Multimodality imaging of the parathyroid adenoma

Multimodality imaging of the parathyroid adenoma Poster No.: C-0256 Congress: ECR 2015 Type: Educational Exhibit Authors: S. Liddy, J. Feeney; Dublin/IE Keywords: Head and neck, Nuclear medicine, Thyroid / Parathyroids, Ultrasound, SPECT-CT, CT, History, Dosimetric comparison, Endocrine disorders, Neoplasia DOI: 10.1594/ecr2015/C-0256 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. www.myesr.org Page 1 of 39

Learning objectives 99m 1. To review the advantages and limitations of ultrasound, Tc-sestamibi scintigraphy and 4-dimensional computed tomography in the imaging of the parathyroid adenoma. 2. To illustrate the typical appearances of a parathyroid adenoma on ultrasound, sestamibi scintigraphy and 4-dimensional computed tomography. 99m Tc- 3. To examine the roles of the various imaging modalities in comtemporary parathyroid imaging. Background Primary hyperparathyroidism is the third most common endocrine disorder after diabetes mellitus and hypothyroidism and is a common reason for patients to be referred for medical imaging. [1] Approximately 90% of such patients are subsequently found to have a single parathyroid adenoma, 10% are found to have multigland hyperplasia or multiple adenomas, and the rare patient is found to have parathyroid carcinoma. [2] Surgical removal of the hyper-functioning parathyroid tissue is the only definitive cure and is warranted in symptomatic patients or in those who develop complications. Traditionally, this was done by way of a bilateral neck exploration with direct visualization of all four glands, with preoperative imaging studies rarely required. In 1986, interventional radiologist John L Doppman famously remarked that "the only localising study indicated in untreated primary hyperparathyroidism is to localise an experienced parathyroid surgeon". [3] The field has come a long way since then. Minimally invasive parathyroidectomy is now the standard of care and is associated with a shorter operative duration, a lower risk of postoperative complications, improved aesthetic outcome and greater patient satisfaction. [4, 5] It also has the added advantage of not requiring a general anaesthetic. This approach is dependent on precise localization of the abnormal gland(s) and is therefore predicated on accurate preoperative imaging. Parathyroid lesions, however, can prove elusive and first-line imaging studies can often be indeterminate, particularly if the lesion is small, has an unusual anatomic location, or if there is coexistent thyroid disease. All of the current imaging modalities experience a significant reduction in sensitivity in cases of mulitgland disease [6, 7]. Furthermore, Page 2 of 39

considerable variation exists between institutions with regard to the imaging studies employed, with the choice of modality now largely based on local experience, regional availability and surgeons' preference. Among the available options are ultrasound, radioisotope scintigraphy (including planar imaging, SPECT and SPECT/CT), CT, MRI and PET/CT. Unsurprisingly, this has resulted in significant confusion with much debate in the published literature regarding the optimal imaging protocol. 99m At our institution we routinely use neck ultrasonography and Tc-Sestamibi SPECT/CT in the preoperative localization of parathyroid lesions, with 4-dimensional CT reserved for equivocal or problematic cases. Here, we present a series of cases of educational value and examine the roles of these modalities in present-day parathyroid imaging. Findings and procedure details Ultrasound Parathyroid ultrasonography was first described in 1975 and has since become widely used in the preoperative localisation of abnormal parathyroid glands. [8] Parathyroid imaging is an excellent application of ultrasound as the superficial location permits the use of high-frequency transducers with their increased spatial resolution. Normal glands are rarely visible on ultrasound. Parathyroid adenomas tend to be round to ovoid in shape and appear hypoechoic in comparison with thyroid tissue. The application of Doppler can assist in distinguishing parathyroid lesions from other surrounding structures. A typical adenoma has a peripheral rim of vascularity and asymmetrically increased blood flow compared to the adjacent thyroid tissue. Furthermore, the identification of a prominent extrathyroidal feeding artery entering at one pole, know as polar artery, can further help in discriminating between an adenoma and a cervical lymph node. [9] Case 1 (figures 1-4), featuring a 49-year-old woman with nephrolithiasis and a surgically confirmed parathyroid adenoma, demonstrates the typical features of a parathyroid adenoma on ultrasound. Page 3 of 39

Fig. 1: Case 1: A 49-year-old female with primary hyperparathyroidism and nephrolithiasis. Plain abdominal radiograph reveals extensive bilateral renal calculi. Page 4 of 39

Fig. 2: Case 1: A 49-year-old female with primary hyperparathyroidism and nephrolithiasis. Neck ultrasonography reveals a well-circumscribed hypoechoic mass with a polar feeding artery (blue). A 13.6g oncocytic parathyroid adenoma was removed at surgery. Page 5 of 39

Fig. 3: Case 1: A 49-year-old female with primary hyperparathyroidism and nephrolithiasis. 99mTc-Sestamibi planar imaging taken 30 minutes and 2 hours following the administration of radioisotope demonstrates focal retention of tracer in the right lower neck. Page 6 of 39

Fig. 4: Case 1: A 49-year-old female with primary hyperparathyroidism and nephrolithiasis. 99mTc-Sestamibi SPECT/CT demonstrates a large parathyroid adenoma arising from the right lower neck, crossing the midline anterior to the trachea and extending towards the left side of the neck. Case 2 (figures 5-7): A 49-year-old man with multiple endocrine neoplasia type 1 and primary hyperparathyroidism. Page 7 of 39

Fig. 5: Case 2: A 49-year-old man with primary hyperparathyroidism and a multiple endocrine neoplasia type 1. Neck ultrasonography demonstrates a 1.1 x 1.6 x 2.0 cm hypoechoic, homogenous nodule with a polar feeding vessel located posterior to the lower pole of the left lobe of the thyroid, consistent with a parathyroid adenoma. Page 8 of 39

Fig. 6: Case 2: A 49-year-old man with primary hyperparathyroidism and a multiple endocrine neoplasia type 1. 99mTc-Sestamibi planar imaging reveals a focus of increased tracer retention in the left lower neck. Page 9 of 39

Fig. 7: Case 2: A 49-year-old man with primary hyperparathyroidism and a multiple endocrine neoplasia type 1. 99mTc-Sestamibi SPECT/CT again demonstrates a focus of increased tracer retention, correlating with a 1.5 x 0.8 cm soft tissue density located in the left tracheo-oesophageal groove, posterior and inferior to the left lower pole of the thyroid, consistent with a parathyroid adenoma. Neck ultrasonography has several advantages in imaging parathyroid adenomas. It is inexpensive, widely available and has sufficient sensitivity to permit its use as a first line investigation. It also enables the concurrent assessment of the thyroid gland and facilitates percutaneous biopsy if necessary. Due to its widespread availability over the last 20 years, ultrasound has been extensively evaluated. One recent meta-analysis from 2012 found it to have a sensitivity of 76% for patients with a first presentation of primary hyperparathyroidism, irrespective of aetiology. [10] However, ultrasound has a number of shortcomings. It is limited in patients with an elevated body mass index and it is highly dependent on an experienced sonographer performing and interpreting the study. It demonstrates reduced sensitivity and specificity in the context of multinodular thyroid disease. In addition, ultrasound has poor penetration of air-filled or bony structures limiting its ability to detect ectopic glands, particularly those located in the mediastinum. For these reasons, many centres are now employing Page 10 of 39

ultrasound in a complementary role with another imaging modality, most commonly SPECT or SPECT/CT. Radioisotope Scintigraphy: Planar imaging, SPECT and SPECT/CT Radioisotope scintigraphy of the parathyroid glands was first reported in 1983, with thallium as the initial radionuclide of choice. [11] Technetium 99m-sestamibi was later introduced in 1989 and greatly increased the sensitivity of nuclear imaging. [12] Sestamibi is a lipophilic cation that accumulates in the mitochondria-rich oxyphil cells of abnormal parathyroid tissue. It then washes out more rapidly from the surrounding tissues than from the parathyroid glands, allowing for the identification of the abnormal gland(s) on interval imaging. This modality has several advantages. Like ultrasound, it is inexpensive and widely available. Its wide field of view enables detection of ectopic lesions, particularly those in the mediastinum. In addition, there is much less inter-observer variation compared to neck ultrasonography. Its most pressing drawback, however, is the potential for false negatives. Thyroid nodules, thyroiditis and cervical lymphadenopathy can all delay the washout of the radionuclide giving the appearance of a parathyroid adenoma. In particular, follicular and Hurthle cell neoplasms readily accumulate sestamibi and can 99m often lend themselves to such errors. [13] Furthermore, the sensitivity of Tc-sestamibi imaging is closely correlated with the size of the adenoma, with adenomas of <600mg being associated with a higher rate of false negatives. [14] The use of single photon emission computed tomography (SPECT) has the advantage of three dimensions, aiding in the identification of pathological tissue within deep body structures or behind the thyroid where it may be obscured on planar imaging. SPECT demonstrates improved sensitivity and accuracy compared to standard, two-dimensional, planar imaging, with a reported sensitivity of approximately 85%. [15] More recently, 99m Tc-sesatmibi SPECT has been fused with conventional, x-ray based CT. These hybrid SPECT/CT images have led to more accurate localization as well as improved differentiation between adenomas and misleading sources of tracer uptake such as the thyroid or cervical lymph nodes. [16] Cases 3 and 4 (figures 8-11) illustrate the typical features of a parathyroid adenoma on planar and SPECT/CT imaging. Page 11 of 39

Fig. 8: Case 3: A 69-year-old man with osteopenia and primary hyperparathyroidism. 99mTc-Sestamibi planar images demonstrate a focus of tracer retention in the right lower neck. Page 12 of 39

Fig. 9: Case 3: A 69-year-old man with osteopenia and primary hyperparathyroidism. 99mTc-Sestamibi SPECT/CT images reveal an intense focus of tracer retention corresponding to a 9mm nodule posterior and inferior to the lower pole of the right lobe of the thyroid, consistent with a parathyroid adenoma. Page 13 of 39

Fig. 10: Case 4: A 64-year-old man with chronic kidney disease and primary hyperparathyroidism. 99mTc-Sestamibi planar imaging shows a focus of tracer retention in the left lower neck two hours after the administration of radioisotope. Page 14 of 39

Fig. 11: Case 4: A 64-year-old man with chronic kidney disease and primary hyperparathyroidism. 99mTc-sestamibi SPECT/CT images confirm the focus of tracer retention correlating with a 1.4cm soft tissue nodule located immediately inferior to the left lobe of the thyroid, consistent with a parathyroid adenoma. Case 5 (figures 12-14) demonstrates the improved sensitivity of SPECT/CT compared to standard planar imaging. The planar images show no obvious lesion but the SPECT/ CT reveals a discrete focus of increased uptake consistent with a parathyroid adenoma at the left lower pole of the thyroid. Page 15 of 39

Fig. 12: Case 5: A 52-year-old man with hyperparathyroidism, chronic kidney disease and osteoporosis. 99mTc-Sestamibi planar images demonstrate diffuse uptake within both lobes of the thyroid gland but no focal area of tracer retention suggestive of parathyroid adenoma. Page 16 of 39

Fig. 13: Case 5: A 52-year-old man with hyperparathyroidism, chronic kidney disease and osteoporosis. 99mTc-Sestamibi SPECT/CT images demonstrate a 1 x 0.5 cm soft tissue nodule immediately lateral to the oesophagus and posterior to the left lower pole of the thyroid. The nodule shows low-grade tracer uptake consistent with a parathyroid adenoma. Page 17 of 39

Fig. 14: Case 5: A 52-year-old man with hyperparathyroidism, chronic kidney disease and osteoporosis. Contrast-enhanced CT thorax demonstrates a 1cm enhancing soft tissue lesion consistent with a parathyroid adenoma (arrow). One of the most notable advantages of nuclear scintigraphy over ultrasound is its ability to detect ectopic lesions. In approximately 16% of cases of primary hyperparathyroidism, one or more hyperfunctioning gland(s) is found in an ectopic location. [17] The location of ectopic glands depends on their embryological origin. The superior glands, which are derived from the fourth branchial pouch, are often found within the thyroid gland, as the parafollicular cells of the thyroid also derive from the fourth brachial pouch. The inferior glands, which are derived from the third brachial pouch, descend with the thymus and undergo a much lengthier migration compared to the superior glands. Hence, they experience more variation in their final location and can be found within the thymus, in several retro-oesophageal locations, or occasionally in the mediastinum. 99m In one study involving 202 patients with ectopic parathyroid lesions, Tc-sesatimibi scintigraphy had a sensitivity of 89%, performing particularly well in cases of thymic, mediastinal and retro-oesophageal adenomas. [18] In contrast, ultrasonography had a Page 18 of 39

sensitivity of only 59% for detecting ectopic glands; and although it performed well in cases of undescended and intrathyroidal glands, it was particularly poor at detecting glands within the thymus or in the retro-oesophageal areas, and failed to detect any glands located within the mediastinum or carotid sheath. Cases 6-8 (figures 15-25) illustrate the value of SPECT/CT in identifying and localizing ectopic parathyroid lesions. Fig. 15: Case 6: A 41-year-old woman with primary hyperparathyroidism. Chest x-ray shows a right, paratracheal, mediastinal mass measuring approximately 5cm. Page 19 of 39

Fig. 16: Case 6: A 41-year-old woman with primary hyperparathyroidism. CT Thorax demonstrates a 6.5 x 5.1 cm soft tissue mass in the right paratracheal region. Page 20 of 39

Fig. 17: Case 6: A 41-year-old woman with primary hyperparathyroidism. 99mTcSestamibi planar images demonstrate a large area of tracer uptake in the right hemithorax. Page 21 of 39

Fig. 18: Case 6: A 41-year-old woman with primary hyperparathyroidism. 99mTcSestamibi SPECT/CT images show a 5.2 x 4.6 x 4.8 cm soft tissue mass centred in the right tracheo-oesophageal groove demonstrating intense heterogenous tracer retention consistent with a lesion of parathyroid origin. Photopenic regions are also seen at the superior and inferior limits of the mass suggestive of lesion necrosis. Histological analysis confirmed an atypical parathyroid adenoma. Page 22 of 39

Page 23 of 39

Fig. 19: Case 6: A 41-year-old woman with primary hyperparathyroidism. Whole body isotope bone scan showing multiple areas of increase isotope uptake consistent with osteitis fibrosa cystica of hyperparathyroidism. Fig. 20: Case 6: A 41-year-old woman with primary hyperparathyroidism. Lateral skull radiograph demonstrating multiple osseous lucencies. Page 24 of 39

Fig. 21: Case 7: A 66-year-old woman with primary hyperparathyroidism and osteopenia. 99mTc-sestamibi planar images show show a focus of uptake in the mediastinum that has partially washed out on the two-hour image. Page 25 of 39

Fig. 22: Case 7: A 66-year-old woman with primary hyperparathyroidism and osteopenia. The 99mTc-sestamibi SPECT/CT images reveal the focus of uptake to originate from a 1.0 x 0.6 cm soft tissue lesion in the anterior mediastinum, interposed between the ascending aorta and pulmonary trunk, concerning for an ectopic parathyroid adenoma. Page 26 of 39

Fig. 23: Case 7: A 66-year-old woman with primary hyperparathyroidism and osteopenia. Contrast-enhanced CT thorax shows a soft tissue nodule between the ascending thoracic aorta and pulmonary outflow tract in the anterior mediastinal fat (arrow). Page 27 of 39

Fig. 24: Case 8: A 60-year-old woman with primary hyperparathyroidism. 99mTcsestamibi planar images shows show an abnormal focus of isotope accumulation in the right inferior neck. Page 28 of 39

Fig. 25: Case 8: A 60-year-old woman with primary hyperparathyroidism. The 99mTcsestamibi SPECT/CT images show that the isotope accumulation in the lower neck corresponds with a 7mm soft tissue density in the right tracheo-oesophageal groove at the level of T1/T2. All imaging modalities, including parathyroid scintigraphy, experience a marked reduction in sensitivity in cases of multigland disease. [6] The prevalence of multiglandular disease in patients with primary hyperparathyroidism is approximately 10%, but rises to 24% in those with unsuccessful localization on first line imaging. [19] Hence, if a patient with confirmed hyperparathyroidism fails to demonstrate a clear-cut focus of activity on 99m Tc-sestamibi scintigraphy, then the possibility of multiglandular hyperplasia or double adenomas should be considered. Cases 9 and 10 (figures 26-29) illustrate two cases in which bilateral lesions were visualised, in keeping with either multigland disease or double adenomas. Page 29 of 39

Fig. 26: Case 9: A 70-year-old man with a previous kidney transplant and primary hyperparathyroidism. 99mTc-sestamibi planar images reveal bilateral foci of abnormal tracer retention. Page 30 of 39

Fig. 27: Case 9: A 70-year-old man with a previous kidney transplant and primary hyperparathyroidism. 99mTc-sestamibi SPECT/CT images demonstrate the dominant abnormal focus to correspond to a 1.5cm soft tissue nodule located posterior and superior to the upper pole of the left lobe of the thyroid, consistent with a parathyroid adenoma. An additional second focus of increased tracer retention is seen at the lower pole on the right, inseparable from the thyroid, and may represent a hyperplastic or adenomatous gland. Page 31 of 39

Fig. 28: Case 10: A 72-year-old woman with polycystic kidney disease, a previous kidney transplant and hyperparathyroidism. 99mTc-sestamibi planar images show no focal tracer retention suggestive of a parathyroid adenoma. Page 32 of 39

Fig. 29: Case 10: A 72-year-old woman with polycystic kidney disease, a previous kidney transplant and hyperparathyroidism. The 99mTc-Sestamibi SPECT/CT images reveal two foci of increased tracer activity, and may represent bilateral parathyroid adenomata or parathyroid hyperplasia. In 2007, Lavely et al compared planar imaging, SPECT and SPECT/CT in 110 patients with primary hyperparathyroidism and concluded that early SPECT/CT in combination with any delayed imaging method was the best overall protocol with an accuracy of approximately 86%. [20] However, any advantages of SPECT/CT must be weighed against the increased cost and time requirements, as well as the additional radiation exposure. This has led some authors to suggest that the use of SPECT/CT should be limited to cases of ectopic lesions. [21] Nonetheless, many centres are now using SPECT/ CT, either alone or in combination with ultrasound, as a first line imaging study. Computed Tomography Historically, conventional CT has performed poorly in comparison to other imaging modalities with regards to imaging of parathyroid adenomas, with a sensitivity of approximately 40-70%. [22] The advent of high-resolution CT and progressively thinner sections allowed radiologists to interpret images with greater confidence than before. However, it still failed to adequately distinguish between parathyroid adenomas and Page 33 of 39

cervical lymph nodes, which can closely resemble adenomas in size and shape. Fourdimensional CT, a recently developed technique that was first described in 2006, addresses this problem by incorporating two more contrast-enhanced phases in addition to the standard, non-contrast phase. Case 11 (figures 30-32) illustrates how 4D-CT assists in distinguishing between parathyroid adenomas and thyroid nodules in cases of coexistent multinodular goiter. Fig. 30: Case 11: A 68-year-old lady with primary hyperparathyroidism, nephrolithiasis and an enlarged, multinodular goiter. 99mTc-sestamibi planar images show mild focal isotope retention in the left lower neck, suspicious for a parathyroid adenoma. Page 34 of 39

Fig. 31: Case 11: A 68-year-old lady with primary hyperparathyroidism, nephrolithiasis and an enlarged, multinodular goiter. The 99mTc-sestamibi SPECT/CT images demonstrate a focus of mild tracer uptake in the left lower neck, on a background of a multinodular goiter. Fig. 32: Case 11: A 68-year-old lady with primary hyperparathyroidism, nephrolithiasis and an enlarged, multinodular goiter. Multiphase, contrast-enhanced CT of the neck. Pre-contrast (A), 25 seconds post-contrast (B) and 85 seconds post-contrast (C) images reveal a 5mm, elliptically-shaped, soft tissue mass lateral to the left lobe of the thyroid. This lesion enhances on the 25 second, contrast-enhanced phase Page 35 of 39

and demonstrates complete washout 85 seconds post-contast, consistent with a parathyroid adenoma. The primary criticism leveled against 4D-CT is the increased dose of radiation involved in acquiring the additional contrast-enhanced phases. Many institutions have adapted the originally described protocol by either omitting the initial, non-contrast phase or by removing one of the subsequent, contrast-enhanced phases. However the radiation dose still remains high, with a representative computed tomography dose index (CDTI) of nearly 20mGy at 150mA per phase of imaging. In a prototypic 20-year-old female this translates into a lifetime risk of 104 cases of thyroid cancer per 100,000 individuals exposed. This risk reduces to 4 cases per 100,000 when 50-year-old females are considered. [23] Hence, 4D-CT should be used sparingly in the younger population but can be reasonably employed in older patients, particularly in those who have undergone prior neck surgery or whose cases are proving problematic. Conclusion The advent of minimally invasive parathyroidectomy has brought with it the need for highly sensitive and increasingly accurate preoperative imaging. There is currently a wide array of imaging modalities and techniques available but little consensus regarding the optimal 99m imaging protocol. Many centres are now using ultrasound and Tc-Sestamibi SPECT/ CT, either alone or in combination, as their initial imaging studies of choice. Several complementary investigations now exist for those with equivocal first line imaging or for those whose cases are proving problematic. There is growing support for the use of 4dimensional CT in this setting but diagnostic algorithms vary between institutions. Personal information References 1. Fraser WD. Hyperparathyroidism. Lancet. 2009 Jul 11;374(9684):145-58. Page 36 of 39

2. Ruda JM, Hollenbeak CS, Stack BC Jr. A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg 2005 132:359-372. 3. Doppman JL. Reoperative parathyroid surgery; localization procedures. Prog Surg. 1986;18:117-132. 4. Udelsman R, Lin Z, Donovan P. The superiority of minimally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Ann Surg. 2011;253:585-591. 5. Kunstman JW, Udelsman R. Superiority of minimally invasive parathyroidectomy. Adv Surg. 2012;46:171-189. 6. Lubitz CC, Hunter GJ, Hamberg LM, et al: Accuracy of 4-dimensional computed tomography in poorly localized patients with primary hyperparathyroidism. Surgery 148:1129-1137, 2010 7. Mortenson MM, Evans DB, Lee JE, et al: Parathyroid exploration in the reoperative neck: Improved preoperative localization with 4D-computed tomography. J Am Coll Surg 206:888-895, 2008 8. Arima M, Yokoi H, Sonoda T. Preoperative identification of tumor of the parathyroid by ultrasonotomography. Surg Gynecol Obstet. 1975;141:242-244. 9. LaneMJ, Desser TS, Weigel RJ, Jeffrey RB Jr. 1998 Use of color and power Doppler sonography to identify feeding arteries associated with parathyroid adenomas. AJR Am J Roentgenol 171: 819-823. 10. Cheung K, Wang TS, Farrokhyar F, Roman SA, Sosa JA. A metaanalysis of preoperative localization techniques for patients with primary hyperparathyroidism. Ann Surg Oncol. 2012;19:577-583. 11. Young AE, Gaunt JI, Croft DN, Collins RE, Wells CP, Coakley AJ. Location of parathyroid adenomas by thallium-201 and technetium- 99m subtraction scanning. Br Med J. 1983;286:1384-1386. Page 37 of 39

12. Coakley AJ, Kettle AG, Wells CP, O'Doherty MJ, Collins RE. 99Tcm Sestamibi-a new agent for parathyroid imaging. Nucl Med Commun. 1989;10:791-794. 13. Vattimo A, Bertelli P, Cintorino M, et al. Hurthle cell tumor dwelling in hot thyroid nodules: preoperative detection with technetium- 99m-MIBI dual-phase scintigraphy. J NuclMed. 1998;39:822-825. 14. Erbil Y, Barbaros U, Tukenmez M, et al. Impact of adenoma weight and ectopic location of parathyroid adenoma on localization study results. World J Surg. 2008;32:566-571. 15. Moralidis E. Radionuclide parathyroid imaging: a concise, updated review. Hell J Nucl Med. 2013 May-Aug;16(2):125-33. 16. Akram K, Parker JA, Donohoe K, Kolodny G. Role of single photon emission computed tomography/computed tomography in localization of ectopic parathyroid adenoma: a pictorial case series and review of the current literature. Clin Nucl Med. 2009;34:500-502. 17. Phitayakorn R, McHenry CR. Incidence and location of ectopic abnormal parathyroid glands. Am J Surg 2006. 191:418-423 18. Roy M, Mazeh H, Chen H, Sippel RS. Incidence and Localization of Ectopic Parathyroid Adenomas in Previously Unexplored Patients. World J Surg (2013) 37:102-106. 19. Chiu B, Sturgeon C, Angelos P. What is the link between nonlocalizing sestamibi scans, multigland disease, and persistent hypercalcemia? A study of 401 consecutive patients undergoing parathyroidectomy. Surgery 2006;140(3):418-422. 20. Lavely WC, Goetze S, Friedman KP, et al. Comparison of SPECT/CT, SPECT, and planar imaging with single- and dual-phase (99m)Tc-sestamibi parathyroid scintigraphy. J Nucl Med. 2007;48: 1084-1089. 21. Gayed IW, Kim EE, Broussard WF, Evans D, Lee J, Broemeling LD, Ochoa BB, Moxley DM, Erwin WD, Podoloff DA. The value of 99mTc-sestamibi SPECT/CT over conventional SPECT in the evaluation of parathyroidadenomas or hyperplasia. J Nucl Med. 2005 Feb;46(2):248-52. Page 38 of 39

22. Kunstman JW, Kirsch JD, Mahajan A, Udelsman R. Clinical review: Parathyroid localization and implications for clinical managemet. J Clin Endocrinol Metab. 2013 Mar;98(3):902-12. 23. Mahajan A, Starker LF, Ghita M, Udelsman R, Brink JA, Carling T. Parathyroid four-dimensional computed tomography: evaluation of radiation dose exposure during preoperative localization of parathyroid tumors in primary hyperparathyroidism. World J Surg. 2012;36:1335-1339. Page 39 of 39