. A questionnaire was used in all patients with questions regarding radiation exposure and history of thyroid disorders (Fig. 1). The therapeutic nature of radiation exposure was confirmed in all patients. Patients with confirmed therapeutic radiation but uncertain field of exposure (patients were certain that they had received therapeutic radiation but uncertain of the site) were considered having had radiation exposure in the analysis, but a subgroup analysis was performed excluding these patients (Table 1). Approval from the Committee on Human Research at the University of California, San Francisco was obtained. Seventy-three patients presented with a previous history of parathyroidectomy and persistent or recurrent primary hyperparathyroidism (none in the radiation group), and 6 patients with unknown outcomes or pathology were excluded, leaving 412 patients with initial primary hyperparathyroidism who were cured postoperatively. Imaging studies and definition of biochemical cure
All patients had a high-resolution neck ultrasound and technetium Tc99m sestamibi scan. Patients then underwent a minimally invasive parathyroidectomy (operation limited to resection of 1 abnormal parathyroid gland without further neck exploration), unilateral neck exploration (identification of both upper and lower parathyroid glands on the same side), or bilateral neck exploration (identification of all 4 parathyroid glands). The intraoperative parathyroid hormone (PTH) assay was used as an adjunct in some cases. Biochemical cure was defined as normalization of both the total serum calcium and intact PTH values postoperatively for at least 6 months. Data analysis
Rates and proportions of categorical data were compared using the Fisher exact test with 2-tailed p values. Nonparametric continuous data was compared using the MannWhitney rank test. A p value ⬍ 0.05 was used to define statistical significance.
RESULTS Demographic and clinical characteristics of the study cohort are summarized in Table 2 by therapeutic radiation exposure status. Four hundred twelve patients (88 men [21.4%] and 324 women [78.6%]) underwent a parathyroidectomy. Fifty-two patients had a history of therapeutic radiation (12.6%). There was no significant difference in gender or ethnicity by radiation exposure status. Patients
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Figure 1. Standard questionnaire used to determine radiation exposure and history of thyroid disease. Patients who reported having only diagnostic radiation exposure were placed in the no-radiation-exposure cohort.
with a history of therapeutic radiation were older at presentation, with an average age of 65.1 years versus 58.8 years for patients without a history of therapeutic radiation (p ⬍ 0.0009). Of the 52 patients exposed to therapeutic radiation, 10 (19.2%) had multigland disease and 42 (80.8%) had single-gland disease. In patients without a history of therapeutic radiation exposure, 52 (14.4%) patients had multigland disease and 308 (85.6%) had single-gland disease (p ⫽ 0.41). In patients with a history of therapeutic radiation exposure, 19 patients (36.5%) underwent bilateral neck exploration, 17 (32.7%) patients underwent unilateral neck exploration, and 16 (30.7%) patients underwent a minimally invasive parathyroidectomy. In patients without a history of therapuetic radiation exposure, 109 patients (30.3%) underwent bilateral neck exploration, 101 (28%) patients underwent unilateral neck exploration, and 150 (41.7%) patients underwent a minimally invasive parathyroidecTable 1. Radiation Exposure Type and Site in 52 Patients Site of radiation
n
%
Head and neck Upper chest Radioactive iodine Other
18 9 5 20
34.6 17.3 9.6 38.5
tomy. There was no statistically significant difference in operative approach used by history of radiation exposure status (p ⫽ 0.32). Three (5.7%) patients in the group with a history of therapeutic radiation had a history of benign thyroid neoplasm; 6 (1.7%) patients without a history of radiation exposure had a history of benign thyroid neoplasm (p ⫽ 0.09). Three (5.7%) patients in the radiation exposure group had a history of thyroid cancer before presentation of primary hyperparathyroidism and 1 patient without a history of radiation exposure had a history of thyroid cancer (p ⫽ 0.007). There was no significant difference in benign thyroid neoplasm at time of presentation for primary hyperparathyroidism between the 2 groups (10 [19.2%] patients in the radiation exposure group vs 43 [11.9%] patients in the nonradiated group [p ⫽ 0.18]). However, there was no significant difference in rate of thyroid cancer at time of presentation for primary hyperparathyroidism between the 2 groups, with 1 (1.9%) patient in the therapeutic radiation group and 11 (3.1%) patients in the nonradiated group (p ⫽ 0.99). Forty of 52 (76.9%) patients in the radiation exposure group had a sestamibi scan positive for single-gland disease. In this subgroup, 16 (40.0%) patients underwent a minimally invasive parathyroidectomy, 14 (35.0%) pa-
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Table 2. Demographic and Clinical Characteristics of 412 Patients with Primary Hyperparathyroidism by Radiation Exposure Status
Characteristics
Radiation exposure Age (y), mean Gender Male Female Ethnicity Caucasian Other Benign thyroid neoplasm Before presentation Time of presentation Thyroid cancer Before presentation Time of presentation Operation Minimally invasive Unilateral Bilateral Type of disease Single-gland Multigland
No radiation n %
Therapeutic radiation n %
360 58.8
87.4
52 65.1
12.6
75 285
20.8 79.2
13 39
25.0 75.0
0.47
305 55
84.7 15.3
46 6
88.5 11.5
0.68
6 43
1.7 11.9
3 10
5.8 19.2
0.09 0.18
1 11
0.3 3.1
3 1
5.8 1.9
⬍0.007 0.65
150 101 109
41.7 28.1 30.3
16 17 19
30.8 32.7 36.5
0.32
308 52
85.6 14.4
42 10
80.8 19.2
0.41
p Value
⬍0.0009
tients underwent unilateral neck exploration, and 10 (25.0%) patients underwent a bilateral neck exploration (Fig. 2). In the group without a history of radiation exposure, 293 of 360 (81.4%) patients had a sestamibi scan positive for single-gland disease. One hundred forty-four (49.1%) patients underwent a minimally invasive parathyroidectomy, 89 (30.4%) patients underwent unilateral neck exploration, and 60 (20.5%) patients underwent bilateral neck exploration (Fig. 2). Thirty of 52 (57.7%) patients in the radiation exposure group had a sestamibi scan and an ultrasound positive for single-gland disease. In this subgroup, 14 (46.7%) patients underwent a minimally invasive parathyroidectomy, 11 (36.7%) patients underwent unilateral neck exploration, and 5 (16.7%) patients underwent a bilateral neck exploration (Fig. 3). In the group without a history of radiation exposure, 226 of 360 (62.8%) patients had a sestamibi scan and an ultrasound positive for single-gland disease. One hundred twentyeight (56.7%) patients underwent a minimally invasive parathyroidectomy, 64 (28.3%) patients underwent unilateral neck exploration, and 35 (15.4%) patients underwent a bilateral neck exploration (Fig. 3). Three-hundred thirty of the 412 patients had intraoperative PTH used
Figure 2. Operative strategy based on sestamibi scan showing single-gland disease by radiation exposure status. Not all patients with single-gland disease had a minimally invasive approach for several reasons. These included the surgeon’s preference to identify the other normal parathyroid gland because intraoperative parathyroid hormone (PTH) level measurement was not available at one of the medical care sites; the removed parathyroid gland was modestly enlarged (unilateral); and/or there was an inappropriate decrease in intraoperative PTH level (not greater than 50%).
during their parathyroidectomy. There was no significant difference in the rate of use of intraoperative PTH by history of therapeutic radiation exposure status (p ⫽ 0.41). When we performed a subset analysis excluding the patients for whom the exact site of therapeutic radiation exposure could not be confirmed (Table 1), there was no significant difference in terms of gender, ethnicity, concurrent benign thyroid neoplasm and thyroid cancer, and type of parathyroid disease (single- versus multigland) between the 2 groups. The radiation group was older at presentation (p ⫽ 0.001) and the rate of previous history of thyroid cancer was higher (p ⫽ 0.02).
DISCUSSION In this study, we sought to determine if a history of radiation exposure in a patient with primary hyperparathyroidism should be considered a contraindication for a minimally invasive parathyroidectomy approach. We found that previous radiation should not be a contraindication for minimally invasive parathyroidectomy in patients who have single-gland disease on localizing studies and have no evidence of coexisting thyroid neoplasm. In our contemporary patient population, 12.6% (52 of 360) had a history of radiation exposure. There was no significant difference
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Figure 3. Operative strategy based on sestamibi and ultrasound showing single-gland disease by radiation exposure status. Not all patients with single-gland disease had a minimally invasive approach for several reasons. These included the surgeon’s preference to identify the other normal parathyroid gland because intraoperative parathyroid hormone (PTH) level measurement was not available at one of the medical care sites; the removed parathyroid gland was modestly enlarged (unilateral); and/or there was an inappropriate decrease in intraoperative PTH level (not greater than 50%).
in the operative approach used between the therapeutic radiation group and the nonradiated group. There was also no significant difference in rates of single-gland disease versus multigland disease between the 2 groups. Furthermore, there was no significant difference between the 2 groups in rate of thyroid cancer at the presentation of primary hyperparathyroidism. The 2 groups differed in age of presentation and remote history of thyroid cancer, likely due to the longer latency of radiation-associated primary hyperparathyroidism. In the United States, approximately 100,000 new cases of primary hyperparathyroidism are diagnosed annually.23 Parathyroidectomy is the only curative therapy for primary hyperparathyroidism. The most common pathologic finding in primary hyperparathyroidism is a parathyroid adenoma (single-gland disease; ⱖ80% of cases). Patients with preoperative studies showing single-gland disease are candidates for minimally invasive parathyroidectomy.18 Many believe that radiation exposure should be a contraindication for minimally invasive parathyroidectomy. This is due to a belief that patients with a history of radiation exposure have an increased risk of concurrent thyroid pathology in particular thyroid cancer.19-21 Some investigators have also suggested that patients with radiation exposure are more
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likely to have multigland parathyroid disease and are less likely to be candidates for minimally invasive parathyroidectomy. However, in the era of improved localizing studies, our data suggest that a similar proportion of patients could have a minimally invasive parathyroidectomy with successful biochemical cure. At the very least, a history of radiation exposure should not be an absolute contraindication for minimally invasive parathyroidectomy. In the study cohort, the radiation exposure group had a higher rate of remote history of thyroid cancer than the nonradiated group: 5.7% versus ⬍1% (p ⬍ 0.007). This finding is consistent with an increased rate of thyroid cancer after radiation exposure, a known risk factor for thyroid cancer with an average latency period of 30 years. Conversely, there was no significant difference between the therapeutic radiation group and the nonradiated group in benign thyroid neoplasm and thyroid cancer at time of presentation for primary hyperparathyroidism: 19.2% and 1.9% versus 11.7% and 3.1%, respectively (p ⫽ 0.18 and p ⫽ 0.65). Furthermore, there was no significant difference in rate of multigland disease versus single-gland disease between the 2 groups. We also excluded the cases of therapeutic radiation for which the exact site could not be accurately determined and found the rate of single-gland disease and minimally invasive parathyroidectomy were similar to those with no history of therapeutic irradiation. Based on these results, patients with a history of therapeutic radiation exposure should be candidates for minimally invasive parathyroidectomy if they have single-gland disease on localizing studies and no thyroid neoplasm on ultrasound. The rate of minimally invasive parathyroidectomy was low in our study, but this was due to the strict definition we used. We considered only patients in whom the enlarged parathyroid gland was identified and removed as minimally invasive parathyroidectomy. If patients who had a unilateral neck exploration (identification of the other ipsilateral parathyroid gland) are included, the rate is similar to those in other studies in the literature (64%). The reason for unilateral neck exploration in patients with positive localizing studies for single-gland disease was that intraoperative PTH measurement was not available at 1 of the 2 hospitals where the parathyroidectomies were performed, and in some cases, the proximity of the other parathyroid gland to the enlarged parathyroid gland. However, the use of intraoperative PTH measurement and the percentage of patients who had their parathyroidectomy at the hospital where intraoperative PTH measurement was not available were not significantly different by therapeutic radiation exposure status. Our study has several limitations that are consistent with
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most retrospective analyses of prospective data. A patient questionnaire was used to determine radiation exposure history, which may result in a recall bias. Although most patients knew that they had therapeutic radiation, they were not sure about the exact age of exposure, dose used, and in some cases, the indication for radiation. Although this does not allow us to determine the exact latency period of radiation-associated primary hyperparathyroidism and the possible effect of the dose of radiation exposure, it does not affect the outcomes because patients with history of therapeutic radiation have significant exposure to the neck region. Furthermore, there is strong evidence that radiation exposure at low doses can lead to radiation-associated primary hyperparathyroidism.12,14 In summary, we have shown that radiation exposure should not be an absolute contraindication for minimally invasive parathyroidectomy. The historical reasons for this contraindication are fear of concurrent thyroid cancer and higher likelihood of multigland disease with a history of therapeutic radiation. We showed no significant differences in these factors. Patients with a history of radiation exposure had a later age of presentation for parathyroidectomy, likely related to a longer latency period (40 years after exposure).2,21 They did have a greater history of thyroid cancer, but thyroid cancer presented before radiationassociated primary hyperparathyroidism, which is consistent with a shorter latency period of radiation-associated thyroid cancer (⬃30 years).2 So, in the era of more accurate localization studies, patients with primary hyperparathyroidism and a history of radiation exposure should be considered for minimally invasive parathyroidectomy depending on the results of the imaging studies. Based on our results, patients with primary hyperparathyroidism, a history of therapeutic radiation exposure, a positive localization study for single-gland disease, and a normal thyroid ultrasound (no evidence of thyroid nodule) would be ideal candidates for a minimally invasive parathyroidectomy. Patients with primary hyperparathyroidism, a history of therapeutic radiation exposure, and a thyroid nodule on ultrasound would need to have a total or near total thyroidectomy because the risk of thyroid cancer is approximately 40% and fine aspiration biopsy is not as accurate.22,24
Author Contributions Study conception and design: Rahbari, Duh, Clark, Kebebew Acquisition of data: Rahbari, Sansano, Elaraj, Duh, Clark Analysis and interpretation of data: Rahbari, Sansano, Elaraj, Kebebew Drafting of manuscript: Rahbari Critical revision: Rahbari, Sansano, Elaraj, Duh, Clark, Kebebew
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REFERENCES 1. Rosen IB, Strawbridge HG, Bain J. A case of hyperparathyroidism associated with radiation to the head and neck area. Cancer 1975;36:1111–1114. 2. Stephen AE, Chen KT, Milas M, Siperstein AE. The coming of age of radiation-induced hyperparathyroidism: evolving patterns of thyroid and parathyroid disease after head and neck irradiation. Surgery 2004;136:1143–1153. 3. Prinz RA, Paloyan E, Lawrence AM, et al. Radiation-associated hyperparathyroidism: a new syndrome? Surgery 1977;82:296– 302. 4. Tisell LE, Hansson G, Lindberg S, Ragnhult I. Hyperparathyroidism in persons treated with x-rays for tuberculous cervical adenitis. Cancer 1977;40:846–854. 5. Tisell LE, Hansson G, Lindberg S, Ragnhult I. Occurrence of previous neck radiotherapy among patients with associated nonmedullary thyroid carcinoma and parathyroid adenoma or hyperplasia. Acta Chir Scand 1978;144:7–11. 6. 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;180:81–87. 7. McMullen T, Bodie G, Gill A, et al. Hyperparathyroidism after irradiation for childhood malignancy. Int J Radiat Oncol Biol Phys 2009;73:1164–1168. 8. Ippolito G, Palazzo FF, Sebag F, Henry JF. Long-term follow-up after parathyroidectomy for radiation-induced hyperparathyroidism. Surgery 2007;142:819–822; discussion 822 e1. 9. Berdjis CC. Parathyroid diseases and irradiation. Strahlentherapie 1972;143:48–62. 10. Lindsay S, Sheline GE, Potter GD, Chaikoff IL. Induction of neoplasms in the thyroid gland of the rat by x-irradiation of the gland. Cancer Res 1961;21:9–16. 11. Fjalling M, Hansson G, Hedman I, et al. Radiation-induced parathyroid adenomas and thyroid tumors in rats. Acta Pathol Microbiol Scand A 1981;89:425–429. 12. Fujiwara S, Sposto R, Shiraki M, et al. Hyperparathyroidism among atomic bomb survivors in Hiroshima. Radiat Res 1992; 130:372–378. 13. Moalem J, Guerrero M, Kebebew E. Bilateral neck exploration in primary hyperparathyroidism–when is it selected and how is it performed? World J Surg 2009;33:2282–2291. 14. Colaco SM, Si M, Reiff E, Clark OH. Hyperparathyroidism after radioactive iodine therapy. Am J Surg 2007;194:323–327. 15. Palazzo FF, Delbridge LW. Minimal-access/minimally invasive parathyroidectomy for primary hyperparathyroidism. Surg Clin North Am 2004;84:717–734. 16. Uruno T, Kebebew E. How to localize parathyroid tumors in primary hyperparathyroidism? J Endocrinol Invest 2006;29: 840–847. 17. Davis ML, Quayle FJ, Middleton WD, et al. Ultrasound facilitates minimally invasive parathyroidectomy in patients lacking definitive localization from preoperative sestamibi scan. Am J Surg 2007;194:785–790; discussion 790–791. 18. Kebebew E, Hwang J, Reiff E, et al. Predictors of single-gland vs multigland parathyroid disease in primary hyperparathyroidism: a simple and accurate scoring model. Arch Surg 2006;141: 777–782; discussion 782. 19. Tisell LE, Carlsson S, Fjalling M, et al. Hyperparathyroidism subsequent to neck irradiation. Risk factors. Cancer 1985;56: 1529–1533.
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20. Prinz RA, Paloyan E, Lawrence AM, et al. Unexpected parathyroid disease discovered at thyroidectomy in irradiated patients. Am J Surg 1981;142:355–357. 21. 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. 22. Gharib H, Papini E, Valcavi R, et al. American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis
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and management of thyroid nodules. Endocr Pract 2006; 12:63–102. 23. Kebebew E, Clark OH. Parathyroid adenoma, hyperplasia, and carcinoma: localization, technical details of primary neck exploration, and treatment of hypercalcemic crisis. Surg Oncol Clin North Am 1998;7:721–748. 24. Vriens MR, Sabanci U, Epstein HD, et al. Reliability of fineneedle aspiration in patients with familial nonmedullary thyroid cancer. Thyroid 1999;9:1011–1016.
In the past, radiation has been used for a wide array of medical problems ranging from benign to malignant disorders. It has been used for conditions such as acne, skin rashes, lymphadenopathy, and enlarged tonsils. In 1975, the first case of primary hyperparathyroidism associated with radiation was reported by Rosen and colleagues.1 The case involved a 57-year-old woman who had received radiation 40 years earlier for facial hirsutism. Multiple series
followed, showing an association between radiation exposure to the head and neck and primary hyperparathyroidism.2-8 In addition, radiation-induced formation of parathyroid adenoma was shown in animal models.9-11 Some early series showed a history of radiation in up to 30% of patients with primary hyperparathyroidism, with more recent series showing a history of head and neck irradiation in anywhere from 1% to 14% of patients with primary hyperparathyroidism.3,7,8 In addition, studies in atomic bomb survivors in Japan showed that even lower doses of radiation exposure than those used in radiotherapy can be associated with hyperparathyroidism.12 Although head and neck radiation for benign disease is no longer used, there are still multiple medical diagnostic and therapeutic procedures associated with significant radiation exposure to the head and neck.2,7,13,14 The continued use of radiation combined with a long latency period before primary hyperparathyroidism
Disclosure Information: Nothing to disclose. Received December 22, 2009; Revised February 13, 2010; Accepted February 15, 2010. From the Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD (Rahbari, Kebebew) and the Departments of Surgery, University of California San Francisco, CA (Sansano, Duh, Clark) and Northwestern University Feinberg School of Medicine, Chicago, IL (Elaraj). Correspondence address: Electron Kebebew, MD, National Cancer Institute, Surgery Branch, CRC, Room 4-5952, 10 Center Dr, MSC 1201, Bethesda, MD 20892-1201. email: [email protected]
© 2010 by the American College of Surgeons Published by Elsevier Inc.
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develops keeps radiation-associated primary hyperparathyroidism and its treatment a relevant concern. Over the last decade, with the advances in localization techniques for parathyroid tumors, the surgical approach to primary hyperparathyroidism has changed from bilateral neck exploration to a focused or minimally invasive approach in most patients with evidence of single-gland disease.15-17 Because most patients with primary hyperparathyroidism have single-gland disease, a minimally invasive approach based on localizing studies showing single-gland parathyroid disease is feasible in up to two-thirds of cases.18 In patients with a history of head and neck irradiation, due to the risk of multigland disease and coexisting thyroid cancer, minimally invasive parathyroidectomy for primary hyperparathyroidism is considered by some surgeons to be contraindicated.19-21 However, in the era of improved localizing studies, which include ultrasonographic evaluation of the thyroid gland, there are limited contemporary data addressing the question of whether a history of head and neck irradiation should be an absolute contraindication for minimally invasive parathyroidectomy.13 We postulated that previous history of head and neck irradiation should not be a contraindication for minimally invasive parathyroidectomy, and we tested this hypothesis in a prospective cohort of patients undergoing parathyroidectomy for primary hyperparathyroidism.
METHODS Study cohort
We did a retrospective analysis of a prospective database of 491 consecutive parathyroidectomies performed at the University of California, San Francisco Medical Centers between May 2005 and May 2007. We reviewed the database, which included demographics, clinical history (history of exposure to head and neck radiation and personal history of thyroid disease or thyroid cancer), radiographic data (high-resolution neck ultrasound and technetium TC 99m sestamibi scan), operative notes, pathology reports, and postoperative clinical follow-ups. Remote history of thyroid cancer was defined as diagnosis of thyroid cancer before presentation of primary hyperparathyroidism. Remote history of benign thyroid neoplasm was defined as diagnosis of benign neoplasm before presentation. Concurrent thyroid cancer was defined as presentation with thyroid cancer at the time of diagnosis of primary hyperparathyroidism, and concurrent benign thyroid neoplasm was defined as diagnosis of benign thyroid neoplasm at the time of diagnosis of primary hyperparathyroidism. All patients with a history of radiation exposure to the head and neck who had a thyroid nodule (benign or malignant
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on fine needle aspiration biopsy) had a total thyroidectomy because of the risk of thyroid cancer.22 Radiation exposure was defined as a history of therapeutic irradiation. A questionnaire was used in all patients with questions regarding radiation exposure and history of thyroid disorders (Fig. 1). The therapeutic nature of radiation exposure was confirmed in all patients. Patients with confirmed therapeutic radiation but uncertain field of exposure (patients were certain that they had received therapeutic radiation but uncertain of the site) were considered having had radiation exposure in the analysis, but a subgroup analysis was performed excluding these patients (Table 1). Approval from the Committee on Human Research at the University of California, San Francisco was obtained. Seventy-three patients presented with a previous history of parathyroidectomy and persistent or recurrent primary hyperparathyroidism (none in the radiation group), and 6 patients with unknown outcomes or pathology were excluded, leaving 412 patients with initial primary hyperparathyroidism who were cured postoperatively. Imaging studies and definition of biochemical cure
All patients had a high-resolution neck ultrasound and technetium Tc99m sestamibi scan. Patients then underwent a minimally invasive parathyroidectomy (operation limited to resection of 1 abnormal parathyroid gland without further neck exploration), unilateral neck exploration (identification of both upper and lower parathyroid glands on the same side), or bilateral neck exploration (identification of all 4 parathyroid glands). The intraoperative parathyroid hormone (PTH) assay was used as an adjunct in some cases. Biochemical cure was defined as normalization of both the total serum calcium and intact PTH values postoperatively for at least 6 months. Data analysis
Rates and proportions of categorical data were compared using the Fisher exact test with 2-tailed p values. Nonparametric continuous data was compared using the MannWhitney rank test. A p value ⬍ 0.05 was used to define statistical significance.
RESULTS Demographic and clinical characteristics of the study cohort are summarized in Table 2 by therapeutic radiation exposure status. Four hundred twelve patients (88 men [21.4%] and 324 women [78.6%]) underwent a parathyroidectomy. Fifty-two patients had a history of therapeutic radiation (12.6%). There was no significant difference in gender or ethnicity by radiation exposure status. Patients
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Figure 1. Standard questionnaire used to determine radiation exposure and history of thyroid disease. Patients who reported having only diagnostic radiation exposure were placed in the no-radiation-exposure cohort.
with a history of therapeutic radiation were older at presentation, with an average age of 65.1 years versus 58.8 years for patients without a history of therapeutic radiation (p ⬍ 0.0009). Of the 52 patients exposed to therapeutic radiation, 10 (19.2%) had multigland disease and 42 (80.8%) had single-gland disease. In patients without a history of therapeutic radiation exposure, 52 (14.4%) patients had multigland disease and 308 (85.6%) had single-gland disease (p ⫽ 0.41). In patients with a history of therapeutic radiation exposure, 19 patients (36.5%) underwent bilateral neck exploration, 17 (32.7%) patients underwent unilateral neck exploration, and 16 (30.7%) patients underwent a minimally invasive parathyroidectomy. In patients without a history of therapuetic radiation exposure, 109 patients (30.3%) underwent bilateral neck exploration, 101 (28%) patients underwent unilateral neck exploration, and 150 (41.7%) patients underwent a minimally invasive parathyroidecTable 1. Radiation Exposure Type and Site in 52 Patients Site of radiation
n
%
Head and neck Upper chest Radioactive iodine Other
18 9 5 20
34.6 17.3 9.6 38.5
tomy. There was no statistically significant difference in operative approach used by history of radiation exposure status (p ⫽ 0.32). Three (5.7%) patients in the group with a history of therapeutic radiation had a history of benign thyroid neoplasm; 6 (1.7%) patients without a history of radiation exposure had a history of benign thyroid neoplasm (p ⫽ 0.09). Three (5.7%) patients in the radiation exposure group had a history of thyroid cancer before presentation of primary hyperparathyroidism and 1 patient without a history of radiation exposure had a history of thyroid cancer (p ⫽ 0.007). There was no significant difference in benign thyroid neoplasm at time of presentation for primary hyperparathyroidism between the 2 groups (10 [19.2%] patients in the radiation exposure group vs 43 [11.9%] patients in the nonradiated group [p ⫽ 0.18]). However, there was no significant difference in rate of thyroid cancer at time of presentation for primary hyperparathyroidism between the 2 groups, with 1 (1.9%) patient in the therapeutic radiation group and 11 (3.1%) patients in the nonradiated group (p ⫽ 0.99). Forty of 52 (76.9%) patients in the radiation exposure group had a sestamibi scan positive for single-gland disease. In this subgroup, 16 (40.0%) patients underwent a minimally invasive parathyroidectomy, 14 (35.0%) pa-
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Table 2. Demographic and Clinical Characteristics of 412 Patients with Primary Hyperparathyroidism by Radiation Exposure Status
Characteristics
Radiation exposure Age (y), mean Gender Male Female Ethnicity Caucasian Other Benign thyroid neoplasm Before presentation Time of presentation Thyroid cancer Before presentation Time of presentation Operation Minimally invasive Unilateral Bilateral Type of disease Single-gland Multigland
No radiation n %
Therapeutic radiation n %
360 58.8
87.4
52 65.1
12.6
75 285
20.8 79.2
13 39
25.0 75.0
0.47
305 55
84.7 15.3
46 6
88.5 11.5
0.68
6 43
1.7 11.9
3 10
5.8 19.2
0.09 0.18
1 11
0.3 3.1
3 1
5.8 1.9
⬍0.007 0.65
150 101 109
41.7 28.1 30.3
16 17 19
30.8 32.7 36.5
0.32
308 52
85.6 14.4
42 10
80.8 19.2
0.41
p Value
⬍0.0009
tients underwent unilateral neck exploration, and 10 (25.0%) patients underwent a bilateral neck exploration (Fig. 2). In the group without a history of radiation exposure, 293 of 360 (81.4%) patients had a sestamibi scan positive for single-gland disease. One hundred forty-four (49.1%) patients underwent a minimally invasive parathyroidectomy, 89 (30.4%) patients underwent unilateral neck exploration, and 60 (20.5%) patients underwent bilateral neck exploration (Fig. 2). Thirty of 52 (57.7%) patients in the radiation exposure group had a sestamibi scan and an ultrasound positive for single-gland disease. In this subgroup, 14 (46.7%) patients underwent a minimally invasive parathyroidectomy, 11 (36.7%) patients underwent unilateral neck exploration, and 5 (16.7%) patients underwent a bilateral neck exploration (Fig. 3). In the group without a history of radiation exposure, 226 of 360 (62.8%) patients had a sestamibi scan and an ultrasound positive for single-gland disease. One hundred twentyeight (56.7%) patients underwent a minimally invasive parathyroidectomy, 64 (28.3%) patients underwent unilateral neck exploration, and 35 (15.4%) patients underwent a bilateral neck exploration (Fig. 3). Three-hundred thirty of the 412 patients had intraoperative PTH used
Figure 2. Operative strategy based on sestamibi scan showing single-gland disease by radiation exposure status. Not all patients with single-gland disease had a minimally invasive approach for several reasons. These included the surgeon’s preference to identify the other normal parathyroid gland because intraoperative parathyroid hormone (PTH) level measurement was not available at one of the medical care sites; the removed parathyroid gland was modestly enlarged (unilateral); and/or there was an inappropriate decrease in intraoperative PTH level (not greater than 50%).
during their parathyroidectomy. There was no significant difference in the rate of use of intraoperative PTH by history of therapeutic radiation exposure status (p ⫽ 0.41). When we performed a subset analysis excluding the patients for whom the exact site of therapeutic radiation exposure could not be confirmed (Table 1), there was no significant difference in terms of gender, ethnicity, concurrent benign thyroid neoplasm and thyroid cancer, and type of parathyroid disease (single- versus multigland) between the 2 groups. The radiation group was older at presentation (p ⫽ 0.001) and the rate of previous history of thyroid cancer was higher (p ⫽ 0.02).
DISCUSSION In this study, we sought to determine if a history of radiation exposure in a patient with primary hyperparathyroidism should be considered a contraindication for a minimally invasive parathyroidectomy approach. We found that previous radiation should not be a contraindication for minimally invasive parathyroidectomy in patients who have single-gland disease on localizing studies and have no evidence of coexisting thyroid neoplasm. In our contemporary patient population, 12.6% (52 of 360) had a history of radiation exposure. There was no significant difference
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Figure 3. Operative strategy based on sestamibi and ultrasound showing single-gland disease by radiation exposure status. Not all patients with single-gland disease had a minimally invasive approach for several reasons. These included the surgeon’s preference to identify the other normal parathyroid gland because intraoperative parathyroid hormone (PTH) level measurement was not available at one of the medical care sites; the removed parathyroid gland was modestly enlarged (unilateral); and/or there was an inappropriate decrease in intraoperative PTH level (not greater than 50%).
in the operative approach used between the therapeutic radiation group and the nonradiated group. There was also no significant difference in rates of single-gland disease versus multigland disease between the 2 groups. Furthermore, there was no significant difference between the 2 groups in rate of thyroid cancer at the presentation of primary hyperparathyroidism. The 2 groups differed in age of presentation and remote history of thyroid cancer, likely due to the longer latency of radiation-associated primary hyperparathyroidism. In the United States, approximately 100,000 new cases of primary hyperparathyroidism are diagnosed annually.23 Parathyroidectomy is the only curative therapy for primary hyperparathyroidism. The most common pathologic finding in primary hyperparathyroidism is a parathyroid adenoma (single-gland disease; ⱖ80% of cases). Patients with preoperative studies showing single-gland disease are candidates for minimally invasive parathyroidectomy.18 Many believe that radiation exposure should be a contraindication for minimally invasive parathyroidectomy. This is due to a belief that patients with a history of radiation exposure have an increased risk of concurrent thyroid pathology in particular thyroid cancer.19-21 Some investigators have also suggested that patients with radiation exposure are more
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likely to have multigland parathyroid disease and are less likely to be candidates for minimally invasive parathyroidectomy. However, in the era of improved localizing studies, our data suggest that a similar proportion of patients could have a minimally invasive parathyroidectomy with successful biochemical cure. At the very least, a history of radiation exposure should not be an absolute contraindication for minimally invasive parathyroidectomy. In the study cohort, the radiation exposure group had a higher rate of remote history of thyroid cancer than the nonradiated group: 5.7% versus ⬍1% (p ⬍ 0.007). This finding is consistent with an increased rate of thyroid cancer after radiation exposure, a known risk factor for thyroid cancer with an average latency period of 30 years. Conversely, there was no significant difference between the therapeutic radiation group and the nonradiated group in benign thyroid neoplasm and thyroid cancer at time of presentation for primary hyperparathyroidism: 19.2% and 1.9% versus 11.7% and 3.1%, respectively (p ⫽ 0.18 and p ⫽ 0.65). Furthermore, there was no significant difference in rate of multigland disease versus single-gland disease between the 2 groups. We also excluded the cases of therapeutic radiation for which the exact site could not be accurately determined and found the rate of single-gland disease and minimally invasive parathyroidectomy were similar to those with no history of therapeutic irradiation. Based on these results, patients with a history of therapeutic radiation exposure should be candidates for minimally invasive parathyroidectomy if they have single-gland disease on localizing studies and no thyroid neoplasm on ultrasound. The rate of minimally invasive parathyroidectomy was low in our study, but this was due to the strict definition we used. We considered only patients in whom the enlarged parathyroid gland was identified and removed as minimally invasive parathyroidectomy. If patients who had a unilateral neck exploration (identification of the other ipsilateral parathyroid gland) are included, the rate is similar to those in other studies in the literature (64%). The reason for unilateral neck exploration in patients with positive localizing studies for single-gland disease was that intraoperative PTH measurement was not available at 1 of the 2 hospitals where the parathyroidectomies were performed, and in some cases, the proximity of the other parathyroid gland to the enlarged parathyroid gland. However, the use of intraoperative PTH measurement and the percentage of patients who had their parathyroidectomy at the hospital where intraoperative PTH measurement was not available were not significantly different by therapeutic radiation exposure status. Our study has several limitations that are consistent with
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most retrospective analyses of prospective data. A patient questionnaire was used to determine radiation exposure history, which may result in a recall bias. Although most patients knew that they had therapeutic radiation, they were not sure about the exact age of exposure, dose used, and in some cases, the indication for radiation. Although this does not allow us to determine the exact latency period of radiation-associated primary hyperparathyroidism and the possible effect of the dose of radiation exposure, it does not affect the outcomes because patients with history of therapeutic radiation have significant exposure to the neck region. Furthermore, there is strong evidence that radiation exposure at low doses can lead to radiation-associated primary hyperparathyroidism.12,14 In summary, we have shown that radiation exposure should not be an absolute contraindication for minimally invasive parathyroidectomy. The historical reasons for this contraindication are fear of concurrent thyroid cancer and higher likelihood of multigland disease with a history of therapeutic radiation. We showed no significant differences in these factors. Patients with a history of radiation exposure had a later age of presentation for parathyroidectomy, likely related to a longer latency period (40 years after exposure).2,21 They did have a greater history of thyroid cancer, but thyroid cancer presented before radiationassociated primary hyperparathyroidism, which is consistent with a shorter latency period of radiation-associated thyroid cancer (⬃30 years).2 So, in the era of more accurate localization studies, patients with primary hyperparathyroidism and a history of radiation exposure should be considered for minimally invasive parathyroidectomy depending on the results of the imaging studies. Based on our results, patients with primary hyperparathyroidism, a history of therapeutic radiation exposure, a positive localization study for single-gland disease, and a normal thyroid ultrasound (no evidence of thyroid nodule) would be ideal candidates for a minimally invasive parathyroidectomy. Patients with primary hyperparathyroidism, a history of therapeutic radiation exposure, and a thyroid nodule on ultrasound would need to have a total or near total thyroidectomy because the risk of thyroid cancer is approximately 40% and fine aspiration biopsy is not as accurate.22,24
Author Contributions Study conception and design: Rahbari, Duh, Clark, Kebebew Acquisition of data: Rahbari, Sansano, Elaraj, Duh, Clark Analysis and interpretation of data: Rahbari, Sansano, Elaraj, Kebebew Drafting of manuscript: Rahbari Critical revision: Rahbari, Sansano, Elaraj, Duh, Clark, Kebebew
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