Left inferior parathyroid adenoma . 62-year-old female with 3–4-year history of nephrolithiasis and hypercalcemia. Presented with a total serum calcium of 10.4 mg/dL (normal 8.6–10.4) and parathormone level of 171 pg/mL (normal 14–64). (a) Early (top) and three-hour delayed (bottom) planar (right anterior oblique—left, anterior—center, and left anterior oblique—right) images were obtained, and revealed focal uptake in the inferior right thyroid bed, which persisted on delayed imaging. (b) Delayed SPECT images of the same patient, reconstructed in the axial (top), sagittal (middle), and coronal (bottom) planes, demonstrate the ability of tomographic imaging to identify parathyroid adenoma with high target-to-background ratio. On surgery, parathyroid adenoma was excised
Less common, though growing in use particularly in Europe, is the use of a dual-tracer technique (using either pertechnetate or radioiodine) which allows for the explicit consideration and subtraction of thyroid uptake from the early planar sestamibi scan. Evidence regarding the advantages and disadvantages of these dual-tracer and subtraction techniques is considered in the discussions below.
The planar scintigraphy technique is the simplest and easiest protocol for the detection of parathyroid disease. Planar images may be obtained using a standard low energy parallel hole collimator, or preferably via pinhole collimation which provides magnification of small structures . When optimized with pinhole imaging, the dual-phase planar technique may be up to 82–91 % sensitive for the detection of adenoma and hyperplasia . When compared to tomographic (SPECT) imaging, the planar protocol is logistically more robust as it does not require patients to remain still for long periods without a break, and it can be performed with even the most basic Anger camera. In addition, planar images can be obtained in patients for whom SPECT may be challenging, such as very obese patients and those with severe claustrophobia. For these reasons, it is unlikely that planar imaging will disappear from the standard parathyroid scintigraphy protocol.
However, data obtained over the past decade suggests that dual-phase planar imaging by itself provides inadequate sensitivity for the detection of parathyroid adenomas, even in single-gland disease (see discussion below). Even the maximal sensitivity of planar imaging is compromised in patients with ectopic disease. Thus, imaging with SPECT has become a mainstay of evaluation.
Single-Photon Tomographic Imaging
The availability of multi-head Anger cameras has allowed for the proliferation of SPECT in scintigraphic imaging protocols. By allowing for a tomographic three-dimensional reconstruction of tracer distribution in the head and neck regions, SPECT overcomes the interpretation difficulties related to the superimposition of tracer activity on planar images (see Fig. 12.1b). Thomas et al.  demonstrated a sensitivity of dual-phase SPECT of 67 % as compared to 42 % for dual-phase planar imaging, somewhat similar to sensitivities of 62 % and 57 %, respectively, as reported by Lavely and colleagues . Additionally, the use of SPECT increases reader confidence when compared to planar imaging .
In that it does not add to patient radiation dose, the primary disadvantage of SPECT as compared to planar scintigraphy is the prolongation of the imaging protocol. In addition, though few, there remain centers with cameras that are not capable of routine tomographic imaging, and in these locations SPECT is simply out of reach.
Finally, SPECT-CT is considered by some to be an expensive add-on to SPECT—while the value of tomographic imaging is recognized [10, 31, 39], the additional cost and radiation exposure imposed by hybrid CT or post-acquisition fusion of diagnostic CT images to the functional SPECT information are not uniformly appreciated [4, 22, 36]. Practically, the addition of anatomic information (CT) to functional information (SPECT) can be achieved by using either a hybrid SPECT-CT capable of the consecutive acquisition of SPECT and multi-slice CT in one unit or the software fusion of separately acquired diagnostic CT and SPECT images. In the former, the CT obtained is often done in the absence of intravenous contrast, and kVp and mAs are minimized. Though this serves to limit radiation dose to the patient, the acquisition of diagnostic-quality CT images, even in the absence of intravenous contrast, increases the utility of the combination image for the purposes of surgical planning and intraoperative correlation. In most cases, the current literature examines the diagnostic capabilities of SPECT-CT obtained utilizing a hybrid SPECT-CT camera, and it is generally assumed that post-acquisition fusion SPECT + CT images are similarly valuable though perhaps technically challenging due to the need for high-accuracy software fusion of SPECT and CT images. In many cases, therefore, hybrid SPECT-CT images are obtained and are correlated with diagnostic CT images preoperatively.
There seems to be little doubt that SPECT-CT is superior to planar-only imaging in the diagnosis of parathyroid adenomas [31, 48]. The exact nature of the benefits provided by SPECT-CT over SPECT remains a source of some debate, though it seems clear that SPECT-CT offers improved accuracy in ectopic glands . A recent meta-analysis of 24 articles on scintigraphy for hyperparathyroidism suggests that SPECT-CT has overall better sensitivity and specificity when compared to planar or SPECT-only protocols . In their study comparing single-photon imaging protocols, Lavely et al.  identified early SPECT-CT imaging in concert with any (three-view planar, SPECT, or SPECT-CT) delayed imaging as the most sensitive protocol for the accurate identification of parathyroid adenomas. Since then, numerous studies have sought to identify the incremental value of the addition of CT to SPECT, with somewhat mixed results. In their subset of patients with hyperparathyroidism, Bural et al.  suggested that SPECT-CT allowed for more accurate parathyroid adenoma localization on a per-patient basis than did SPECT (sensitivities of 97 % for SPECT-CT and 61 % for SPECT-only). Furthermore, the addition of CT to SPECT has been shown to increase reader confidence, thereby decreasing the number of false-positive SPECT findings (see Fig. 12.2). In a retrospective analysis of SPECT-CT images from 50 patients undergoing preoperative parathyroid localization, Mandal et al.  suggest that early-only MIBI SPECT-CT is sufficiently sensitive and specific, and that delayed-phase images may be unnecessary. In large part, the gains seen with SPECT-CT over SPECT relate partially to improvements in the localization of ectopic versus eutopic glands and partially to increased reader confidence [20, 42] (see Fig. 12.3). A recent study  has suggested that the method of imaging reconstruction utilized in SPECT-CT versus that performed with SPECT-only scanning may also contribute to the superior performance of the former; further study in this area may be of benefit, as it may have important clinical implications for centers with the capability to perform SPECT but not SPECT-CT.
False-positive sestamibi uptake within mediastinal brown fat. 80-year-old female presented with a history of hypercalcemia and intact PTH of 93.1 pg/mL (normal 12.0–88.0). No focal MIBI was seen in the neck, but focal retention was noted in the chest on functional imaging (right). SPECT-CT fused image (left) reveals this focus to be within brown fat within the mediastinum
Ectopic (superior mediastinal) parathyroid adenoma . 69-year-old male with total serum calcium of 11.5 mg/dL (normal 8.6–10.2) and parathormone level of 132 pg/mL (normal 14–64). (a) Delayed anterior planar MIBI image reveals focal activity in the anterior chest. Hybrid SPECT-CT coronal (b) and axial (c) views confirmed focal uptake in a 2 cm soft-tissue nodule in the anterior superior mediastinum. On surgery, a 2.5 cm parathyroid adenoma was excised
Single-Tracer Versus Dual-Tracer Imaging Protocols
It is worth noting at the outset that dual-tracer protocols impart a higher radiation dose to patients than do protocols that utilize MIBI only. Members of the medical imaging community consider this incremental increase in radiation dose to have a high risk-benefit profile, and therefore, it is not typically considered to be prohibitive. For further discussions of radiation doses related to scintigraphic imaging, please see Chap. 41.
In an unselected representative patient population, the addition of planar thyroid imaging with subtraction to a dual-phase MIBI imaging protocol has been shown to increase specificity for parathyroid adenoma detection to over 94 % . In a small study comparing dual-tracer techniques to four different single-tracer (MIBI) protocols, Tunninen et al.  concluded that the dual-tracer technique utilizing I-123 sodium iodide was superior to MIBI protocols employing either pinhole planar or SPECT-CT methodologies. Interestingly, recent work by Heiba and colleagues  compared dual-tracer dual-phase pinhole planar imaging to various protocols (including single-tracer MIBI imaging) with and without SPECT-CT. Their findings suggest that dual-tracer pinhole planar imaging is equivalent to dual-phase single-tracer pinhole imaging, but that the addition of SPECT-CT to dual-tracer pinhole planar protocol yields the highest performance with an accuracy of over 95 %. Neumann and colleagues  performed thyroid subtraction SPECT, and evaluated its performance with and without concomitant CT, concluding that the addition of CT to the SPECT protocol significantly improved specificity on a per-lesion basis (96 % for SPECT-CT as compared to 48 % for SPECT-only), with both having sensitivities of about 70 %. These studies suggest that, while dual-tracer methodologies are valuable particularly in patients with thyroid disease, they cannot supplant the benefit of CT correlation with SPECT. Further evaluation of these options may be valuable, as even low-dose CT adds, on average, 1–2 mSv to the approximately 8 mSv effective radiation dose of a planar + SPECT sestamibi protocol [as a comparison, a dose of pertechnetate for thyroid imaging adds up to 2 mSv to the dose of the same protocol, and a typical dose of I-123 NaI would add ~4 mSv to a sestamibi parathyroid imaging study] [43, 57].
Performance of Single-Photon Imaging in Multi-Glandular and Hyperplastic Disease
The literature clearly documents that the accuracy of scintigraphic imaging suffers in the setting of multi-glandular disease. Katz et al.  demonstrated that study sensitivity decreased to 23 % in patients with pathologically proven multi-gland disease as compared to a sensitivity of 70 % in solitary adenomas; in their study, none of the bilaterally diseased glands among 15 patients in their cohort were correctly localized on preoperative planar MIBI (an undisclosed number of patients also underwent SPECT imaging). In an analysis of just over 400 patients, Chiu et al.  found that patients with multi-gland disease were more likely to have non-localizing MIBI scans, frequently revealing no focal uptake at all. Similarly, a multicenter study examining primary hyperparathyroid patients with failed surgery revealed that over half of patients with persistent postoperative hyperparathyroidism suffered from multi-gland disease not localized on the combination of ultrasound and MIBI scintigraphy . Notably, using a dual-tracer dual-phase protocol, Guerin et al.  showed preoperative parathyroid scintigraphy to be localizing in as many as 61 % of patients with multi-glandular disease.
Secondary and Tertiary Hyperparathyroidism
In patients with renal failure resulting in secondary and/or tertiary hyperparathyroidism, typically more than one parathyroid gland becomes hyperfunctional. In an analysis of 166 patients with secondary and tertiary hyperparathyroidism, Cruz de Andrade et al.  demonstrated an overall sensitivity of 91 % for MIBI scintigraphy, with scintigraphy correctly localizing only 26 % of ectopic glands but virtually all eutopic glands; notably, this retrospective study included scintigraphic image reports from numerous sites, and the utilization of planar versus SPECT or SPECT-CT is not clear. Likewise, in additional studies of patients with secondary hyperparathyroidism related to renal failure, preoperative dual-tracer dual-phase scintigraphic imaging and MIBI single-tracer dual-phase SPECT-CT imaging have been shown to be valuable in accurately localizing hyperfunctioning parathyroid glands [17, 53].
Overall, as these patients tend to represent a small minority of patients presenting for parathyroid scintigraphy, thus far there is inconclusive data regarding the accuracy of scintigraphy in this patient population and larger studies in this patient population are needed.
Known or Suspected Thyroid Adenoma or Thyroid Disease
Intuitively, it is patients with known or suspected thyroid disease in whom the dual-tracer and SPECT-CT protocols may be most beneficial. A prospective study of 50 patients with primary hyperparathyroidism and nodular goiter on physical exam demonstrated superiority of SPECT-CT as compared to SPECT and planar imaging in a dual-phase single-tracer protocol, with accuracies of 85 %, 75 %, and 65 %, respectively . Utilizing a novel protocol of both dynamic planar imaging and subtraction dual-tracer tomography, Berner et al.  demonstrated per-lesion sensitivity, specificity, and accuracy of 71 %, 94 %, and 76 %, respectively. This was superior to ultrasound, which had sensitivity, specificity, and accuracy of 60 %, 72 %, and 62 % in this same patient population; similar results were reported by Markovic and colleagues . It should be noted, however, that while this represents very good performance of scintigraphy in these patients, these groups utilized software developed locally for the subtraction and quantification of relative parathyroid uptake on planar images; such software is not widely available or accessible for most imaging centers and clinicians. Importantly, Pata et al.  showed that SPECT-CT provides sensitivity and specificity of 94 % and 93 % in side localization in patients with nodular goiter, and that it decreased operating time. Even in the absence of quantitation, the availability of contemporaneous thyroid images is highly desirable for accurate preoperative findings in patients with known thyroid abnormalities as defined by ultrasound . Thus, the use of thyroid imaging in concert with dual-phase MIBI parathyroid imaging is desirable in patients with known or suspected thyroid disease.
Postsurgical Recurrent Hyperparathyroidism
Even after successful parathyroidectomy (as defined by criteria with a post-excisional drop in intact parathormone (iPTH) level of >50 %), some patients will go on to have recurrent hyperparathyroidism. In these patients, the rate of ectopic parathyroid adenoma is disproportionately high as compared to the general population of those with hyperparathyroidism. In small studies, MIBI scintigraphy has demonstrated poor performance in the re-operative setting, with sensitivity as low as 33 % for dual-phase MIBI SPECT . In contrast, both sensitivity and specificity of scintigraphy in this subpopulation of patients were shown to be higher when SPECT and/or SPECT-CT are utilized in addition to planar imaging with MIBI by Lu and colleagues , who described a small series of patients with recurrent hyperparathyroidism in whom MIBI SPECT-CT successfully guided mediastinal parathyroidectomy.
Comparison and Correlation with Other Imaging Modalities
Guidelines by the Society of Nuclear Medicine and Molecular Imaging (SNMMI) as well as the American Association of Clinical Endocrinologists (AACE) and the European Association of Nuclear Medicine (EANM) uniformly recognize the complementary role of ultrasound and scintigraphy in preoperative localization and surgical planning [57, 59, 60]. Numerous retrospective studies have suggested that the use of neck ultrasound plus scintigraphy is superior to either imaging method alone in the preoperative diagnosis of parathyroid adenomas [25, 26, 40]. Some studies have suggested that, despite the inter-operator variability in ultrasound performance, there is some evidence that ultrasound in the hands of highly skilled practitioners may reliably detect culprit parathyroid glands as readily as dual-phase MIBI and dual-tracer planar imaging [45, 50, 51]. Conversely, when SPECT-CT is available, the data is less compelling regarding the additional utility of ultrasound above that of dual-phase SPECT-CT in the localization of solitary parathyroid adenomas and minimization of surgical extent . In patients found to have ectopic adenomas on surgical exploration, planar and/or tomographic scintigraphy successfully identified and localized the diseased gland even in ultrasound-negative patients . While ultrasound infrequently identifies adenomas not seen on scintigraphy, ultrasound can identify thyroid abnormalities and thereby provide vital information for scintigraphic correlation or identification of patients in whom concurrent thyroid imaging should be performed (i.e., patients for whom a dual-tracer protocol should be considered) .