Ectopic parathyroid tissue has an incidence as high as 35% due to aberrations in migration during the early stages of development. Like entopic parathyroid tissue, it can be hyperplastic, symptomatic, and associated with secondary HP. It is a common cause of persistent or recurrent HP and failure of parathyroid surgery (23, 24). It can present as symmetrical even when ectopic (25). Ectopic parathyroid thyroid tissue can become adenomatous and cause primary HP, hypercalcemia, and other associated symptomatology (23).

Ectopic parathyroid glands occur along the path of migration of the branchial pouches from the level of the carotid sheath to the heart. Ectopic superior parathyroid glands are most frequently located posteriorly near the tracheoesophageal groove or retroesophageal region (24). Ectopic locations of the inferior parathyroid glands most typically occur in the anterior mediastinum in association with the thymus gland or thyroid gland (26). Ectopic parathyroid glands can also occur along the course of the vagus nerves (27), within the thyroid gland (28), pyriform sinus (29), retropharyngeal region, and axilla (30).

A parathyroid gland, whether normal or abnormal, surrounded entirely by thyroid parenchyma with no capsule is considered an intrathyroidal parathyroid and occurs due to aberrant migration of the parathyroid glands during embryogenesis (31). Intrathyroidal parathyroid can be confused with intracapsular parathyroid gland, which is a parathyroid gland situated within the crevices of the thyroid (32, 33).

Intrathyroidal parathyroid glands are rare but intrathyroidal parathyroid tissue is not. In a survey of 350 children, the presence of parathyroid and thymic tissue within the thyroid gland was suggested to be so common that it is a normal occurrence (34). Intrathyroidal parathyroid tissue was found in 3% of infants on routine sections and 70% on step sections (34). Intrathyroidal parathyroid glands may develop adenomatous and hyperplastic pathologies like other parathyroid glands (35, 36).

The incidence of true functioning intrathyroidal parathyroid gland represents less than 1% of all hyperparathyroidism cases in a large series (37, 38) with 3:1 female predominance. Over 400 cases of intrathyroidal parathyroid adenoma have been described in case reports and series, with less than 10 cases of intrathyroidal parathyroid carcinoma identified. Intrathyroidal parathyroid is three times more likely to be in the superior pole of the thyroid and slightly favors the right over the left.

In parathyroid hyperplasia there is typically more than one gland involved and the weight of all of the hyperplastic glands usually measures between 1-3 g. Hyperplastic parathyroid cells may show clonality and involve mainly the chief cells. Parathyroid hyperplasia can be sporadic or in patients with a history of prior radiation to the neck. In the setting of MEN1 or 2A patients may begin with multigland hyperplasia and progress to multiple adenomas. Hyperplasia of parathyroid adipose tissue is rare.

In primary chief cell hyperplasia, there is increased production of PTH associated with MEN1 or MEN2A. There is no association with MEN2B. Parathyromatosis, when microscopic foci of hyperplastic parathyroid tissue are found in the neck, is associated with chief cell hyperplasia and prior surgery (40). Bilateral primary chief cell hyperplasia is associated with loss of the APC gene (41).

Cystic parathyroid lesions often contain turbid or colored fluid, present at all ages, and can be diagnosed by FNA where high PTH is found in the fluid (42). Cysts measure 1-10 cm and are unilocular, and thin walled.

Parathyroid cysts are a rare cause of neck swelling, accounting for 0.6% of thyroid and parathyroid lesions (43). Functional parathyroid cysts are more common than nonfunctional parathyroid cysts (44). Patients are usually normocalcemic and present with an asymptomatic neck mass, including in the low cervical region and anterosuperior mediastinum. They may occur in a hyperplastic gland (45), due to cystic degeneration within an adenoma, or within heterotopic salivary gland-like tissue (46).

Patients with large cysts should be managed expectantly to avoid development of symptomatic hypocalcemia. Cyst rupture should be avoided during resection. Many cysts are amenable to aspiration for diagnosis and treatment and ethanol ablation can be considered for recurrent cases (47). Cystic parathyroid lesions are a common cause of false negative results on molecular imaging.

Parathyroid adenoma (PA) typically involves a single gland and represents neoplasia of parathyroid cells with nuclear pleomorphism more common than in hyperplasia (48). Chief cells within parathyroid adenomas are most commonly responsible for elevated PTH levels (49–51). Parathyroid adenomas more commonly involve the inferior glands over superior glands. The diagnosis of parathyroid adenoma is typically derived from an intraoperative finding of solitary, or less commonly two, enlarged parathyroid gland(s) with histology of a hypercellular parathyroid tumor and compressed adjacent normal parathyroid tissue. Adenomas can occur in ectopic locations similar to normal parathyroid tissue, which are found in up to 16% of cases and most commonly occur in the neck or mediastinum ( Figure 1 ) (20, 52, 53). Simultaneous adenomas can occur involving multiple glands (54). Parathyroid adenoma can mimic follicular thyroid neoplasm at FNA.

The incidence of parathyroid adenoma has increased over the past 50 years, perhaps due to routine biochemical testing, with adenomas often detected early in asymptomatic patients. Most are sporadic cases of unknown etiology. Women are more frequently affected and it is common for adenomas to occur in the 30s-60s (55). When symptoms occur in the setting of PA, they are typically related to hypercalcemia due to primary HP.

Syndromes associated with parathyroid adenoma include hyperparathyroidism jaw tumor syndrome (HRPT2 gene germline mutation) and multiple endocrine neoplasia (MEN1 > MEN2A) (54). Risk factors include radiation exposure and long-term lithium therapy (56, 57).

Parathyroid carcinoma is rare. At a large tertiary cancer center within the United States, a study identified only 20 patients over a 15-year period who had been operated on for parathyroid carcinoma with at least one preoperative imaging exam at the same institution (58). Conventional structural imaging may be helpful to identify this entity as it is typically poorly circumscribed, which can distinguish it from parathyroid adenoma (59). The mean diameter of parathyroid carcinomas at histopathology is suggested to be 3.4 cm with a weight of 19.2 g (60), considerably larger than the typical adenoma. The role of imaging in parathyroid carcinoma is primarily for evaluation of metastatic disease for which FDG PET/CT has demonstrated promise (61, 62).

Rarely, neoplasms can involve the parathyroid through metastasis or direct involvement. A literature review of 127 reported cases revealed the most common primary malignancies were breast carcinoma (66.9%), melanoma (11.8%), and lung carcinoma (5.5%) (63). Patients with metastatic parathyroid lesions typically had widespread metastatic disease and were reported to develop abnormal calcium homeostasis even greater than those with primary parathyroid disease. Thyroid neoplastic disease is reported to typically secondarily involve the parathyroid gland by direct extension (64). These entities are potential masqueraders of parathyroid disease on imaging.

In the 1970s, imaging of the parathyroid gland was initially attempted with ⁷⁵Se methionine (71). Further advancement through double-tracer image subtraction techniques remained suboptimal [ Figure 2 (71)]. The intention of these subtractions was to separate thyroid lesions from parathyroid lesions using the second radiotracer [¹²⁵I (72), or ¹³¹I (73), or ^99mTc-pertechnetate (74)] in addition to ⁷⁵Se-methionine. ²⁰¹Tl was then investigated for parathyroid imaging with ^99mTc-pertechnetate subtraction, which in the 1980s became the standard of care (75–78) [ Figure 3 (75)]. However, ²⁰¹Tl was suboptimal for imaging due to its physical characteristics.

High resolution neck ultrasound is an accessible structural imaging technique that is capable of visualizing diseased parathyroid glands without the use of ionizing radiation. The cost of neck ultrasound is approximately $200, with other imaging studies costing over $1000 (68, 111). The examination is best performed with a linear array high frequency probe (7.5-13 MHz) by transverse and longitudinal scanning. The parathyroid ultrasound should include the paratracheal spaces, the carotid-jugular axis with the superior aspect reaching the carotid bifurcation, and thyroid gland with the inferior aspect reaching the sternal notch (112–115).

The morphology of a parathyroid adenoma on ultrasound is described as an oblong or ovoid shaped, hypoechoic structure with uniform echogenicity, with echogenic capsule, which is typically hypervascular on color doppler around the capsule and centrally. Internal heterogeneity can result from fat, hemorrhage, or calcification. The parathyroid may have an identifiable feeding vessel at the pole (68) [ Figure 7 (116)]. The normal parathyroid gland is difficult to reliably identify on ultrasound. Asking the patient to swallow can increase conspicuity of the inferior glands. The parathyroid gland should not be confused with lymph nodes which have a feeding vessel leading to the hilum which is typically echogenic due to fat. By now, it is widely recognized that ultrasound can be helpful as a quick, well tolerated, cost effective first line imaging exam for patients with primary HP. Ultrasound is rarely the only preoperative imaging examination performed, and should not be relied upon in isolation in the usual standard of care for these patients.

The AHNS Endocrine Section 2019 guidelines also suggest a benefit of intraoperative ultrasound to more precisely guide the surgical approach and localization (68). They also suggest that in rare instances, PTH assay of an ultrasound guided fine needle aspiration (FNA) of an indeterminate lesion along the posterior aspect of the thyroid can have a benefit in distinguishing intrathyroidal parathyroid from a thyroid nodule. There is however a risk of seeding parathyroid tissue and in most cases FNA of parathyroid lesions is not necessary or recommended. Molecular or structural imaging has been suggested to provide an anatomical map with which to compare intraoperative findings.

To identify the source of PTH excessive secretion, multiphasic dynamic contrast enhanced CT imaging was first implemented in 2006 (117). This technique, termed 4DCT, uses both morphological and enhancement patterns of lesions to identify and differentiate them from mimickers such as lymph nodes or the thyroid gland (68, 118, 119). The typical protocol is either 4 phases or 3 phases: a non-contrast phase, followed by an arterial phase (25-30 seconds after contrast bolus), a venous phase (~30 seconds after arterial phase), with or without delayed venous phase (~60 seconds after the arterial phase) (68, 118) [ Figure 8 (120, 121)].

Benefits of 4DCT include: (1) short imaging time and (2) high spatial resolution to detect small and ectopic glands. Drawbacks include high radiation dose to the thyroid at approximately 92 mGy with 4DCT compared to 1.6 mGy with ^99mTc-sestamibi, or about 57 times more radiation (120, 122). Higher radiation dose could, at least in theory, contribute to increased risk of future thyroid malignancy and should be cautioned particularly in younger patients. Although 4DCT sensitivity for single adenomas was reported up to 94% in one study, the sensitivity for multigland disease (MGD)–which is a common presentation—is reported less than 60% (118). Sho et al. reported the sensitivity of 4DCT for MGD is as low as 32-53% (123). It is possible that modality independent factors, such as the field of view or satisfaction of search could contribute in part to these results.

The principle of 4DCT is based on the assumption that PA has distinct enhancement kinetics. In general, lymph nodes progressively enhance and are darker on earlier phases of CT imaging compared to both thyroid and PA (124). However, the enhancement pattern alone is not sufficient for accurate diagnosis. Bahl et al. discuss three distinct patterns of PA enhancement defined in comparison to adjacent thyroid gland tissue: (1) Type A–PA significantly darker than thyroid on unenhanced phase, significantly brighter than thyroid on arterial phase, and significantly darker than thyroid on delayed phase; (2) Type B–PA significantly darker than thyroid on unenhanced phase, similar to thyroid on arterial phase, and darker than thyroid on delayed phase; (3) Type C–PA significantly darker than thyroid on unenhanced phase, similar to thyroid on arterial phase, and similar to thyroid on delayed phase (118). In their study, the thyroid had similar Hounsfield units (HU) in the non-contrast and arterial phases, however there were significant differences in the thyroid HU in the delayed phase images between groups A and B versus group C, which was not explained. Moreover, only 20% of PA in the series including 94 patients and 110 lesions were brighter than thyroid on the arterial phase, which calls into question the utility of the thyroid as a relevant comparison for arterial hyperenhancement in PA in this study. In another 22% of cases, the pattern was darker than the thyroid in the arterial phase and indistinguishable in the delayed phase, similar to the lymph node enhancement pattern. There was no reported relation between the kinetic pattern relative to the thyroid and the lesion size, weight, or ectopic location. In contrast, Lee et al. described differences in enhancement patterns related to tumor volume with PA>=1cm having greater arterial enhancement and venous washout compared to PA<=1cm which demonstrated more progressive enhancement from arterial to venous phases (121).

Multiple groups attempted to optimize the number of CT phases and accuracy of the test. Hunter et al. found that 3-phases resulted in increased detection accuracy (sensitivity 98%, specificity 97%) compared to arterial only (sensitivity 52%, specificity 75%) in 120 lesions. Contrarily, Raghavan et al. suggested that arterial only (without even an unenhanced phase) was not significantly different from the combination of 2, 3, or 4 phase imaging in a smaller cohort of 29 patients at around 91% accuracy (125). To address this conundrum, a large meta-analysis of 2563 patients found that more post contrast phases of 4DCT in addition to the unenhanced phase resulted in detection improvements concluding that unenhanced plus two post contrast phases was optimal (single contrast: 71%; two-contrast phases: 76%; three-contrast phases: 80%) (126). Ongoing controversy remains regarding the optimal number of phases however, particularly due to the high radiation dose of 4DCT (127). One might consider eliminating the unenhanced phase, however we must remember this phase provides the greatest differences in HU between the thyroid and the PA (118). Dual-energy CT has been suggested capable of reducing dose by 50% (128). Although there is limited evidence regarding its utility in parathyroid disease, dual energy CT could decrease radiation exposure through incorporation of a virtual non-contrast phase (129).

In addition to the kinetic characteristics, the polar vessel sign can be seen on 4DCT in the arterial phase and is the finding of an enlarged feeding vessel of a PA, typically the inferior thyroid artery (130). There is not always a clear fat cleft with examples being subcapsular parathyroid and extracapsular sequestration (131) [ Figure 9 (130, 131)].

In a large systematic review of patients with non-familial primary HP having surgery following CT localization, the overall pooled sensitivity was 73% (95% CI: 69-78%) for localization of the correct quadrant and 81% (95% CI: 75-87%) for localization to the correct laterality (126).

Practical advantages of 4DCT could be in the setting of discordant or inconclusive ^99mTc-sestamibi and US examination (as a second line test), after unsuccessful initial surgery, or when there is distorted neck anatomy (132–135). To evaluate the utility of 4DCT as a second line test, Tian et al. included 104 patients with inconclusive first line imaging and demonstrated sensitivity of 73% and specificity of 86% compared to ^99mTc-sestamibi sensitivity of 48% and ultrasound sensitivity of 52% (136). To evaluate the performance of 4DCT in the re-operative setting, a prospective study of 45 patients showed sensitivity of 88% compared to 54% with ^99mTc-sestamibi (135).

Practical limitations of 4DCT include detection of multigland disease (MGD) and ectopic lesions outside of the field of view.

4DCT can be combined with emerging PET/CT agents to achieve even greater diagnostic accuracy. ¹⁸F-Fluorocholine (FCH) PET/4DCT in 44 patients was found superior ¹⁸F-FCH PET/CT alone or 4DCT alone achieving 100% sensitivity in 31 of 31 operated patients, which could be considered in patients with primary HP and negative or inconclusive first line imaging (137).

MRI has gained attention in localization of the etiology of primary HP due to its ability to perform reliable cross-sectional imaging of the neck and mediastinum without ionizing radiation and with high soft tissue contrast resolution.

Initial evaluation of MRI performance in 2000 by Hanninen et al. found 82% sensitivity for localization of abnormal parathyroid glands or ectopic glands in the mediastinum and submandibular region (138). However, in 2003 Wakamatsu et al. found lower sensitivity of MRI in detection of PA at 43% when using a 0.5 Tesla magnet in conventional approaches (139). Initial challenges in MRI evaluation of the parathyroid, such as motion artifacts and suboptimal fat saturation have been addressed through newer MRI technology and techniques, such as newer time resolved imaging and chemical shift fat saturation imaging sequences.

​​In a study that compared MRI features with findings on ultrasound or ^99mTc-sestamibi, five correlative MRI features were identified associated with PA (141) [ Figure 10 (140, 141)]. These included (1) elongated morphology (ratio of longest to shortest diameter >=2.0) with either (2) homogeneous or (3) ‘marbled’ T2 hyperintensity appearance. Out of phase imaging often revealed (4) a fluid fat interface representing the facial plane between the thyroid gland and the PA (although this would not be expected to be present in the case of an intrathyroidal parathyroid adenoma). Dynamic MRI (4DMRI) enhancement characteristics revealed (5) rapid enhancement in post-contrast T1 images.

More recently, Argiro et al. and Becker et al. found excellent sensitivity (up to 97.8%) and specificity (up to 97.5%) for MRI in the detection of PA, which could be due to further optimization of equipment, such as the use of a 3 Tesla magnet and more modern imaging protocols (142, 143). Importantly, Argiro also found good performance in MGD with 8/8 enlarged glands detected and 6/7 ectopic parathyroid glands detected in their series (142). Merchavy et al. found 100% sensitivity for PA in a series of 11 patients using 4DMRI (144).

Anecdotal evidence suggested that MR spectroscopy using the proton high-resolution magic angle spinning with the Algorithm to Determine Expected Metabolite Level Alterations (ADEMA) approach could be used to measure differences in metabolites in primary HP. Using this technique, one group reported increased levels of choline, glycerophosphocholine, phosphorylcholine, glucose, lactate, succinate, glutamine, and ascorbate in single gland disease, however this was not observed in MGD (145). The fact that choline and choline derivatives were selected for MRI spectroscopic analysis supports the use of these agents in molecular imaging techniques, such as choline PET discussed in detail later.

In the standard of care today, MRI is primarily used as a second line modality for problem solving, however 4DMRI could be a modality of choice for localization of PA in patients with MGD or in similar utility as 4DCT while avoiding radiation dose.

In the future, ¹⁸F-fluorocholine (FCH) PET could augment dynamic structural imaging. Huber et al. found that ¹⁸F-FCH PET/CT or PET/MRI was able to achieve 96.2% accuracy in detection of PA in 25/26 patients (146). One study found that ¹⁸F-FCH PET/MRI was even capable of detecting cystic adenomas with comparably lower tracer uptake (147).

Selective catheterization of the parathyroid drainage pathways allows performance of selective venous sampling (SVS) for localization of PTH secretion (148). This invasive technique was originally developed for patients with recurrent or persistent primary HP following surgery. For successful application of this technique, one must know the thyroid vein anatomy to choose sampling points in the internal jugular and brachiocephalic veins to access the thyroid veins and venous anastomoses. This approach is however limited for assessment of PTH from ectopic PA in the neck or chest due to differences in venous drainage.

A randomized controlled clinical trial evaluated the use of intraoperative Indocyanine green (ICG) parathyroid gland angiography (149). The results suggested that ICG reliably illustrated vascularization of the parathyroid glands. The authors suggested this decreased the need for postoperative measurement of calcium and PTH and that patients with at least one well perfused parathyroid gland did not require calcium supplementation. A recent literature review also suggested this method was effective in reducing postoperative hypoparathyroidism (150) [ Figure 11 (150)].

Intraoperative localization of parathyroid tissue using ^99mTc-sestamibi has been explored and is also termed ‘radioguided surgery’ or ‘minimally invasive radioguided parathyroidectomy’. Buicko et al. found that the gamma probe was a useful tool to complement a localization study, particularly in patients with multiple ectopic adenomas or with history of prior parathyroid surgery (151). In a large study of 769 patients with primary HP undergoing radioguided parathyroidectomy using a handheld gamma probe, Chen et al. reported that radioguided techniques were equally effective between patients with negative and positive imaging exams and that the gamma probe allowed detection of all abnormal parathyroid glands, including those that were ectopic (152). The authors suggested a potential benefit in patients with negative preoperative sestamibi scans. Lim et al. recently suggested fewer false positives with intraoperative guidance by a radionuclide probe and reduced operative failure compared to intraoperative parathyroid hormone (IOPTH) measurement in a retrospective cohort of 298 patients (153).

Ultrasound and ^99mTc-sestamibi scintigraphy are complementary as the first line of imaging.

There are a couple of controversial studies claiming the sufficiency of ultrasound prior to surgery with the conclusion that it is unnecessary to perform both ultrasound and ^99mTc-sestamibi since the latter did not significantly increase diagnostic accuracy (116). One limitation of this study was that it compared the use of planar scintigraphy alone, whereas most nuclear medicine departments today routinely perform SPECT in assessment of primary HP as the standard of care. The other consideration is the design; this study had a single operator during 16 years of the study, meaning it is more representative of the accuracy of that single sonographer rather than the accuracy of ultrasonography, which is known to be subject to high inter-operator variability (68, 154). Apparently, the claims of 90% sensitivity of ultrasonography reported in the literature are highly unlikely, even if by consideration of the high frequency of ectopic parathyroid adenoma alone (155).

Cost and radiation exposure are concerns of any multiphasic CT. 4DCT cost was reported at $1296 compared to $1112 for ^99mTc-sestamibi scintigraphy, which can vary more widely based on the radiotracer costs among other factors (156).

Radiation dose of 4DCT is reported to range from 5.56-28 mSv (median 9.3 mSv), typically more than ^99mTc-sestamibi planar and SPECT scintigraphy at 3.33-5.6 mSv, but similar to or less than ^99mTc-sestamibi SPECT/CT, which is reportedly 12.4 mSv (134, 157), depending on the dose of ^99mTc-sestamibi and CT parameters used. We remind the reader however that the radiation dose to the thyroid is reported to be 57 times higher with 4DCT compared to scintigraphy (120), although this will vary by equipment and specific institutional protocols.

Comparative effectiveness of 4DCT relative to other parathyroid disease imaging techniques is an area of considerable debate with various protocols explored in the literature (158–161). Investigations on comparative effectiveness for detection of parathyroid adenoma must be carefully and critically evaluated for experimental design in order to better understand the meaning of the results.

To objectively compare the accuracy of ultrasound, sestamibi, and 4DCT, Kedarisetty et al. evaluated 58 patients and found the accuracy of 4DCT was not significantly different compared to ^99mTc-sestamibi SPECT/CT (162). Although 4DCT did find 3 true positives that were initially false negatives, this was not sufficient to raise the sensitivity, specificity, or accuracy enough to be statistically significant. They found 4DCT was useful for localizing ectopic glands occurring in the mediastinum, thymus, tracheoesophageal groove, and retrosternal space, but was less helpful in the setting of multigland disease (MGD). These findings were consistent with other reports that 4DCT can be less accurate in diagnosis of smaller lesions and cases with multiple culprit lesions. They encouraged the main utility of 4DCT is in the setting of negative ^99mTc-sestamibi SPECT/CT. In 28 patients where 4DCT was performed out of 1485 total adult patients in their retrospective cohort study, Broome et al. suggested 4DCT performed better than 99Tc-sestamibi SPECT in single adenomas and better than other modalities investigated for MGD and double parathyroid adenoma (163). These findings were however underpowered and compared 4DCT to SPECT rather than SPECT/CT.

The EANM 2021 practice guidelines (164) suggest 4DCT has similar diagnostic performance compared to ^99mTc-sestamibi SPECT based on meta-analysis (165), however acknowledges protocols vary among institutions and the referenced meta-analysis suggested cervical ultrasound and ^99mTc-sestamibi SPECT or SPECT/CT as first line approaches.

PET imaging has improved sensitivity and spatial resolution over SPECT imaging. PET provides better accuracy and clearer images with faster acquisition compared to SPECT (166). Several molecular tracers are currently being evaluated for PET imaging of the parathyroid.

Although earlier work in PET imaging for patients with primary HP suggested ¹¹C-methionine as a promising agent, more recent studies have focused on choline due to its increased accuracy (167). ¹¹C-choline and ¹⁸F-fluorocholine (FCH) have been reported useful in imaging parathyroid hyperplasia and adenomas. ¹¹C requires an on-site cyclotron having only a 20 min half-life. Therefore ¹⁸F-FCH is a more practical PET tracer for potential commercial use.

The major pitfall of choline is that it traces general neoplastic processes and is not a targeted biomarker of parathyroid disease. Uptake of choline in neoplastic cells is felt to be due to the increased demand for phospholipid synthesis in cells with a high proliferative rate (168). In benign parathyroid adenomas, it has been postulated that increased lipid-dependent choline kinase activity due to PTH hypersecretion may account for increased choline uptake (169). ¹⁸F-FCH PET is also present in brown tumors [ Figure 12 (170, 171)].

¹⁸F-FCH PET/MRI may provide improved structural characterization of parathyroid lesions, particularly in pediatric patients and in more challenging/subtle cases such as secondary hyperparathyroidism (182–184) [ Figure 13 (184)]. Two recent articles supported improved accuracy of ¹⁸F-FCH PET/MRI in detection of PA in a cohort of 98 patients and an expanded cohort of 101 patients (180, 185). The authors reported that ¹⁸F-FCH PET/MRI was more successful in guiding curative surgery (83%) compared to ultrasound (35%) and ^99mTc-sestamibi (24%).

Use of dual time point PET and dynamic PET have also been initially explored (186–188). Total Body PET has been reported to be a promising approach to dramatically improve the temporal resolution of dynamic PET imaging (189, 190).

¹⁸F-Flurpiridaz is derived from the insecticide pyridaben, an analog of rotenone. ¹⁸F-Flurpiridaz is a lipophilic antagonist of mitochondrial complex I (NADH:ubiquinone oxidoreductase) competing for the ubiquinone binding site at the inner mitochondrial membrane. As ¹⁸F-Flurpiridaz’s efflux half-time from the mitochondria is greater than the half-life of the ¹⁸F isotope any potential imaging impact of redistribution is minimized (166, 191–196). ¹⁸F-flurpiridaz (¹⁸F-BMS, ¹⁸F-BMS-747158-02) is under phase 3 clinical investigation for myocardial perfusion imaging. ¹⁸F-flurpiridaz has shown promise in imaging mitochondria in other organs, such as liver (197), and has the potential to become an important parathyroid imaging agent (166). The agent is promising because it targets mitochondria similar to ^99mTc-sestamibi, the current molecular imaging standard of care, due to the high mitochondria content of the parathyroid. In a study of 132 patients comparing ¹⁸F-flurpiridaz PET to ^99mTc-sestamibi SPECT in myocardial perfusion, ¹⁸F-flurpiridaz PET was consistently rated to provide improved image quality and approximately 3-fold diagnostic certainty (198). It is hoped that the same could hold true in parathyroid imaging.

¹⁸F-(4-Fluorophenyl)triphenylphosphonium is another agent originally investigated in nuclear cardiology that could be explored. It traces mitochondria on a similar principle to sestamibi as a lipophilic cation that is trapped due to the high mitochondria membrane potential (199).

Several issues remain areas of investigation that deserve more exploration in future research.

Multigland disease (MGD) includes multiple PA or hyperplasia. MGD is challenging and can be susceptible to satisfaction of search. MGD occurs in 15-20% of cases and should not be thought of as rare. The trend toward minimally invasive parathyroidectomy can contribute to missed MGD. In cases of suspected MGD not identified by standard imaging techniques, open neck exploration is and will be the standard of care.

Ectopic glands or recurrence in unusual regions remains a clinical challenge. In the pericardial region, ectopic PA can occur, but are difficult to localize due to cardiac activity for instance. Although issues such as these are rare, they do occur and continue to pose a diagnostic challenge.

The Achilles heel of current parathyroid imaging techniques is that none of the current methods of diagnostic imaging for PA are precisely targeted to disease biology. On dynamic imaging, wash in and wash out characteristics vary. ^99mTc-sestamibi was not designed for PA imaging and thyroid nodules or malignancy can be confounding.

A targeted agent specific for a parathyroid tissue biomarker is awaited.