Selective venous sampling (SVS) was introduced for localization of hyperfunctioning parathyroid glands in 1969 by Reitz and colleagues [13]. Results from studies evaluating the accuracy of this invasive technique have not been consistent. The range of positive predictive results has varied from 39 to 93 % [12, 14]. Most studies have been retrospective and have not included direct comparison with other techniques. Some of the differences in outcome are explained by selection bias (selected patients only or up to 100 % of patients included having single adenoma disease with exclusion of multiglandular disease). Schalin-Jäntti and colleagues prospectively compared the performance of SVS, planar scintigraphy with ¹²³I/^99mTc-sestamibi, ^99mTc-sestamibi SPECT/CT, and ¹¹C-methionine PET/CT in PHPT patients scheduled for reoperation and found that SVS was the least accurate technique with a high proportion of false predictive findings [11].

As introduced by Coakley et al. in 1989, ^{99mTc-sestamibi} scintigraphy has gained great popularity. Worldwide, this is probably the imaging modality used most often before primary surgery of PHPT [15]. Uptake of ^99mTc-sestamibi is, however, not tissue-specific but is sequestered within mitochondria both in the thyroid and parathyroid tissue, as well as in the salivary glands and normal cardiac cells [16]. Imaging using the single-tracer technique is based on the different washout kinetics for thyroid and parathyroid tissue. While maximum thyroid gland activity is reached within 5 min, parathyroid activity is sustained with delayed washout, which allows for parathyroid imaging two hours after the injection [16]. Thyroid nodules may have a prolonged washout and thus cause false-positive findings when using the single-tracer technique.

^99mTc-sestamibi can also be used in combination with iodine-123 (¹²³I) or technetium-99 m pertechnetate (^99mTcO4⁻), which are thyroid-specific isotopes. In this dual-isotope technique, the thyroid image is digitally subtracted from the ^99mTc-sestamibi image and thus allows for the visualization of parathyroid tissue alone (Figs. 14.1 and 14.2). The EANM guidelines recommend the use of an additional thyroid-specific isotope over ^99mTc-sestamibi imaging alone [17].

SPECT and SPECT/CT have gained much popularity for acquisition of abnormal parathyroid glands [18]. The combination of SPECT with CT allows for better anatomical identification of the abnormal gland. SPECT and SPECT/CT can also be performed either in combination with the single-isotope or dual-isotope method (Fig. 14.3). Using the single-isotope technique, Lavely and colleagues concluded that early SPECT/CT in combination with any delayed imaging performs better than planar scintigraphy or SPECT alone [19]. Tunninen et al. compared five parathyroid scintigraphic protocols in patients with primary or secondary hyperparathyroidism, including three scintigraphic protocols with dual-isotope (parallel-hole planar, pinhole planar, and SPECT/CT) and two with single-isotope (double-phase parallel-hole planar and SPECT/CT) and concluded that any dual-isotope protocol performs better than the single-isotope protocols [20].

A recent large retrospective study comparing the performance of dual- versus single-isotope ^99mTc-sestamibi before primary surgery of PHPT demonstrated that dual-isotope ^99mTc-sestamibi scintigraphy was significantly more accurate than ^99mTc-sestamibi alone, with accuracies of 63.4 and 34.9 %, respectively [10]. Figure 14.2 demonstrates the ¹²³I/^99mTc-sestamibi scintigraphy findings in a patient with PHPT; while ^{99mTc-sestamibi} imaging at 5 min and 2 h remained negative, subtraction imaging revealed an abnormal uptake in the left inferior parathyroid gland, compatible with a parathyroid adenoma.

¹¹C-methionine PET/CT has good specificity for hyperfunctioning parathyroid compared to surrounding head and neck tissue [21]. The use of ¹¹C-methionine PET has since been suggested for difficult cases of PHPT, with negative imaging results on conventional imaging [22–25]. ¹¹C-methionine PET is not available in all centers and the complicated labeling procedure may be regarded as a limitation. A prospective study comparing the accuracy of five different localization techniques (planar scintigraphy with ¹²³I/^99mTc-sestamibi, ^{99mTc-sestamibi} SPECT/CT, SVS, and ¹¹C-methionine PET/CT) in complicated PHPT recommended planar scintigraphy with ¹²³I/^99mTc-sestamibi as first-line imaging before reoperation and concluded that ¹¹C-methionine PET/CT provides additional information if ¹²³I/^99mTc-sestamibi scintigraphy remains negative [11]. Figure 14.4 demonstrates a case in whom an ectopically located parathyroid adenoma was located with ¹¹C-methionine PET/CT before reoperation.

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