localization Studies in Patients with Hyperparathyroidism

0039-6109/95 $0.00 + .20

ENDOCRINE SURGERY

LOCALIZATION STUDIES IN PATIENTS WITH HYPERPARATHYROIDISM Bradford K. Mitchell, MD, Ronald C. Merrell, MD, and Barbara K. Kinder, MD

The surgical management of hyperparathyroidism is successful in 93% to 98% of cases in experienced hands. 3• 46 Failure of surgical treatment is due either to inability to identify and remove an adenoma or to failure to recognize and treat multiple gland disease. 49 Several authors have recently suggested that the use of newer localization techniques might improve surgical outcome in patients with hyperparathyroidism. 6 , 45, 50 This article summarizes the rationale for and the use of imaging studies in patients with hyperparathyroidism. A review of localization studies in the management of patients with hyperparathyroidism must consider sensitivity and specificity of the different techniques, their costs and limitations, and the impact of successful imaging on surgical treatment outcome. This review assesses the contribution of the five most commonly used noninvasive parathyroid localization studies-ultrasonography, computed tomography scanning (CT), magnetic resonance imaging (MR), and radionuclide imaging with technetium thallium subtraction (TTS) and technetium sestamibi (MIBI), in patients newly diagnosed with hyperparathyroidism and in those who have undergone previous neck exploration. Other intraoperative and invasive modalities such as fine-needle aspiration of putative parathyroid tumors, angiography, and selective venous sampling are also discussed.

From the Department of Surgery, West Haven Veterans Affairs Medical Center, West Haven (BKM, BKK); and the Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

SURGICAL CLINICS OF NORTH AMERICA VOLUME 75 • NUMBER 3 • JUNE 1995

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ASSESSMENT OF NONINVASIVE TECHNIQUES Ultrasonography

Parathyroid localization by ultrasonography is a useful noninvasive test that is relatively inexpensive. There is, however, a wide discrepancy in the reported sensitivities (36% to 76%) for previously operated patients33 ,34 (Table 1). This is in part related to the location of the glands. Inferior and juxtathyroidal or intrathyroidal glands are better visualized than superior or deep cervical glands. 20, 27 Substernal, retrotracheal, and retroesophageal glands are difficult to visualize owing to overlying bone or air, which create acoustic shadows. The experience of the sonographer, the use of a small parts transducer, and 10 MHz frequency improve the quality of localization. 10, 23, 29, 30 Attention to positioning of the patient with the neck extended during the sonography may optimize visualization of the inferior glands. 53 Nuclear Medicine

Nuclear medicine imaging offers a variety of scans to localize parathyroid neoplasms. As Doppman noted,51 despite initially encouraging results after introduction of a new radionuclide, larger series have failed to demonstrate significant improvements over previous imaging methods. A wide range from 26% to 75% accurate localization of glands has been reported in the preoperative setting. 33 Scintigraphy has been hindered by the requirement for subtraction techniques to delete the thyroid image from an image of both parathyroid and thyroid, twodimensional representation, and poor quality images due to the physical characteristics of the agents used. 36 Many of these problems appear Table 1. CHARACTERISTICS OF NONINVASIVE PARATHYROID IMAGING MODALITIES WITH PREVIOUS SURGERY

Scintigraphy Sensitivity

26-68% 86% sestamibi 77-100% $300-1000

Ultrasonography

Computed Tomography

Magnetic Resonance Imaging

Angiography

Venous Sampling

36-76%

46-55%

50-78%

60-85%

69-80%

Specificity Costs (approx) Well Juxtathyroid visualized Mediastinum Poorly visualized deep neck

56-100% $300

43-98% $1000

70-100% $1200

95-100%

100%

Upper neck

Mediastinum

Mediastinum

Mediastinum TE groove

Technical points

10 MHz small parts very helpful

Thyroid metal clips Iodine contrast reaction

STIR T1 SE Limited Gadolinium availability contrast

SPECT very helpful

Needs angiogram first

Adapted from Miller DL: Pre-operative localization and interventional treatment of parathyroid tumors: When and how? World J Surgery 15:706, 1991, © 1991 by Societe Internationale de Chirurgie; with permission.

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to have been overcome by the introduction of technetium sestamibi scanning. Sestamibi is a cationic, lipophilic, isonitrile derivative of technetium developed as an alternative cardiac imaging agent and incidentally noted by Coakley et aP4 to exhibit uptake and retention in abnormal parathyroid glands. Since that original report, many others have described experience with sestamibi in both initial and reoperative cases of hyperparathyroidism. 6• 36. 45. 47. 50-52 The actual mechanism of uptake by parathyroid tissue remains unclear. However, mitochondria have been implicated in sestamibi uptake in cardiac tissue 9 and may contribute to parathyroid imaging. 36 In addition P-glycoprotein, a membrane transport protein encoded for by the multidrug resistance gene (MDR), transports many chemotherapeutic agents and natural products with structural homology to technetium sestamibi, and it may be responsible for sestamibi uptake in some tissues, including parathyroid. 38 Because of the more favorable physical characteristics of sestamibi, it is possible to obtain planar imaging without the requirement for subtraction techniques and, more important, its use permits three-dimensional SPECT imaging. As a result, much clearer images are obtained, and even deep cervical and mediastinal glands are more readily visualized anatomically (Fig. 1). Thus, this technique combines the functional identification of parathyroid tissue provided by radionuclide uptake with the anatomic detail available from the three-dimensional modalities of CT, ultrasonography, and MR imaging. Although larger series will be necessary prior to drawing any firm conclusions regarding overall sensitivity and specificity of sestamibi, it is encouraging that in the initial experience of Weber et al,50 12 of 14 patients undergoing reoperation had successful localization by sestamibi scans. False-positive sestamibi scans can occur in patients with thyroid nodules,5.7 although these can usually be detected with comparison to ultrasonography or the iodine images obtained in the technetium sestamibi subtraction technique. False-negative scans tend to occur in patients with small adenomas and with hyperplasia. 50 Technical details that may influence the quality of imaging include the dose of sestamibi given, the timing of acquisition of the image, the use of subtraction techniques, and the type of collimator and image acquisition device. Doses of technetium sestamibi as low as 2 to 4 mCi with immediate imaging and iodine or technetium pertechnetate thyroid subtraction techniques47.50-52 and as large as 25 mCi and delayed imaging at 2 to 4 hours 45 after clearance of the radionuclide from the thyroid gland have been reported. Satisfactory results have been described with all of these methods. Difficulty in visualizing small adenomas and hyperplasia or normal glands raises the question of whether visualized uptake and retention of radionuclide are functions of size alone or are due to an alteration in the biology of the neoplastic tissues. This latter rationale is more appealing in that it explains the occasionally noted large adenoma 47 that is not visualized or the small ectopic implant that is seen (Fig. 2).

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Figure 1. A, Technetium sestamibi scan of MEN (multiple endocrine neoplasia) 1 patient with recurrent hyperparathyroidism following right thyroid lobectomy and resection of right upper and lower parathyroid glands. Scan shows third gland (arrow) adjacent to the right carotid artery. B, Delayed technetium image shows retention only in parathyroid (arrow) adjacent to sternal notch marker (arrowhead). Illustration continued on opposite page

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Figure 1 (Continued). C, Ultrasonography confirms position of gland (arrow) localized on sestamibi imaging between the right carotid artery (C) and jugular (J).

Computed Tomography

Following unsuccessful surgery, localization by CT scanning has been reported to be able to detect adenomas in 46% to 76% of patients. 33,46 Metallic clips from previous surgery may cause artifact in the region of interest, and intrathyroidal glands can be difficult to detect because the CT appearance is similar to that of the adjacent thyroid. Differentiation from lymph nodes can also be problematic. Ectopic and particularly mediastinal glands are well localized by CT.20,46 Magnetic Resonance Imaging

The most costly noninvasive imaging modality, MR imaging, is similar to CT in its ability to detect abnormal parathyroid tissue in previously operated patients. Miller33 noted a range of sensitivity for MR imaging of 50% to 78%. Because the signal intensity of parathyroid adenomas is similar to that of thyroid gland and fat, MR imaging is best suited for locating ectopic glands. To overcome the similarity of the signal to fat, short tau inversion recovery or STIR sequence MR imaging has been used to locate parathyroid adenomas. 54 Although this technique compromises image detail, it provides high-contrast imaging between

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Figure 2. A, Technetium sestamibi planar imaging of patient who underwent multiple operations for recurrent parathyroid carcinoma (arrow). fIIustration continued on opposite page

fat and parathyroid tissue by suppressing the image generated by the fat. Comparison of the STIR sequence images with concomitant T1 images, which have better image detail, provides improved anatomic localization. Surface coil MR imaging has been reported to give comparable results. 26 With increasing experience and improved technology, the accuracy of parathyroid localization by MR imaging may improve. In some centers it is the most accurate noninvasive localization study, especially when gadolinium is used. Fine-Needle Aspiration

Fine-needle aspiration (FNA) is a minimally invasive method that can confirm the parathyroid lesions identified by imaging studies. Cytology, assay for parathyroid hormone (PTH), and immunohistochemical staining for PTH have all been used. 12, 19,22,44 Material for PTH assay does require additional preparation but is less expensive than cytology and is extremely sensitive and specific. 19 Cytologic examination depends upon the experience of the pathologist. In our experience, this procedure is accurate and well tolerated by patients (Fig. 3) .

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Figure 2 (Continued). Band C, SPECT images with three-dimensional reconstruction clearly show anterior location (arrow) of tumor. Localization study and intraoperative use of hand-held gamma detector help locate and resect parathyroid carcinoma embedded in the scar overlying the previous median sternotomy.

EVALUATION OF INVASIVE TECHNIQUES Angiography and Venous Sampling

Angiography can localize parathyroid tumors in 60% of cases33 and allows the option of angioablation techniques, which may be particularly useful in treating mediastinal ectopic glands. 18 The specificity is also excellent, with less than 5% false-positive tests. Venous sampling offers comparable regional localization results but is most accurate when an angiographic road map of the venous drainage is obtained first/I, 33 requiring the patient to be subjected to the risk of both procedures.

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Figure 3. A, Technetium sestamibi delayed image in elderly man with persistent hyperparathyroidism of 17 years' duration, following left thyroid lobectomy and unilateral exploration with removal of left superior adenoma and left inferior normal parathyroid glands. B, Large right inferior adenoma (arrow) not seen on ultrasound scan 5 months previously was readily localized to the tracheoesophageal groove, guided by the sestamibi images. Fine-needle aspiration cytology (TIP) to confirm parathyroid tissue was followed by curative resection. Right carotid artery (C) and jugular (J) lateral to the adenoma .

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Both of these tests are best performed by radiologists with substantial experience in localizing tumors. To paraphrase Doppman on the subject of the ideal localization technique, the best parathyroid angiographic localization is the localization of the best parathyroid angiographer.

Intraoperative Localization

Intraoperative ultrasonography is an adjunct to preoperative localization studies and may limit the extent of dissection in a previously operated field. It can identify intra thyroidal glands 25 but has limited utility in the mediastinum, where the sternum blocks the sound waves. Accuracy is also limited by the experience of the ultrasonographer or surgeon. Availability of a specific lO-MHz probe is critical to the success of intraoperative imaging of small lesions. We have used a hand-held gamma detector intraoperatively to identify implants of parathyroid carcinoma in a patient given sestamibi preoperatively (Fig. 2). This was helpful in locating the tumor in the midst of scar from a previous median sternotomy. Confirmation of the radionuclide in resected tissue limited the need for further dissection; in this case a repeat sternotomy was avoided. Intraoperative gamma detectors may allow the localization of a small volume of benign or neoplastic cells that have been labeled with a radionuclide, below the level of detection with conventional radiologic methods. 2, 17, 28, 48 The most important intraoperative localization modality remains careful surgical dissection based on knowledge of the embryologic derivation of the parathyroid glands (Fig. 4). Knowledge of the embryologic origin is essential in order to understand the ectopic or normal variants in the location of parathyroid glands at the time of the initial exploration for hyperparathyroidism. Failure to locate these glands has been noted as a source of surgical failure by many and can make subsequent dissection more complicated, increasing the risk of failure or morbidity. A number of methods have been developed to confirm the identity of parathyroid tissue and to assess the adequacy of resection. Frozen section pathology is valuable in differentiating parathyroid tissue from other tissue, a critical aid to the surgeon, but is less reliable than the surgeon in differentiating adenoma from hyperplasia41 (i.e., single versus multiple gland disease) and thus cannot predict when a resection is complete. Assessment of cellular or tissue fat content by special stains and tissue density has been described but remains of limited utility. Nephrogenous cyclic AMP, an accurate indicator of the biologically active PTH whose half-life is 2 to 4 minutes, can be measured intraoperatively; a decline is noted within minutes following removal of hyperfunctioning parathyroid tissue. 16 This permits intraoperative assessment of the adequacy of resection but is infrequently used because it is timeconsuming and expensive. More recently, "quick" PTH immunoradiometric 35 and immunochemiluminometric15,24 assays have been described which recognize the intact PTH molecule. These may allow accurate

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Figure 4. A, Path of descent (arrows) of upper parathyroid IV and lower parathyroid III showing common ectopic locations. Illustration continued on opposite page

determination of removal of the hyperactive tissue and may even predict which patients will be normal or transiently or permanently hypoparathyroid in the postoperative period. 24 The role of such sophisticated biochemical evaluation in the routine intraoperative management of hyperparathyroidism is unclear at this time. What Are the Indications for Parathyroid Localization? Improvement in outcome or long-term cure rates, decrease in morbidity, and reduction in cost and duration of operation have all been proposed to result from accurate preoperative parathyroid localization.4, 6, 32 However, in experienced hands, parathyroidectomy in patients who have not had prior neck surgery is a relatively short operation with cure rates of 93% to 98%.3,46 Morbidity, other than persistent or recurrent disease, is rare at the time of initial operation for hyperparathyroidism, even when no localization studies have been used. On the other hand, patients who have had previous operations for thyroid or parathyroid disease have lower cure rates, higher morbidity, and usually longer operations. s, 11 Preoperative localization studies in these patients can minimize the risks of reoperative surgery and increase the chance of a successful outcome. 8 ,20

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Figure 4 (Continued). B, Sites of ectopic location of 104 glands found at reoperation. (B from Wang CA: Parathyroid re-operation. Ann Surg 167:147, 1977; with permission.)

Does Preoperative Localization Alter the Success Rate or Length of an Initial Cervical Exploration? Many studies have addressed the routine use of preoperative localization in improving the success rate of surgery for hyperparathyroidism. 6 ,55 Unfortunately, most of the reports include too few patients to demonstrate with any statistical accuracy20 any improvement over the success rate for the experienced surgeon of 93% to 98%. Documenting improvement in outcome for inexperienced surgeons would be even more problematic because data would have to be collected from multiple institutions to obtain meaningful numbers and it is unlikely that the uniformity of the localization studies could be assured. Although Casas et al6 have suggested that preoperative localization improves the success rate of the initial operation and decreases the duration of the initial exploration for hyperparathyroidism, the study was a retrospective analysis using a historical control group as the group without preoperative localization. This certainly raises the possibility that experience alone decreases the length and increases the success of exploration. Other collective series 20. 33. 40 have not shown any benefit to preoperative localization in improving outcome or length of

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operation. 4D, 43, 51 Finally, studies that have shown a time savings in the operating room have not, however, provided an overall cost benefit when the expense of routine screening is considered. 20 Because the most frequent causes of unsuccessful treatment of hyperparathyroidism are failure to find ectopic glands or to recognize and adequately treat multiple gland disease,! localization studies are not likely to significantly change the outcome of initial parathyroid exploration. First, ectopic glands in different locations are detected best by different modalities (Table 1). Because the noninvasive imaging modalities visualize abnormal parathyroid tissue based upon different physical and physiologic characteristics (echogenicity, absorbance, uptake of radionuclide), they identify glands in different anatomic areas with variable success, based upon location, depth, and overlying and surrounding structures. Prospective selection of the appropriate test to take advantage of these properties is not possible, and the routine application of multiple modalities is expensive. Additionally, all procedures are limited in their ability to identify small or hyperplastic glands. 3D Thus, patients with multiple gland disease or small adenomas are less likely to have successful localization studies. Preoperative localization of a single abnormal gland in patients with multiple gland disease may mislead the surgeon regarding the appropriate extent of surgery.46 Because the most accurate differentiation between normal parathyroid, adenoma, hyperplasia, and carcinoma is the gross anatomic assessment by the surgeon, inspection of all the glands is indicated at the time of the initial surgery.6, 13, 51 It is difficult to save a significant amount of time in the operating room by localizing some parathyroid glands preoperatively. In summary, the patients most likely to fail operation without preoperative localization (namely those with ectopic or multiple gland disease) are also those most likely to have inaccurate localization studies. Because they represent a small percentage (2% to 7%) of all hyperparathyroid patients, it seems unjustified at this time to recommend routine preoperative imaging.

Preoperative Localization for Unilateral Exploration

Some have advocated unilateral exploration if an enlarged and a normal-sized gland are identified on the side initially explored. The putative advantages of this approach include the ability to limit dissection (and potentially injury to contralateral structures) and decreased operative time. On the other hand, there is risk of failure due to unrecognized asymmetric hyperplasia and to the presence of double adenomas. 37,39 Duh et al have estimated the risk using unilateral exploration of missing additional abnormal parathyroid tissue on the contralateral side at between 3.6% and 7.9%. The risk is increased in elderly, especially female, patients, who have a greater incidence of double adenomas. Their calculations suggested that, using preoperative imaging methods with 80% sensitivity and a unilateral approach, the risk of

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mIssmg multiple gland disease would be decreased to 2%. This risk must be compared with the risk of hypoparathyroidism or nerve injury from contralateral exploration, which should be less than 2%. Therefore, bilateral exploration without preoperative imaging is safe and effective. Localization in Reoperative Cases

Since the first descriptions of parathyroidectomy, epitomized by the case of Captain Martell and his subsequent persistent hyperparathyroidism associated with significant morbidity and his ultimate demise, it has been clear that failure of the surgeon to locate the abnormal parathyroid tissue is a grave complication. Following surgical failure, the diagnosis of hyperparathyroidism must be confirmed and the severity of the condition assessed because, even when successful, reoperation is associated with some increased morbidity.3, 12, 42 Previous operative and pathology reports are reviewed to assess the adequacy or extent of the previous operation and to gain insight regarding the most likely sites of failure (Fig. 4). This helps in planning subsequent localization studies and the surgical approach. In reoperative patients the use of localization studies has improved the ability to identify the site of the remaining abnormal parathyroid tissue. 21 , 30, 34, 53 Confidence in the imaging data increases when more than one study localizes the same gland. 21 , 30, 34 It is appropriate to begin with the less invasive procedures such as ultrasonography, CT, and/or MR imaging, and nuclear medicine scintigraphy. Because false-positive studies are not infrequent (0 to 57%)? ultrasonography- or CT-guided FNA for PTH assay or cytology can be used to confirm that a suspicious lesion is in fact parathyroid tissue. If these studies do not provide two results indicating the same site, then invasive tests such as angiography or selective venous sampling for PTH are recommended. Successful localization and a directed operation by a skilled surgeon can result in a successful outcome with removal of parathyroid tissue in most cases (about 90%).3,20,31 Recently we have developed a variation of the preceding algorithm for localization in reoperative cases. Technetium sestamibi planar and SPECT imaging are followed by ultrasound-guided FNA confirmation of parathyroid tissue (see Fig. 3). This combination of a functional (sestamibi) and a three-dimensional anatomic study (SPECT) with a specific cytologic diagnosis has resulted in successful localization of parathyroid tissue in our last five reoperative cases. Importantly, these studies are less expensive than the other noninvasive studies and expose the patient to minimal risks (minimal radiation and no iodinated contrast). If this approach fails to localize the abnormal parathyroid tissue, the other modalities reviewed above are utilized. SUMMARY

Patients with hyperparathyroidism who have not had previous neck surgery do not require preoperative localization because of the high

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success rate of cervical exploration (95%) and the limited sensitivity and specificity of all imaging modalities currently in use. Successful parathyroid exploration requires knowledge of the normal and frequently encountered variations in parathyroid anatomy (Fig. 4). Experience permits recognition of often subtle multiple gland disease. In skilled surgical hands, results are excellent with minimal morbidity. When recurrent or persistent disease or previously operated patients are encountered, confirmation of the diagnosis and attempts at localization should precede operation. Technetium sestamibi SPECT imaging and ultrasonography with FNA of suspicious glands are complementary tests that are readily available, inexpensive, and well tolerated by patients. If these tests are unsuccessful, MRI, CT, and invasive procedures should be pursued until the gland is localized. ACKNOWLEDGMENTS We are indebted to Eugene Cornelius, MD, Cheryl Granucci, and Bob Varsanick for their assistance in preparing the nuclear medicine figures in this article.

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15. Curley IR, Wheeler MH, Aston JP, et al: Studies in patients with hyperparathyroidism using a new two-site immunochemiluminometric assay for circulating intact (1-84) parathyroid hormone. Surgery 102:926, 1987 16. Darling GE, Marx SI, Spiegel AM, et al: Prospective analysis for intraoperative and postoperative urinary cyclic adenosine 3',5'-monophosphate levels to predict outcome of patient undergoing reoperation for primary hyperparathyroidism. Surgery 104:1128, 1988 17. Doerr RI, Abdel-Nabi H, Krag DN, et al: Radiolabeled antibody imaging in the management of colorectal cancer. Results of a multicenter clinical study. Ann Surg 214:118, 1991 18. Doherty GM, Doppman JL, Miller DL, et al: Results of a multidisciplinary strategy for management of mediastinal parathyroid adenoma as a cause of persistent primary hyperparathyroidism. Ann Surg 215:101, 1992 19. Doppman JL, Krudy AG, Marx SI, et al: Aspiration of enlarged parathyroid glands for parathyroid hormone assay. Radiology 148:31, 1983 20. Doppman JL, Miller DL: Localization of parathyroid tumors in patients with asymptomatic hyperparathyroidism and no previous surgery. J Bone Miner Res 6 (Suppl 2):S153, 1991 21. Erdman WA, Breslau NA, Weinreb Jc, et al: Noninvasive localization of parathyroid adenomas: A comparison of x-ray computerized tomography, ultrasound, scintigraphy and MRI. Magn Res Imaging 7:187, 1989 22. Gooding GAW, Clark OH, Stark DD, et al: Parathyroid aspiration biopsy under ultrasound guidance in the postoperative hyperparathyroid patient. Radiology 155:193, 1985 23. Hasselgren P, Fidler JP: Further evidence against the routine use of parathyroid ultrasonography prior to initial neck exploration for hyperparathyroidism. Am J Surg 164:337, 1992 24. Kao Pc, Van Heerden JA, Taylor RL: Intraoperative monitoring of parathyroid procedures by a 15 minute parathyroid hormone immunochemiluminometric assay. Mayo Clin Proc 69:532, 1994 25. Kern KA, Shawker TH, Doppman JL, et al: The use of high resolution ultrasound to locate parathyroid tumors during reoperations for primary hyperparathyroidism. World J Surg 11:579, 1987 26. Kneeland JB, Krusback AI, Lawson TL, et al: Enlarged parathyroid glands: High resolution local coil MR imaging. Radiology 162:143, 1987 27. Kohri K, Ishikawa Y, Kodama S, et al: Comparison of imaging methods for localization of parathyroid tumors. Am J Surg 164:140, 1992 28. Krag DN, Weaver DL, Alex Jc, et al: Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 2:335, 1993 29. Krudy AG, Shawker TH, Doppman JL, et al: Ultrasonic parathyroid localization in previously operated patients. Clin Radiol 35:113, 1984 30. Krusback AI, Wilson SD, Lawson TL, et al: Prospective comparison of radionuclide, computed tomographic, sonographic, and magnetic resonance localization of parathyroid tumors. Surgery 106:639, 1989 31. Levin KE, Gooding GAW, Okerlund MD, et al: Localizing studies in patients with persistent or recurrent hyperparathyroidism. Surgery 102:917, 1987 32. Maltby C, Russel CFI, Laird JD, et al: Thallium technetium isotope subtraction scanning in primary hyperparathyroidism. J R Coli Surg Edinb 34:40, 1989 33. Miller DL: Preoperative localization and interventional treatment of parathyroid tumors: When and how? World J Surg 15:706, 1991 34. Miller DL, Doppman JL, Shawker TH, et al: Localization of parathyroid adenomas in patients who have undergone surgery. Part I. Noninvasive imaging methods. Radiology 162:133, 1987 35. Nussbaum SR, Thompson AR, Hutcheson KA, et al: Intraoperative measurement of parathyroid hormone in the surgical management of hyperparathyroidism. Surgery 104:1121, 1988 36. O'Doherty MI, Kettle AG, Wells CP, et al: Parathyroid imaging with technetium99m-sestamibi: Preoperative localization and tissue uptake studies. J Nucl Med 33:313, 1992

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37. Palmer M, Adami H, Bergstrom R, et al: Mortality after surgery for primary hyperparathyroidism: A follow-up of 441 patients operated on from 1956 to 1979. Surgery 102:1, 1987 38. Piwnica-Worms 0, Chiu ML, Budding M, et al: Functional imaging of multidrugresistant P-glycoprotein with an organotechnetium complex. Cancer Res 53:977, 1993 39. Proye CAG, Carnaille B, Bizard JP, et al: Multiglandular disease in seemingly sporadic primary hyperparathyroidism revisited: Where are we in the early 1990s7 A plea against unilateral parathyroid exploration. Surgery 112:1118, 1992 40. Roe SM, Burns RP, Graham LD, et al: Cost effectiveness of preoperative localization studies in primary hyperparathyroid disease. Ann Surg 219:582, 1994 41. Saxe AW, Baier R, Tesluk H, et al: The role of the pathologist in the surgical treatment of hyperparathyroidism. Surg Gynecol Obstet 161:101, 1985 42. Saxe AW, Brennan MF: Strategy and technique of reoperative parathyroid surgery. Surgery 89:417, 1981 43. Serpell JW, Campbell PR, Young AE: Preoperative localization of parathyroid tumours does not reduce operating time. Br J Surg 78:589, 1991 44. Solbiati L, Montali G, Croce F, et al: Parathyroid tumors detected by fine needle aspiration biopsy under ultrasonic guidance. Radiology 148:793, 1983 45. Taillefer R, Boucher Y, Potvin C, et al: Detection and localization of parathyroid adenomas in patients with hyperparathyroidism using a single radionuclide imaging procedure with technetium-99m-sestamibi (double phase study). J Nucl Med 10:1801, 1992 46. Thompson NW: Localization studies in patients with primary hyperparathyroidism. Br J Surg 75:97, 1988 47. Thule P, Thakore K, Vansant J, et al: Preoperative localization of parathyroid tissue with technetium-99m sestamibi 1-123 subtraction scanning. J Clin Endocrinol Metab 78:77, 1993 48. Wallace 0, Fromm 0, Thomas 0: Accessory splenectomy for idiopathic thrombocytopenic purpura. Surgery 91:134, 1982 49. Wang CA: Parathyroid re-exploration. Ann Surg 186:140, 1977 50. Weber CJ, Vansant J, Alazraki N, et al: Value of technetium-99m-sestamibi iodine-123 imaging in reoperative parathyroid surgery. Surgery 114:1011, 1993 51. Wei JP, Burke GJ, Mansberger AR Jr: Prospective evaluation of the efficacy of technetium-99m-sestamibi and iodine-123 radionuclide imaging of abnormal parathyroid glands. Surgery 112:1111, 1992 52. Wei JP, Burke GJ, Mansberger AR Jr: Preoperative imaging of abnormal parathyroid glands in patients with hyperparathyoid disease using combination Tc-99m pertechnetate and Tc-99m-sestamibi radionuclide scans. Ann Surg 219:568, 1994 53. Winzelberg GG: Imaging techniques for identifying parathyroid tumors. Trends Endocrinol Metabol 10:335, 1990 54. Wright AR, Goddard PR, Nicholson S, et al: Fat suppression magnetic resonance imaging in the preoperative localization of parathyroid adenomas. Clin Radiol 46:324, 1992 55. Young AE, Guant JI, Croft ON, et al: Location of parathyroid adenomas by thallium201 technetium-99m subtraction scanning. Br Med J 286:1384, 1983

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