Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism

INTRODUCTION — Primary hyperparathyroidism is usually caused by a solitary benign adenoma (80 to 85 percent) but can also be due to double adenomata (2 to 5 percent), diffuse or nodular hyperplasia (10 to 15 percent), or parathyroid carcinoma (<1 percent) [1]. An open four-gland parathyroid exploration has traditionally been considered the gold standard for patients undergoing surgery for primary hyperparathyroidism. However, a more focused, minimally invasive approach to parathyroid surgery has been adopted at many centers [2,3].

Localization techniques are primarily used in patients who have biochemically confirmed sporadic primary hyperparathyroidism to identify patients who are candidates for a minimally invasive approach. They are also important in patients who have persistent or recurrent disease, or who have had prior cervical exploration and require remedial surgery. Patients with hereditary primary hyperparathyroidism generally undergo bilateral parathyroid exploration, even in the event of a positive localizing study, because of the high likelihood of multiglandular disease. Localization studies, in conjunction with intraoperative parathyroid hormone testing, can help minimize the extent of surgical dissection, identify concurrent thyroid pathology, and detect ectopic parathyroid tissue, the latter being a particular advantage for patients who had prior failed parathyroid exploration. However, localization studies should not be used to diagnose or confirm the diagnosis of primary hyperparathyroidism or determine the need for surgery. Use of localization studies does not override the recommendation that parathyroid surgery should only be performed by highly experienced surgeons [2,4].

The techniques and role of preoperative localization in patients with primary hyperparathyroidism will be reviewed here. Decision making regarding the role of surgical therapy, the details of surgical management in these patients, and the role of surgery for secondary hyperparathyroidism in patients with end-stage kidney disease are discussed elsewhere. (See "Refractory hyperparathyroidism and indications for parathyroidectomy in adult patients on dialysis" and "Parathyroid exploration for primary hyperparathyroidism", section on 'Focused parathyroid exploration' and "Primary hyperparathyroidism: Management", section on 'Candidates for surgery'.)

ROLE OF PREOPERATIVE LOCALIZATION — The diagnosis of primary hyperparathyroidism should be made based upon biochemical findings. Imaging studies are not used as a diagnostic tool, because of high false-positive rates, which can range from 5 to 25 percent (table 1). In addition, a single-focus positive imaging result does not reliably exclude the presence of multiglandular parathyroid disease [5]. Rather, preoperative localization studies help plan the operative approach in patients who have a biochemically confirmed diagnosis of primary hyperparathyroidism, and in whom other pathologies have been appropriately ruled out (eg, familial hypocalciuric hypercalcemia). For patients undergoing initial surgery, these studies are predominantly used to determine whether or not a patient is a candidate for a minimally invasive approach [6-8]. Parathyroid localization techniques are generally less successful in normocalcemic primary hyperparathyroidism than in hypercalcemic disease [9]. This may be due to a greater incidence of multiglandular disease and smaller adenoma size in normocalcemic patients. (See "Parathyroid hormone assays and their clinical use".)

Available radiologic expertise is an important factor in choosing the type of localization testing to be performed. Localization images should be displayed and available intraoperatively since review during exploration often usefully guides successful surgery. (See 'Imaging modalities' below.)

Minimally invasive and unilateral parathyroidectomy — Preoperative localization reduces operative time in unilateral parathyroid surgery and is required if a minimally invasive procedure is contemplated [10-12]. The success of a minimally invasive approach is dependent upon accurate imaging results, which aid in limiting the dissection to the region where the adenoma has been localized. For every parathyroid operation, the goal is cure of the biochemical condition, and, thus, intraoperative parathyroid hormone (PTH) assay should be used to confirm success of the operation by demonstrating a substantial drop in parathyroid hormone level [13-15]. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Intraoperative assessment' and "Intraoperative parathyroid hormone assays".)

Reoperation for recurrent or persistent hyperparathyroidism — Two to 10 percent of patients undergoing surgery for hyperparathyroidism have recurrent or persistent disease, and the likelihood of failed surgery is dependent on the length of postoperative follow-up and surgeon volume [16,17]. In such cases, the diagnosis of primary hyperparathyroidism should be confirmed biochemically, and indications for surgery should be reevaluated. Accurate localization studies are mandatory in patients undergoing reoperative surgery. Because of fibrosis from the previous surgery and alterations in parathyroid gland location, the rate of complications, such as recurrent laryngeal nerve injury, permanent hypoparathyroidism, and persistent disease, is typically higher [18,19].

At least one preoperative imaging study should localize hyperfunctional parathyroid tissue before proceeding with re-exploration and may include sestamibi scan, sestamibi with single-photon emission computed tomography (SPECT), ultrasound, and/or four-dimensional computed tomography (4D-CT) [2,20,21]. The success rate of reoperative surgery without preoperative localization is only 60 percent. Several observational studies have reported success rates of 95 percent or more with positive preoperative localization before reoperation [18,22,23]. Almost 30 percent of patients undergoing reoperation have multiple gland disease. Thus, localization studies identifying an apparent single adenoma do not exclude the existence of abnormal parathyroid glands in other locations.

The best imaging study or combination of studies for persistent disease has not been determined. In most reports assessing different imaging modalities, SPECT/CT often is the first imaging study utilized in the reoperative setting and can detect 60 to 80 percent of the abnormal glands [24,25]. A study of 90 patients who required reoperative surgery reported high postoperative cure rates but shorter operative times when 4D-CT was used for preoperative localization [26].

Ultrasound- or CT-guided fine needle aspiration of suspicious lesions for PTH assay can be performed to confirm that the lesion is parathyroid tissue [27,28]. In a study of 44 patients, fine needle aspiration with PTH assay had a specificity and sensitivity of 100 and 70 percent, respectively [28]. Fine needle aspiration should not be performed if the diagnosis of parathyroid cancer is considered likely, as seeding of the cancer is a potential complication [2]. Selective arterial or venous angiography is usually the next localization modality used if multiple noninvasive imaging techniques fail to identify an abnormality [29-31].

Algorithms for the evaluation of patients undergoing reoperation have been developed (figure 1) [32,33]. These algorithms, which are based upon clinical experience, suggest performing two noninvasive procedures prior to reoperation, one of which should be sestamibi imaging. The other is often ultrasonography, but choice is dictated by available expertise. If the results of these studies are concordant, surgery is performed. If the results are discordant or inconclusive, the next step depends upon the expertise of the referral center and may include either surgery with intraoperative monitoring of PTH or additional testing [32,33]. Further testing includes additional imaging (CT, MRI) or possible invasive procedures (selective venous sampling). Several observational studies showed that this approach allowed the identification of the offending parathyroid gland or glands in 92 to 97 percent of reoperated cases [23,32,33].

Bilateral neck exploration — Bilateral parathyroid exploration should be planned when imaging studies are negative or show more than one focus of activity, in cases of secondary or tertiary hyperparathyroidism, suspected hereditary etiology, or when concurrent thyroid pathology is present and warrants surgery. Bilateral exploration should also be considered for male patients under the age of 30 years because of the increased incidence of multiple endocrine neoplasia in these patients [34]. In the hands of experienced surgeons, bilateral exploration has a high cure rate and low morbidity [35-39]. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Bilateral parathyroid exploration'.)

IMAGING MODALITIES — As mentioned above, imaging studies are obtained only after biochemical confirmation of primary hyperparathyroidism and are used predominantly to help plan the operative approach [40]. (See 'Role of preoperative localization' above.)

Sestamibi scintigraphy (technetium-99-sestamibi scanning) combined with sestamibi single photon emission computed tomography (SPECT) has the highest positive predictive value of the available imaging techniques, and some prefer this as the localizing procedure of choice for initial surgery [3,41,42]. However, SPECT is not available at all centers, and some use planar sestamibi as the initial localizing study. Additional complementary techniques are needed for patients with persistent/recurrent disease or inconclusive results on sestamibi or SPECT scanning. Imaging modalities that have also been used successfully include ultrasound, SPECT combined with computed tomography (MIBI-SPECT-CT fusion), four-dimensional computed tomography (4D-CT), and 11C-methionine positron emission tomography (PET) combined with CT [29,41,43-48]. The utility of these tests is discussed in the following sections. The sensitivity and positive predictive value of the imaging modalities are summarized in the table (table 1).

Sestamibi scintigraphy — Technetium-99m-methoxyisobutylisonitrile (99mTc-sestamibi or MIBI) was first used for cardiac scintigraphy and was noted to concentrate in parathyroid adenomas. 99mTc-sestamibi is taken up by the mitochondria in thyroid and parathyroid tissue; however, the radiotracer is retained by the mitochondria-rich oxyphil cells in parathyroid glands longer than in thyroid tissue [49]. Planar images are typically obtained shortly after injection of 99mTc-sestamibi and again at approximately two hours to identify foci of retained radiotracer activity consistent with hyperfunctioning parathyroid tissue. Sestamibi scintigraphy alone provides limited anatomic detail.

A negative 99mTc sestamibi scan does not negate the diagnosis of primary hyperparathyroidism, since it occurs in 12 to 25 percent of patients with disease [50,51]. Sestamibi scanning is often unrevealing, or misleading, in patients with parathyroid hyperplasia, multiple parathyroid adenomas, and coexisting thyroid disease [10,52-58]. Thyroid disease requiring surgery significantly increases both the false positive and false negative rate of sestamibi scanning [59]. Falsely negative scans can also be caused by calcium channel blockers that interfere with the uptake of the isotope by parathyroid cells [56]. Other gland characteristics that can increase the likelihood of a negative scan include small size, superior position, and a paucity of oxyphil cells [57,58].

Sestamibi scanning for parathyroid tissue can be enhanced by combination with three-dimensional imaging (SPECT), a subtraction thyroid scan, or fusion with computed tomography images (MIBI-SPECT-CT) [52,60,61]. These are discussed below.

SPECT — Sestamibi-single photon emission computed tomography (SPECT or MIBI-SPECT) is a three-dimensional sestamibi scan that provides higher-resolution imaging and improves the performance of sestamibi scanning (image 1). The multidimensional images illustrate the depth of the parathyroid gland or glands in relation to the thyroid and improve detection of ectopic glands, which facilitates minimally invasive parathyroidectomy [55,60,62,63].

In single-institution comparison studies utilizing a variety of imaging protocols, the addition of SPECT improves the sensitivity for identifying abnormal parathyroid glands to 92 to 98 percent as compared with 71 to 79 percent for planar sestamibi scintigraphy [52,55,60,62,63]. As an example, in a prospective study of 338 patients with primary hyperparathyroidism, SPECT imaging successfully detected 96 percent of solitary adenomas and 83 percent of double adenomas [52]. However, only 45 percent of multiglandular hyperplasias were detected.

SPECT imaging substantially reduces the likelihood of missing multiglandular disease compared with planar imaging [5,64]. However, even with imaging showing a clear, bright focus of increased uptake, multiglandular disease is still a possibility [5,50,52,64]. Because SPECT imaging has a high rate (7 to 16 percent) [5,65,66] of missed multiglandular disease, a validated adjunct to exclude multiglandular disease such as intraoperative parathyroid hormone monitoring or four-gland parathyroid exploration should be routinely utilized.

SPECT and CT fusion — SPECT-CT adds the ability to discriminate parathyroid adenomas from other anatomic landmarks, which may facilitate the surgical procedure [43,61,64,67]. In a single-institution retrospective and observational study of 1388 patients who underwent parathyroid exploration for primary hyperparathyroidism, SPECT-CT had greater accuracy for both single-gland disease (83 versus 77 percent) and multigland disease (36 versus 22 percent) than SPECT alone. The negative imaging rates were similar between the two imaging cohorts (about 10 percent) [68].

Subtraction thyroid scan — Even with the addition of SPECT, distinguishing abnormal parathyroid glands from thyroid pathology can be difficult. If necessary, a subtraction thyroid scan can be obtained by using two radiotracers (dual isotope scintigraphy). The use of technetium plus a second radiotracer such as 123I or 99mTc pertechnetate (thallium) permits selective imaging of the thyroid gland.

Ultrasound — Neck ultrasonography (US) is also often utilized for parathyroid localization (image 2). Sonographic characteristics of parathyroid adenomas include homogeneous hypoechogenicity and an extrathyroidal feeding vessel with peripheral vascularity seen on color Doppler imaging (image 3).

US is highly sensitive in experienced hands and is inexpensive, noninvasive, and reproducible in the operating room. In reoperative cases, intraoperative US can be used to localize the adenoma and facilitate surgery in a previously dissected and scarred field. However, the accuracy of ultrasound is operator dependent as the sensitivity of ultrasound for detecting enlarged parathyroid glands ranges from 72 to 89 percent [47,69-71]. It is advantageous for experienced endocrine surgeons to learn to perform neck ultrasound [65], and studies have shown comparable sensitivity for localizing parathyroid adenomas compared to radiologist-performed ultrasound (77 to 87 percent) [65,72].

As with sestamibi-based techniques, the sensitivity of ultrasound for parathyroid adenoma localization is reduced in patients with thyroid nodules [73]. However, US is helpful for the characterization and evaluation of any thyroid pathology, facilitating operative planning. This is a common problem since concurrent thyroid pathology is present in 20 to 30 percent of patients with primary hyperparathyroidism [74]. Concurrent thyroid disease should be addressed preoperatively (eg, with fine needle aspiration) and/or intraoperatively (eg, with concurrent thyroidectomy). In addition, US-directed fine needle aspiration biopsy with analysis of parathyroid hormone (PTH) levels can be helpful for confirming suspected parathyroid lesions such as intrathyroidal adenomas or cysts [27,28].

Most experts in parathyroid surgery rely on both US and SPECT for preoperative localization, although this varies by geography and institutional expertise [15,75,76]. Combining 99mTc-sestamibi scintigraphy with neck ultrasound provides high sensitivity (79 to 95 percent) for predicting the location of a single parathyroid adenoma [63,64,77]. Sonography provides additional anatomic information about the thyroid gland that could alter surgical management [78,79]. In a cost analysis study, initial ultrasound is the most cost-effective imaging modality, followed by 4D-CT [80]. No imaging technique, even in combination, accurately predicts multiglandular disease, and a bilateral neck exploration should be strongly considered when the studies are discordant, equivocal, or negative [52,81].

Disadvantages to the use of US alone include decreased accuracy in patients with smaller parathyroid gland size, obesity, or mediastinal glands located behind the clavicles [82].

Four-dimensional computed tomography — Four-dimensional computed tomography (4D-CT) scans take advantage of the rapid contrast uptake and washout that is characteristic of parathyroid adenomas for precise anatomic localization (image 4). The primary disadvantage of 4D-CT is the radiation exposure, which, compared with sestamibi imaging, results in a >50-fold higher dose of radiation absorbed by the thyroid. The additional radiation leads to an age-dependent higher risk of developing thyroid cancer; hence, the use of 4D-CT should be highly selective in younger patients [83]. Most protocols include noncontrast images followed by additional acquisitions (up to three) after contrast injection. However, protocols vary by center, and some utilize fewer acquisitions to limit the radiation exposure. In a meta-analysis inclusive of 34 published studies that evaluated CT imaging for parathyroid adenoma localization using a wide variety of protocols, each additional imaging acquisition resulted in a marginal increase in the pooled sensitivity for abnormal gland lateralization (sensitivity of single phase, 71 percent; two phase, 76 percent; three phase, 80 percent) [84].

4D-CT is particularly useful in the reoperative setting when initial imaging with sestamibi is negative. In a study of 45 patients who had undergone previous neck exploration, 4D-CT had 88 percent sensitivity for abnormal parathyroid glands compared with sestamibi SPECT or neck US (54 and 21 percent, respectively) [85].

Magnetic resonance imaging — Parathyroid adenoma characteristics on magnetic resonance imaging (MRI) include intermediate to low signal intensity on T1 imaging and high intensity on T2 imaging. Cervical lymph nodes can also have similar imaging characteristics, which limits the accuracy of MRI.

For reoperative surgery, MRI may provide a useful noninvasive imaging modality to localize abnormal parathyroid tissue and does not require iodinated contrast or exposure to ionizing radiation [86,87]. The reported sensitivity of MRI for abnormal parathyroid tissue ranges from 40 to 85 percent [40,88,89].

Positron emission tomography and CT — The combination of 11C-methionine positron emission tomography and computed tomography (MET-PET-CT) uses 11C-methionine as a radiotracer to identify pathologic parathyroid glands [90-92].

●A prospective study that included 102 patients undergoing a parathyroidectomy for primary hyperparathyroidism found that MET-PET-CT scan correctly located a single-gland adenoma in 83 of 97 patients (86 percent), with a positive predictive value of 93 percent [93].

●In a small single-institution series, MET-PET-CT has also been described as a useful option for patients who need reoperative surgery but have initial negative imaging [94].

In Europe and some selected centers, 18-fluorocholine-PET-CT has been used successfully and accurately to localize parathyroid adenomas. However, this technique is not widely adopted as the nuclear radiotracer is not commercially available and needs to be synthesized locally [6].

●In a 2019 systematic review, it had a sensitivity of 80 to 100 percent and a specificity of 95 to 100 percent [95].

●In a single US institution study of 58 patients undergoing initial parathyroid exploration with six-month cure, 18f-fluorocholine-PET findings were associated with the highest likelihood of cure (83 percent) compared with sestamibi (28 percent) or ultrasound (37 percent) [96].

●A meta-analysis comparing 18-fluorocholine PET with 99mTc in identifying abnormal parathyroid glands in primary hyperparathyroidism demonstrated higher sensitivity for the former (97 percent, range 94 to 100) than the latter (55 percent, range 32 to 78) [97]. The results were confounded by significant heterogeneity in imaging techniques for both nuclear radiotracers but particularly notable in the 99mTc studies.

Invasive localization — Invasive procedures, such as selective venous sampling or selective arteriography, are reserved for patients who have had prior neck surgery and require reoperative surgery, in whom noninvasive testing has been unrevealing. Risks associated with invasive localization procedures include groin hematoma, anaphylaxis from the iodinated contrast, contrast-induced acute renal failure, and stroke. They are also expensive and require an experienced interventional radiologist to perform. Because of improvements in scanning and ultrasonography, as noted above, the need for invasive testing has declined substantially.

Selective venous sampling — Selective venous sampling is the most common invasive modality used for parathyroid localization. A 1.5- to 2-fold increase in parathyroid hormone levels obtained from representative cervical vein drainage locations (inferior, middle, superior thyroid, thymic, and/or vertebral veins) compared with a peripheral location is considered an abnormal elevation. Selective venous sampling can identify hyperfunctioning parathyroid tissue when all other imaging modalities are negative [71,98].

Selective arteriography — Selective arteriography is performed by combining selective transarterial hypocalcemic stimulation with nonselective venous sampling. Baseline and timed superior vena cava samplings are taken after injection with sodium citrate to induce hypocalcemia while simultaneous arteriography is performed. A positive localization is considered an increase in the parathyroid hormone level to 1.4 times the baseline or a blush seen on arteriography [71].

NEGATIVE IMAGING — Nonlocalizing imaging studies should not preclude initial surgery for patients with biochemically confirmed primary hyperparathyroidism who meet operative criteria. In such patients, a single adenoma is still the most likely intraoperative finding (62 to 77 percent); however, multiglandular disease is more common than is typical in patients with primary hyperparathyroidism (20 to 38 percent) [56,57]. These patients require bilateral exploration by an experienced parathyroid surgeon and the use of intraoperative parathyroid hormone monitoring [51,99]. When compared to patients with localized studies, equivalent long-term biochemical cure rates can be achieved, although more extensive surgery may be needed [56,71]. (See "Parathyroid exploration for primary hyperparathyroidism".)

It should also be mentioned that if initial imaging is negative at a medical facility that does not commonly perform parathyroid imaging, referral to a high-volume center should be considered. Sensitivity of localization has been reported to increase to as high as 92 percent in higher-volume centers [48].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parathyroid surgery".)

SUMMARY AND RECOMMENDATIONS

●Role of preoperative localization – Results of localization studies, interpreted in conjunction with intraoperative parathyroid hormone testing, can guide incision placement, minimize the extent of surgical dissection, and locate ectopic parathyroid tissue. The latter is particularly helpful in patients with recurrent or persistent hyperparathyroidism. (See 'Minimally invasive and unilateral parathyroidectomy' above.)

Localization studies do not confirm the diagnosis of primary hyperparathyroidism when positive or rule out the diagnosis when negative. The diagnosis of primary hyperparathyroidism should be based upon biochemical evaluation. Localization studies do not reliably exclude multiglandular parathyroid disease and should not be used to select patients for surgery. (See 'Introduction' above.)

●Initial parathyroidectomy – For initial minimally invasive surgery, the preferred localizing imaging studies include sestamibi scintigraphy (MIBI-SPECT imaging), ultrasound, and/or four-dimensional computed tomography (4D-CT). The type and number of studies ordered preoperatively are influenced by institutional and geographical expertise, as well as other clinical considerations. Additional complementary techniques are sometimes needed for patients with persistent/recurrent disease. (See 'Imaging modalities' above.)

●Reoperative parathyroidectomy – For all patients undergoing reoperation, we recommend performing preoperative localization (Grade 1B). We suggest obtaining at least two imaging studies to assure concordance under these circumstances (Grade 2C). (See 'Reoperation for recurrent or persistent hyperparathyroidism' above.)