Parathyroid Imaging: Technique and Role in the Preoperative Evaluation of Primary Hyperparathyroidism

Transcription

1 Johnson et al. Parathyroid Imaging and Hyperparathyroidism Head and Neck Imaging Review Nathan A. Johnson 1 Mitchell E. Tublin 1 Jennifer B. Ogilvie 2 Johnson NA, Tublin ME, Ogilvie JB Keywords: head and neck imaging, hyperparathyroidism, nuclear medicine, sonography, thyroid gland DOI: /AJR Received July 19, 2006; accepted after revision November 8, Department of Radiology, University of Pittsburgh Medical Center and School of Medicine, 200 Lothrop St., 3950 CHP/MT, Pittsburgh, PA Address correspondence to M. E. Tublin. 2 Department of Surgery, University of Pittsburgh Medical Center and School of Medicine, Pittsburgh, PA CME This article is available for CME credit. See for more information. AJR 2007; 188: X/07/ American Roentgen Ray Society Parathyroid Imaging: Technique and Role in the Preoperative Evaluation of Primary Hyperparathyroidism OBJECTIVE. This article discusses the commonly used techniques for imaging the parathyroid glands and their role in the preoperative evaluation of patients with primary hyperparathyroidism. CONCLUSION. The importance of sonography and sestamibi scintigraphy in the preoperative evaluation of patients with primary hyperthyroidism has increased with the adoption of minimally invasive parathyroidectomy techniques at most medical centers. When the results of these studies are concordant, the cure rates of minimally invasive surgery equal those of traditional bilateral neck exploration. rimary hyperparathyroidism, whether P caused by an adenoma or hyperplasia, can be cured surgically with a high rate of success. When performed by experienced surgeons, traditional surgical therapy bilateral four-gland exploration is successful in more than 95% of cases [1]. The development of unilateral and focused surgical approaches over the past decade, however, has made it even more imperative for imaging to accurately locate abnormal parathyroid glands before surgery. With optimized preoperative mapping, the success rate of these less invasive techniques equals that of the traditional bilateral approach [2 7]. The purpose of this article is to review the imaging techniques and rationale for the preoperative localization studies that are frequently used before parathyroidectomy. After a brief review of relevant anatomy and the physiology of primary hyperparathyroidism, we present current surgical approaches. The commonly used noninvasive imaging techniques sonography, scintigraphy, CT, and MRI will be discussed. Sonography and 99m Tc-sestamibi scintigraphy will be emphasized because these have clearly emerged as dominant, and potentially complementary, techniques in the preoperative evaluation of primary hyperparathyroidism. Embryology and Anatomy Autopsy series show two superior and two inferior parathyroid glands in most individuals (Fig. 1). Supernumerary glands are seen Fig. 1 Diagram shows posterior view of typical locations of paired superior (white arrows) and inferior (arrowheads) parathyroid glands and their relationship to thyroid gland and surrounding structures. Note close relationship parathyroid glands have with recurrent laryngeal nerves (black arrows), illustrating why nerve injury is a significant concern of endocrine surgeons, particularly with four-gland explorations. approximately 3 5% of the time, and fewer than four glands are found in up to 3% of patients [8, 9]. The superior glands are derived from the fourth branchial pouch along with 1706 AJR:188, June 2007

2 Parathyroid Imaging and Hyperparathyroidism Fig. 2 Sonogram of 25-year-old woman with possible thyroid enlargement (thyroid was normal). Note subtle isoechoic parathyroid gland inferior to lower pole of thyroid (arrows). Normal parathyroid glands are uncommonly seen on sonography because of their small size. the lateral lobes of the thyroid; the inferior glands arise from the third branchial pouch along with the thymus gland. These embryologic relationships help to explain the normal and variable anatomic locations of the superior and inferior parathyroid glands. The superior glands tend to be more consistent in location with most (> 90%) glands located deep in relation to the mid portion of the superior pole of the thyroid near the cricothyroid junction. Infrequently, the superior glands can be seen more inferiorly, deep in relation to the mid pole of the thyroid lobes (4%), or they may be located at or above the most superior aspect of the thyroid (3%). Rarely, the superior glands can be found in the retropharyngeal (1%) or retroesophageal (1%) spaces or in the thyroid gland itself (0.2%) [8, 9]. The inferior parathyroid glands are more variable in location but most commonly are located inferior, posterior, or lateral to the lower thyroid pole (69%). Because of their common origin with the thymus gland, they can also commonly be found more inferiorly in the neck, in the thymic tongue, or in the cervical portion of the thymus (26%). Very rarely, the inferior parathyroid glands can fail to descend with the thymus and may remain cephalad to the superior glands. Inferior glands can also be found in the anterior mediastinum with the thymus (2%) or even inferior to the thymus gland in the mediastinum (0.2%) [8, 9]. The average size of a normal parathyroid is mm; normal glands weigh between 40 and 50 mg. They are thus infrequently identified at imaging [10] (Fig. 2). Adenomas, on the other hand, are considerably larger; they have a mean mass of greater than 10 times the normal parathyroid gland and are thus often identified at cross-sectional imaging [11]. Hyperplastic glands can be quite variable in size, both within the same patient and among populations, but they tend to have a total gland volume comparable to that of adenomas [12]. Pathophysiology of Primary Hyperparathyroidism The parathyroid glands are responsible for calcium homeostasis via the production of parathyroid hormone (PTH). PTH raises the serum calcium level by promoting the renal tubular absorption of calcium, decreasing tubular reabsorption of phosphate, and stimulating osteoclasts. In addition, PTH stimulates vitamin D production, which, in turn, raises serum calcium by promoting its absorption by the gastrointestinal tract. Primary hyperparathyroidism is considered to be present when serum calcium is elevated and PTH is increased or inappropriately normal. The condition is most commonly diagnosed in the fifth through seventh decades of life and is a common endocrine disorder affecting approximately one in 500 women and one in 2,000 men. There are numerous, often nonspecific, clinical manifestations of hypercalcemia. The most common presenting symptoms include fatigue, hypertension, bone pain, muscle weakness, and psychiatric illness [13]. Most cases of primary hyperparathyroidism are caused by a single parathyroid adenoma (89%). Other causes include hyperplasia of all four glands (6%), double adenomas (4%), and, rarely, parathyroid carcinoma [2]. In most instances, parathyroid adenomas are sporadic. There is an increased incidence of parathyroid hyperplasia in multiple endocrine neoplasia, type I and multiple endocrine neoplasia, type IIA, although the incidence of these disorders is not sufficiently high to justify screening in all instances of primary hyperparathyroidism [14]. Another rare cause of primary hyperparathyroidism is familial hypocalciuric hypercalcemia, an autosomal dominant condition that produces PTH-dependent hypercalcemia. It is associated with mild parathyroid hyperplasia, but subtotal parathyroidectomy is not an effective treatment and is contraindicated in these cases. Current Surgical Approach Preoperative imaging is less critical for the endocrine surgeon when a traditional bilateral cervical dissection is used for parathyroid exploration. A transverse cervical incision made approximately 2 cm above the sternal notch, just below the cricoid cartilage, permits identification of all four glands and allows access to nearly all ectopic parathyroid sites. In solitary adenoma cases, all four glands are sampled and the adenomatous gland is resected. Treatment success using this approach exceeds 95%. Imaging is used only after failed initial surgery. For multigland disease, the approach involves either a subtotal 3.5-gland resection with cryopreservation or a total parathyroidectomy with autotransplantation into the forearm or neck muscle. Over the past decade, the development of minimally invasive approaches to parathyroid surgery has made accurate preoperative localization of parathyroid disease absolutely critical for effective surgical treatment. Currently practiced minimally invasive techniques include unilateral open parathyroidectomy, video-assisted parathyroidectomy, and videoscopic parathyroidectomy. All of these techniques involve a more focused approach, limiting the dissection to the abnormal parathyroid gland and thus substantially decreasing operative time. The unilateral open technique involves a small unilateral transverse or lateral incision positioned for access to the parathyroid adenoma. The video-assisted technique is performed without insufflation, using a 5-mm endoscope and small conventional instruments through a 1.5-cm midline incision to identify and resect the abnormal gland or glands. Videoscopic techniques use carbon dioxide insufflation to create a working space for dissection and use three small incisions and endoscopic instruments to remove the abnormal gland, usually from a lateral cervical approach. AJR:188, June

3 Johnson et al. A Fig year-old woman with hyperparathyroidism due to right inferior parathyroid adenoma. Resected gland weighed 629 mg, nearly 15 times weight of a normal gland (40 50 mg). A, Sonogram shows typical hypoechoic adenoma (arrows) deep in relation to lower pole of thyroid. B, Color Doppler sonogram shows peripheral feeding vessel (arrow) characteristic of parathyroid adenomas. Also note typical arc or rim vascularity. The extent of minimally invasive parathyroidectomy is often guided by rapid intraoperative PTH testing. A greater than 50% drop in the serum PTH to normal or near-normal levels 10 minutes after parathyroid resection accurately predicts removal of all offending parathyroid tissue. Radioguided parathyroidectomy, which involves preoperative injection of 99m Tc sestamibi, may also aid the endocrine surgeon in gland localization and may improve success rates, although this approach is controversial and is used in very few centers. Accurate preoperative localization of parathyroid adenomas, particularly when combined with intraoperative PTH assays, enables use of these less invasive techniques; numerous studies comparing unilateral with bilateral approaches have shown similar success rates when preoperative imaging is highly suggestive of single-gland disease [7, 15 18]. Cases of suspected multiglandular disease and those with equivocal preoperative localization still require the traditional bilateral cervical approach because imaging studies have been shown to have low sensitivity for the detection of hyperplasia and double adenomas. In addition, the surgical treatment for hyperplasia requires a bilateral approach; moreover, double adenomas are bilateral in most cases. Thus, the primary benefit of preoperative imaging studies is the accurate determination of uniglandular disease to help select patients most appropriate for unilateral and minimally invasive approaches. Imaging is also important in the small percentage of cases of failed initial parathyroidectomy. Failures are most commonly due to undetected multiglandular disease but may also be due to ectopic glands or incomplete resection of a parathyroid tumor. Imaging studies can help to locate the offending tissue in these cases, facilitating a more focused approach and fewer surgical complications. In addition, these patients may benefit from MRI or CT of the mediastinum to search for ectopic parathyroid glands. Parathyroid Imaging Sonography and 99m Tc-sestamibi scintigraphy are the dominant imaging techniques for preoperative location of parathyroid adenomas. Numerous studies comparing these techniques suggest similar sensitivities and specificities for solitary adenoma detection. B Localization accuracy is also improved when both studies are obtained preoperatively [2, 19 22]. Contrast-enhanced CT and MRI can also effectively locate parathyroid adenomas but are less commonly used for preoperative location and are more commonly used in the setting of failed parathyroidectomy for the detection of suspected ectopic often mediastinal glands. Rarely, cross-sectional imaging will be used if the findings at sonography and 99m Tc-sestamibi scintigraphy are discordant. Sonography Technique The patient should be scanned supine with a pillow beneath the shoulders to slightly hyperextend the neck. Gray-scale imaging should be performed with a high-frequency linear transducer; the study should include longitudinal images extending from the carotid artery to midline and transverse images extending from the hyoid bone superiorly to the thoracic inlet inferiorly. Scanning at MHz is possible with currently available higher level platforms. Having the patient swallow under real-time observation may help show inferior glands located deep in relation to the clavicles [23]. The thyroid is also imaged and nodules, particularly those with worrisome sonographic features (e.g., microcalcifications, lobulation), are documented. The size and volume of both lobes are also recorded. Gray-scale imaging is supplemented by color and power Doppler imaging to look for feeding vessels and vascularity of suspected adenomas shown at initial gray-scale imaging. Graded compression of subcutaneous tissues and strap muscles may also be helpful in difficult-to-scan patients. Imaging Findings Parathyroid adenomas are nearly always homogeneously hypoechoic to the overlying thyroid gland on gray-scale imaging and are commonly detected using gray-scale imaging alone when they are larger than 1 cm in diameter (Fig. 3A). Hypoechogenicity may be a result of the marked, compact cellularity that is characteristic of adenomas at sectioning. They are usually oval or bean-shaped, but larger adenomas can be multilobulated. Color and power Doppler imaging commonly show a characteristic extrathyroidal feeding vessel (typically a branch off the inferior thyroidal artery), which enters the parathyroid gland at one of the poles (Fig. 3B). Internal vascularity is also commonly seen in a peripheral distribution. The artery feeding the adenoma 1708 AJR:188, June 2007

4 Parathyroid Imaging and Hyperparathyroidism A Fig year-old woman with primary hyperparathyroidism due to large left superior adenoma. A, Sonogram shows hypoechoic nodule suspected of being parathyroid medial to common carotid artery (arrow). B, Graded compression sonogram increases conspicuity of adenoma (arrows). tends to branch around the periphery of the gland before penetrating deeper, resulting in a characteristic arc or rim of vascularity. In addition, color Doppler sonography of the overlying thyroid gland may show an area of asymmetric hypervascularity that may help to locate an underlying adenoma [24 26]. When gray-scale and Doppler imaging fail to show an abnormal parathyroid gland, graded compression may show a relatively incompressible gland to help differentiate an adenoma from surrounding soft tissue [26] (Fig. 4). This technique is often helpful in detection of ectopic glands in the lower neck. Normal parathyroid glands average mm and are uncommonly seen with sonography; the histology of the normal parathyroid gland chief cells, fibrovascular stroma, and adipocytes may account for the isoechogenicity of the gland relative to adjacent thyroid. Hyperplasia is also a more difficult diagnosis to make sonographically because the single gland size is generally much smaller than an adenoma [12] (Fig. 5). However, as with adenomas, compact cellularity may render hyperplastic glands hypoechoic relative to the overlying thyroid. Cervical lymph nodes can commonly be mistaken for parathyroid glands. Central compartment lymph nodes may be particularly prominent when the patient has coexistent lymphocytic thyroiditis (Figs. 6A and 6B). Several features may help in distinguishing lymph nodes from adenomas, however. An echogenic fatty hilum usually indicates a benign lymph node. At color Doppler examination, lymph nodes are supplied by small hilar vessels, whereas a polar, peripheral distribution of color flow is commonly seen with parathyroid adenomas [25, 27] (Fig. 6C). Concomitant thyroid disease also contributes to imaging pitfalls. Enlarged multinodular thyroid glands can limit the sonographic evaluation of parathyroid adenomas: Anatomy is distorted and posterior nodules may mimic parathyroid disease. Posterior thyroid nodules can have a similar sonographic appearance to intracapsular parathyroid glands, although the typical vascular pattern of a parathyroid adenoma is uncommonly seen in thyroid nodules (Fig. 7). The rare intrathyroid parathyroid gland is difficult, if not impossible, to distinguish from a thyroid nodule. Some ectopic glands can be difficult to detect sonographically, particularly those in the retrotracheal region, because of the poor acoustic window caused by the tracheal air column. Sonography has poor sensitivity for detecting ectopic glands in the mediastinum as well. B Sonographically Guided Percutaneous Biopsy and Ethanol Ablation In cases in which a more definitive preoperative localization is necessary and sonographic findings are equivocal, sonographically guided fine-needle aspiration (FNA) of the suspected gland with subsequent PTH assay has been shown to be a safe and highly specific technique to confirm whether the suspected lesion is parathyroid tissue [28 30]. A study by Stephen et al. [28] of 57 preoperative sonographically guided FNAs in 54 patients found a specificity of 100% and no false-positive findings. The three false-negative FNAs occurred when small glands were sampled. Although PTH aspiration is rarely necessary for routine cases, this procedure can be particularly helpful in cases in which prior thyroid or parathyroid surgery has distorted neck anatomy or when preoperative confirmation of unusual-appearing or ectopic glands is needed. A theoretic complication of the procedure is seeding of abnormal parathyroid tissue along the biopsy track, resulting in an entity known as parathyromatosis. This has been described in cases of recurrent hyperparathyroidism after parathyroidectomy in which the capsule of the parathyroid gland was disrupted during the procedure. However, a study by Kendrick et al. [31] followed 81 patients after percutaneous parathyroid FNA for a mean of 5.8 years and found no cases of parathyromatosis. Although it is primarily used as a therapy to treat tertiary hyperparathyroidism (most often in the setting of renal failure), sonographically guided parathyroid ablation with ethanol is a potential treatment option for patients with primary hyperparathyroidism. The procedure involves placement of the needle in the parathyroid gland and slowly injecting a volume of ethanol equal to approximately 50% of the volume of the gland until the absence of blood flow to the gland is confirmed on color Doppler sonography [32]. Because surgery is more effective at achieving a longterm cure for primary hyperparathyroidism, this procedure is mostly used in the setting of prohibitive risk due to medical comorbidities or a high risk of surgical morbidity in reoperative cases [32, 33]. Effectiveness of Preoperative Localization and Role in Surgical Planning Reported sensitivities for the detection of solitary parathyroid adenomas with preoperative sonography range from 72% to 89% in recent large series [34 37]. A meta-analysis performed by Ruda et al. [2] encompassing 54 studies performed between 1995 and 2003 using sonography for preoperative localization in primary hyperparathyroidism calculated AJR:188, June

5 Johnson et al. A C Fig year-old girl with hyperparathyroidism due to parathyroid hyperplasia. A D, Sonograms show four slightly enlarged parathyroid glands (arrows): right superior (A), right inferior (B), left superior (C), and left inferior (D). Patient subsequently underwent four-gland exploration and subtotal parathyroidectomy, leaving portion of right superior gland. Largest of resected hyperplastic glands weighed only 322 mg. Relatively small size of typical hyperplastic glands decreases sensitivity of sonography. sonographic sensitivities for the detection of solitary adenoma, hyperplasia, and double adenoma to be 79% (95% confidence interval, 77 80%), 35% (95% confidence interval, 30 40%), and 16% (95% confidence interval, 4 28%), respectively. B D Although much of the literature on this topic is retrospective, Siperstein et al. [37] recently published one of the largest prospective studies, involving 350 patients with primary hyperparathyroidism who underwent preoperative sonography. This study was unique in that initially a focused unilateral parathyroidectomy was attempted based on preoperative localization studies, and intraoperative PTH assays were performed irrespective of the success of the initial focused parathyroidectomy. Thereafter, all patients underwent a four-gland exploration to determine where there was any additional parathyroid abnormality that was not suspected on preoperative evaluation. In this manner, the success of a focused parathyroidectomy based on preoperative imaging studies could be estimated, but there was pathologic analysis of all glands in each patient. Given preoperative sonographic findings suggestive of a single adenoma, a unilateral approach would yield a single abnormal gland at the correct site in 74% of patients. If it was assumed that the operation would be converted to a bilateral approach if no adenoma was found on the abnormal side, the surgical success rate was improved to 90%. This is somewhat lower than the cure rate of 95 97% reported in retrospective series of focused techniques. A selection bias may explain the discrepancy: Prior retrospective series of focused techniques have included stratified patient cohorts with diagnostic preoperative mapping, whereas in the study by Siperstein et al., all subjects were ultimately subjected to traditional surgical exploration. Another prospective study by Rickes et al. [34] involving 98 patients with primary hyperparathyroidism suggests that particular sonographic findings namely, a polar feeding vessel significantly increase specificity for detecting parathyroid adenomas. Of those suspected adenomas that showed a feeding vessel using color Doppler sonography, the abnormal gland was correctly identified 93% of the time. For the 40% of suspected adenomas without a visualized feeding vessel, localization was correct only 39% of the time. These findings are similar to those in the retrospective study of Lane et al. [25], which found that a prominent feeding artery increased accuracy of localization from 73% to 88%. Series in which endocrine surgeons performed parathyroid sonography before surgery have reported similar results. Solorzano et al. [36] retrospectively studied 226 patients with primary hyperparathyroidism and found preoperative sonography correctly identified all abnormal glands 77% of the time. The 1710 AJR:188, June 2007

6 Parathyroid Imaging and Hyperparathyroidism A B C Fig year-old woman with Hashimoto s thyroiditis. A and B, Sonograms show how prominent central compartment lymph nodes (arrows) may mimic adenomatous parathyroid glands. C, Color Doppler sonogram may aid in differentiating between lymph nodes and adenomas: Lymph nodes are supplied by a central hilar vessel (arrow), whereas vessels that supply adenomas typically enter either pole. Fig year-old woman with hyperparathyroidism and left tracheoesophageal groove adenoma that could easily be mistaken for posterior thyroid nodule. Peripheral, polar vascularity seen on color Doppler sonogram helps to identify this as adenoma. Subsequent parathyroidectomy preformed at time of total thyroidectomy revealed this to be a supernumerary hyperplastic parathyroid gland. study of Milas et al. [38] involved 350 patients, and sonography correctly identified the site in 72% of patients. These studies suggest the importance of a detailed knowledge of cervical anatomy and of operator experience in the successful use of sonography for preoperative localization. Multiple studies confirm the poor sensitivity of sonography for the detection of double adenomas. In the study of Haciyanli et al. [39], 21 of 287 consecutive patients were found to have double adenomas. A retrospective analysis of preoperative sonography showed a 40% sensitivity for detection of both adenomas [39]. Similarly, Sugg et al. [40] found 23 cases of double adenoma in 233 consecutive patients, and sonography had a 23% sensitivity. The similarly low sensitivities seen with 99m Tc sestamibi, a relatively operator-independent technique, might suggest double adenomas are an inherently different disease process than the typically easily shown solitary adenoma. Given the significant operator dependence of parathyroid sonography, comparisons between studies is particularly difficult. In addition, substantial advancements in sonography technology over the past 10 years likely will improve the ability of sonography to detect very small structures with specific vascular patterns, such as adenomas. In our recent experience, a highquality sonographic examination is often sufficient for preoperative mapping of adenomas; nuclear medicine studies, although still routinely performed before attempted focused resection, often add little, although they may be helpful when sonography is nondiagnostic (e.g., with ectopic parathyroid adenomas). A well-performed sonographic examination also aids the surgeon because the adenoma location is precisely described. Moreover, preoperative evaluation of thyroid nodules (with sonographically guided FNA) can often be performed in the same setting. Clearly, an up-to-date assessment of the ability of state-of-the-art sonography to identify and locate parathyroid adenomas as a stand-alone technique is needed. Parathyroid Scintigraphy Sestamibi with 99m Tc is the most commonly used radiotracer for imaging the parathyroid glands and has been extensively studied in the setting of primary hyperparathyroidism. Sestamibi is taken up by both the thyroid and parathyroid glands, but adenomatous and hyperplastic parathyroid tissue shows more avid uptake of the radiotracer and often retains the radiotracer longer than adjacent thyroid tissue. Thus, initial planar images obtained shortly after the administration of radiotracer will show both thyroid and parathyroid tissue. Asymmetric foci of increased radiotracer uptake on early images can be seen, representing abnormal parathyroid tissue superimposed on the normal thyroid. Delayed images, obtained approximately 2 hours after radiotracer administration, are acquired to look for foci of retained radiotracer characteristic of hyperfunctioning parathyroid tissue (Fig. 8). AJR:188, June

7 Johnson et al. A Fig year-old woman with hyperparathyroidism and right superior parathyroid adenoma. A, Early-phase 99m Tc-sestamibi SPECT image shows physiologic uptake in salivary glands and thyroid gland, with focus of more intense uptake overlying superior pole of right thyroid lobe (arrow). B, Two-hour delayed SPECT image shows radiotracer retention in adenoma (arrow) but clearing of tracer from overlying thyroid. SPECT of the neck through a pinhole collimator can help to differentiate parathyroid activity from the overlying thyroid and has been shown to increase the sensitivity of scintigraphic parathyroid imaging [41 43]. Subtraction techniques have also been used to image the parathyroid glands by administering a second radiotracer taken up only by the thyroid gland. Either 123 I or 99m Tc pertechnetate can be used in conjunction with 99m Tc sestamibi to produce subtraction images of the parathyroid glands, although these techniques have not been clearly shown to be diagnostically superior to nonsubtracted techniques. The reported sensitivity of 99m Tc-sestamibi scintigraphy is similar to that of sonography. Recent large series using SPECT show sensitivities for detection of solitary adenomas in the range of 68 95% [37, 44 46]. The metaanalysis of Ruda et al. [2] included 96 studies using 99m Tc-sestamibi scintigraphy between 1995 and 2003 in the setting of primary hyperparathyroidism and calculated the sensitivity for detection of solitary adenomas at 88% (95% confidence interval, 87 89%). Similar to sonography, sensitivities for detection of hyperplasia and double adenomas were low, calculated at 44% (95% confidence interval, 41 48%) and 30% (95% confidence interval, 2 62%), respectively [2]. Civelek et al. [44] reported their experience with 338 consecutive patients undergoing preoperative 99m Tc-sestamibi SPECT studies in which the scans were interpreted with the reviewers blinded to the clinical status of the patient or results of other imaging tests such as sonography. In this setting, 99m Tc-sestamibi SPECT precisely located 90% of solitary adenomas, 73% of double adenomas, and 45% of hyperplastic glands. In the large prospective study of Siperstein et al. [37] discussed previously, a similar analysis using preoperative 99m Tc sestamibi alone to direct a focal approach resulted in proper identification of the site 68% of the time. As with the results regarding preoperative sonography, this is somewhat lower than similar retrospective studies. Jones et al. [47] also prospectively interpreted preoperative sestamibi scans and found a high sensitivity for adenomas > 500 mg, with 93% (91/98) accurately located versus only 51% (18/35) for those < 500 mg. This shows the disadvantage of the limited resolution of scintigraphic imaging in the setting of smaller adenomas. Combined Sonography and Scintigraphy for Preoperative Evaluation of Hyperparathyroidism A preoperative approach that combines both the anatomic information of sonography and the physiologic information of scintigraphy has been shown to predict the presence and location of solitary adenomas more accurately than either technique alone. Lumachi et al. [48] retrospectively reviewed preoperative sonography and 99m Tc-sestamibi findings in patients with B proven solitary adenomas and found a combined sensitivity of 95% versus 80% for sonography and 87% for scintigraphy alone. Similarly, Siperstein et al. [37] predicted 79% surgical success in their prospective study combining both techniques versus 74% for sonography and 68% for scintigraphy alone. Solorzano et al. [36], who advocate preoperative sonography as the only preoperative location test, found that, used separately, sonography and scintigraphy each correctly predicted uniglandular disease in 77% of patients, but this increased to 90% when the techniques were combined. Using concordant results on sonography and scintigraphy to plan a focal surgical approach has resulted in high cure rates similar to the traditional bilateral approach. Sonography has the advantage of being more specific regarding the site of an adenoma in relation to the thyroid gland. Scintigraphy clearly has an advantage in the detection of ectopic glands, particularly in the mediastinum. Both techniques remain similarly insensitive for the detection of multiglandular disease and double adenomas. Sugg et al. [40] retrospectively studied preoperative imaging findings in 23 of 233 patients found to have multiglandular disease and found that even when combining both techniques, multiglandular disease was correctly predicted in 30% of patients, single-gland disease was incorrectly predicted in 30%, abnormal parathyroid glands were not located in 30%, and discordant results were provided in 10%. Haciyanli et al. [39] specifically studied double adenomas and found combined techniques were only 60% sensitive. Even with the addition of intraoperative PTH assays of the abnormal glands, double adenoma was correctly predicted in 80% of patients, emphasizing the need for a traditional bilateral approach in patients with suspected multiglandular disease [39]. Given that the operation of choice for both multiglandular disease and double adenomas is a traditional bilateral approach, some endocrine surgeons have advocated that equivocal, negative, or discordant results on both preoperative studies warrant a nonselective approach because a high proportion of these patients will have multifocal disease. Thus, the role of the radiologist is to provide highly accurate location of singlegland disease to facilitate focal surgical approaches. When findings are equivocal, suggestive of multiglandular disease, or discordant with other imaging tests, this should be clearly stated as well because these patients will more likely be treated with a traditional bilateral approach AJR:188, June 2007

8 Parathyroid Imaging and Hyperparathyroidism Fig year-old woman who presented with recurrent hypercalcemia and hyperparathyroidism after resection of both left-sided glands. Contrast-enhanced CT scan shows brisk enhancement of 8-mm soft-tissue nodule (arrow) in mediastinum that correlated anatomically with focus of radiotracer retention in mediastinum on prior sestamibi SPECT. This was found to be a hyperplastic right inferior parathyroid gland. CT Axial contrast-enhanced thin-collimation CT images through the neck show intense enhancement in the typical locations for parathyroid tissue in the setting of adenoma. Scanning from the skull base through the mediastinum has the additional advantage of A C Fig year-old woman with left superior adenoma showing typical MRI signal characteristics. A, T2-weighted MR image shows increased T2 signal in adenoma (arrow) relative to thyroid gland and surrounding soft tissues. B, Axial T1-weighted MR image shows typical intermediate T1 signal (arrow) seen in adenomas. C, Gadolinium-enhanced T1-weighted image with fat suppression shows intense enhancement typical of adenomas (arrow). These imaging characteristics can be indistinguishable from those of lymph nodes and thus must be interpreted in clinical context and in concert with other imaging techniques. B detecting most ectopic glands (Fig. 9). In cases of failed initial parathyroidectomy, artifacts from surgical clips placed in the neck often limit the diagnostic quality of CT. Reported sensitivities of CT range from 46% to 87% [49]. Combined studies of sonography and CT suggest that supplemental CT will detect few additional adenomas over sonography alone. Thus, CT is usually reserved for cases of failed parathyroidectomy or in cases of altered anatomy, in which CT may aid in operative planning [50 52]. Recent studies have combined 99m Tc-sestamibi SPECT with coregistered CT in an attempt to improve sensitivity by combining anatomic and functional information, but results from these initial studies are conflicting in their conclusions about the added usefulness of CT. More study is required before the appropriate usefulness of this combined technique is established [53 55]. MRI Although less commonly used for preoperative localization than sonography and scintigraphy, MRI provides similar sensitivity to other techniques in the detection of abnormal parathyroid tissue [56, 57]. More commonly, MRI is used in patients with persistent or recurrent hyperparathyroidism, in whom it has been shown to be effective in locating remaining abnormal parathyroid tissue [58]. Images of the neck are generally obtained with an anterior neck surface coil from the hyoid bone to the sternal notch. Axial T1- and T2-weighted fast spin-echo sequences are commonly acquired. In instances in which no neck lesion is identified or an ectopic parathyroid gland is suspected, ECG-gated axial images of the mediastinum can be effective. The T1 and T2 characteristics of abnormal parathyroid tissue are variable. The most common tissue characteristics are intermediate- to low-intensity T1 signal and high-intensity T2 signal (Fig. 10). Less commonly, fibrosis or old hemorrhage can cause low signal intensity on T1- and T2-weighted images. Subacute hemorrhage into adenomas can cause high signal intensity on both T1- and T2-weighted images [59]. The acquisition of gadolinium-enhanced T1-weighted images with fat suppression has not been shown to significantly increase detection of adenomas when they exhibit T2 hyperintensity. However, false-negative studies are most commonly associated with adenomas that are isointense on T1 and T2 sequences; the addition of contrast-enhanced images can increase sensitivity for these cases [57]. Abnormal parathyroid tissue cannot be diagnosed on MRI by signal characteristics alone because cervical lymph nodes have similar signal characteristics. Therefore, accurate MRI diagnosis depends on knowledge of the typical morphology and location of the AJR:188, June

9 Johnson et al. parathyroid glands and common sites of ectopic glands. Conclusion Over the past decade, the surgical treatment of primary hyperparathyroidism has changed from predominantly a bilateral approach with four-gland exploration in all cases to unilateral and focused approaches guided by preoperative imaging showing single adenomas. Sonography and 99m Tc-sestamibi scintigraphy have assumed dominant roles in preoperative location of solitary adenomas, and focused approaches based on concordant findings from both techniques have cure rates equal to that of the traditional approach. Sonography is particularly diagnostic when a typical polar feeding vessel and peripheral vascularity are shown. Preoperative identification of multiglandular disease and double adenomas remains poor; thus, patients with negative, discordant, or equivocal results will commonly undergo bilateral procedures because of the high incidence of multifocal disease in patients without definitive preoperative imaging findings. MRI and CT are generally reserved for cases of failed initial surgery or recurrent hyperparathyroidism because the prevalence of supernumerary and ectopic glands is much higher in this select population. Acknowledgment We thank Eric Jablonowski for his illustration of normal parathyroid anatomy. References 1. Sosa JA, Powe NR, Levine MA, Udelsman R, Zeiger MA. Profile of a clinical practice: thresholds for surgery and surgical outcomes for patients with primary hyperparathyroidism a national survey of endocrine surgeons. 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