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Address reprint requests and correspondence: David L. Steward, MD, Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati Medical Center, ML 0528, Cincinnati, OH 45239.
Parathyroid localization is an essential component in the surgical management of hyperparathyroidism (HPT). Using preoperative imaging improves localization and allows focused single-gland surgery in many cases of sporadic primary HPT. In this article, we describe the most commonly used types of parathyroid imaging and their role in the preoperative imaging of patients with HPT. Ultrasound is an excellent first-line test that provides high-resolution real-time images with minimal cost and time and no radiation exposure. It also allows evaluation of concomitant nodular thyroid disease but is limited by ectopic glands in the chest and is operator dependent. Nuclear imaging is effective in localizing enlarged parathyroid glands, including ectopic mediastinal glands, but is more expensive, is time consuming, involves radiation, may be less sensitive for small adenomas, and gives less anatomical detail unless paired with computed tomography. Parathyroid protocol multiphase scans are sensitive and less operator dependent but require more radiation.
Hyperparathyroidism is a common endocrine disorder caused by elevated secretion of parathyroid hormone (PTH) and presents in primary, secondary, and tertiary forms. Primary hyperparathyroidism (HPT) affects approximately 1 in 700 people and occurs owing to unregulated overproduction of PTH, causing a secondary hypercalcemia. It is most commonly sporadic in nature and is most often caused by a single adenoma (~90%); however, it can also happen because of multigland disease in approximately 10% of patients. Hereditary primary HPT is less common but is clinically important, as it is most often a multigland disease. Important examples are the multiple endocrine neoplasia syndromes: MEN 1, which is associated with multigland (often supernumerary) hyperplasia, and MEN 2a, which is often associated with multiple adenomas. Parathyroid surgery for sporadic primary HPT is associated with a greater than 95% success rate in experienced hands.
Traditional surgery consisted of bilateral exploration of the 4 glands; however, focused single-gland excision has comparable cure rates in well-localized cases, with decreased morbidity, including lower rates of both recurrent laryngeal nerve (RLN) injury and hypocalcemia, and shorter operative time.
In this focused paradigm, preoperative imaging is essential to localize the suspected adenoma or conversely to raise suspicion for multigland disease before surgery.
Secondary HPT occurs owing to overproduction of PTH secondary to an abnormal stimulus, such as chronic renal disease, vitamin D deficiency, or gastrointestinal malabsorption. Medical management is the mainstay of therapy in these patients. Patients with chronic renal failure present with low to normal calcium level and an elevated PTH, with accompanying hyperphosphatemia, renal osteodystrophy, and impaired vitamin D production. Parathyroid imaging is performed to determine if the parathyroid glands are in their orthotopic or ectopic locations before surgical treatment in severe secondary HPT with chronic renal failure.
Tertiary HPT occurs because of excessive PTH production and the resultant hypercalcemia owing to long-term secondary HPT, usually seen after renal transplantation, when previously hypertrophied parathyroid glands remain enlarged and hyperfunctional despite resolution of the renal failure. Parathyroid imaging is helpful in delineating surgical anatomy and presence of orthotopic or ectopic parathyroid glands or both. We describe the indications and the use of imaging in parathyroid disease with a focus on sporadic primary HPT.
Parathyroid anatomy
Any discussion of parathyroid imaging must begin with a review of embryology and anatomy. Most humans have 4 parathyroid glands, with 2 paired superior and 2 inferior glands. Supernumerary glands are found in approximately 13% of patients, whereas fewer than 4 glands are also found in approximately 3% of patients, indicating that the surgeon must always consider the presence of 5 glands in surgical planning, especially for hereditary cases.
The inferior glands arise from the third branchial pouch with the thymus and are pulled inferiorly as they migrate during the embryologic development. Owing to their longer migration, they are more variable in location than superior glands but are generally found along the inferior pole of the thyroid gland near the inferior thyroid artery, which is the most common blood supply for the inferior glands. Ectopic locations for inferior glands include the thymus, the anterior mediastinum, intrathyroidal in the inferior pole, or undescended near the carotid bifurcation. It is important to note for surgery that the inferior glands are always found ventral to the RLN, which derives from the fourth branchial cleft.
The superior glands develop from the fourth branchial pouch and tend to be more consistent in their location at the posterior aspect of the thyroid pole just posterior to the insertion point of the RLN. Ectopic locations for superior glands include retroesophageal, retropharyngeal, the inferior tracheoesophageal groove, the posterior mediastinum, or the carotid sheath. The superior gland can also have an intrathyroidal ectopic location near the tubercle of Zuckerkandl owing to migration of the gland with ultimobranchial bodies during development. In contrast to the inferior glands, the superior glands are found deep to the RLN. These anatomical and embryologic relationships are key features when evaluating imaging findings before and during operative management.
The relationship of the parathyroid glands to the RLN is especially important in understanding ectopic locations, with ectopic inferior glands always superficial to the RLN and ectopic superior glands deep to the RLN
Parathyroid imaging is not used for diagnosis of HPT, which is determined biochemically, but is rather performed in patients who are candidates for parathyroidectomy. Imaging is especially important in patients for whom focused parathyroidectomy is being considered and also for those with prior neck surgery or undergoing revision parathyroid surgery, as previous surgical scars can lead to distorted anatomy and higher complication rates.
The most common contemporary parathyroid imaging tests include nuclear imaging, ultrasonography, and computed tomography (CT). Other localization studies such as magnetic resonance imaging (MRI) and selective venous sampling are occasionally used and are briefly discussed.
Nuclear imaging
Sestamibi Tc99m
Nuclear imaging is based on differential uptake of various radionuclide substrates by parathyroid tissue. The origin of parathyroid imaging is based on this concept, and the first dedicated images obtained from the 1970s used the Thallium 201TI–99mTc-pertechnetate subtraction method. Thyroid tissue takes up both 201TI and 99mTc-pertechnetate, whereas hyperfunctioning parathyroid glands take up 201TI but not 99mTc-pertechnetate.
Based on this principle, subtraction allows localization of hyperfunctioning parathyroid glands. The technique was refined in the 1990s when 99mTc-sestamibi was introduced. Sestamibi is a lipophilic cation preferentially taken up by mitochondria-rich tissue, which includes salivary glands, thyroid tissue, parathyroid glands, and cardiac muscle. Parathyroid adenomas have sustained sestamibi uptake, and owing to this characteristic, it can be used as a single agent in a dual-phase fashion.
Washout of the agent from the parathyroid adenomas is slower than that from the normal thyroid tissue, and taking 2 images at early (20-30 minutes) and delayed (2 hours) intervals separates the parathyroid adenoma with remaining uptake on the delayed image
(Figure 2). A recently performed meta-analysis suggests a sensitivity of approximately 88% for sestamibi scans for solitary adenomas, but this drops dramatically to 44% for multiple gland hyperplasia.
False-negative results for sestamibi scanning are generally secondary to rapid washout of tracer from smaller adenomas posterior to the thyroid, and false-positive results are often seen from uptake in thyroid nodules. Additional radionuclide subtraction methods may be another way to improve detection of abnormal parathyroid tissue in rapid washout situations. Using 123I, which is not taken up by the parathyroid glands, is one potential way of improving accuracy by allowing subtraction of thyroid tissue uptake.
An important weakness of traditional planar dual-phase sestamibi scans is difficulty with anterior-posterior localization. The inability to distinguish anterior-posterior location is especially important owing to the embryonic relationship between the ventral location of inferior parathyroid glands and the dorsal location of superior parathyroid glands. Because of this, additional refinements have been made to improve anterior-posterior localization. Single-photon emission computed tomography (SPECT) was added to the protocols in the late 1990s. SPECT uses a gamma camera to acquire multiple 2-D images in a fashion similar to traditional CT. This allows anterior-superior spatial localization by providing axial, coronal, and sagittal tomographs. A head-to-head trial of the techniques found that addition of SPECT enhances overall sensitivity for parathyroid abnormalities (both hyperplasia and adenomas) to approximately 67% compared with 42% with sestamibi alone. However, the rates of detection of parathyroid hyperplasia remain poor for SPECT imaging at approximately 25%
Single photon emission computed tomography (SPECT) should be routinely performed for the detection of parathyroid abnormalities utilizing technetium-99m sestamibi parathyroid scintigraphy.
Figure 3Series of coronal SPECT images in a patient undergoing revision parathyroidectomy. Image shows likely ectopic inferiorly located left superior parathyroid adenoma. Note areas of high uptake in the anterior submandibular glands and the more posterior parotid glands. Elevated uptake is seen at the level of parotid glands, making superior parathyroid adenoma the more likely diagnosis. This was confirmed intraoperatively.
Further refinement of spatial localization is achieved by fusing CT scans with SPECT imaging, similar to PET/CT scans. The patient׳s head is fixed during imaging, and the scans obtained are overlapped using software (Figure 4). Sensitivities of 93% have been reported for SPECT/CT in determining the position of enlarged parathyroid glands.
Further studies confirm that SPECT/CT improves anatomical localization compared with SPECT or dual-phase planar scintigraphy alone, especially for ectopic gland identification.
Weaknesses of SPECT-CT include additional radiation exposure from CT scan in addition to radionuclide tracer and the cost. Its strengths include more accurate localization, improved identification of ectopic adenomas, and ability to identify the size of adenomas.
Figure 4Axial CT scan in the same patient as in Figure 3. Overlying SPECT on CT scan shows likely ectopic L superior parathyroid adenoma near the thoracic inlet, subsequently confirmed pathologically.
Ultrasound is an attractive first-line parathyroid imaging technique owing to low cost, high resolution, accurate anatomical detail, quick scan times, lack of radiation, and improved patient convenience, especially when performed by the surgeon at the initial clinic visit. It is based on the principle that high-frequency sound waves penetrate and reflect off different tissue in a differential manner. Clinical applications of this principle have greatly advanced over the past decade, and current machines provide high-resolution, real-time images for analysis. Furthermore, thyroid nodules are identified on parathyroid ultrasound in a significant number of patients, allowing ultrasound-guided fine needle aspiration and evaluation for concurrent thyroidectomy as needed.
Parathyroid adenomas are typically seen on ultrasound as hypoechoic extrathyroidal masses (Figure 5). Ultrasound may be performed by radiologists, surgeons, and endocrinologists, though data suggest that surgeon-performed ultrasound in particular is highly sensitive for laterality and quadrant, with sensitivities of upward of 90% and 80%, respectively.
Cervical ultrasound is performed in the office by placing the patient in a supine position with the neck slightly extended. A high-frequency ultrasound probe is then used in the transverse and longitudinal planes to identify any extrathyroidal or intrathyroidal hypoechoic masses. In most patients, a high-frequency linear transducer is used (8-15 MHz), with lower frequencies required for larger patients for optimal sonographic penetration. Doppler may be used to assess vascularity. A systematic approach that assesses the entire thyroid gland, anterior neck, and superior mediastinum in both longitudinal and transverse planes is important to avoid missing parathyroid adenomas, while taking care to evaluate for ectopic parathyroid adenomas, including retroesophageal, intrathyroidal, carotid sheath, and superior mediastinal locations.
Figure 5(A) Transverse view on ultrasonography of enlarged L inferior parathyroid mass, measuring 1.3× 0.7 cm. Found to be consistent with adenoma on surgical pathology. Note labels: T = Trachea, P = Parathyroid, C = Carotid. (B) Longitudinal view on ultrasonography of enlarged L inferior parathyroid mass, measuring 1.1 cm in length consistent with adenoma on surgical pathology. Note labels: Th = Thyroid, P = Parathyroid. (C) Transverse view on ultrasonography of enlarged L inferior parathyroid mass on Doppler mode, showing hypervascular nature of suspected adenoma. Note arrow indicating possible inferior thyroidal artery.
First, the central neck is evaluated, and the orthotopic locations of the parathyroid glands in the central neck are assessed. The superior parathyroid gland is commonly posterior to the middle third of the thyroid gland, and the inferior parathyroid gland usually is near the inferior pole of the thyroid gland. The thyroid gland itself is evaluated concurrently for nodules or intrathyroidal parathyroid adenomas, and the esophagus is visualized on the left side of the trachea. The superior gland is occasionally found in the tracheoesophageal groove. Now, achieving adequate tissue penetration is important to differentiate between deeper prevertebral musculature and parathyroid tissue.
After evaluating the central neck for orthotopic glands, the ectopic locations described previously are evaluated.
Compared with traditional sestamibi scanning, ultrasound is more sensitive for identification of both single orthotopic adenomas and ectopic adenomas in the neck, and the exquisite anatomical detail available with sonography improves the three-dimensional surgical planning based on real-time feedback.
Other advantages include the ability to evaluate for thyroid pathology concurrently and high sensitivity (approximately 80%) in previously operated necks.
Weaknesses of ultrasound include operator dependence, decreased sensitivity in the presence of thyroid nodules and obesity, and difficulty in identifying ectopic glands in the mediastinum compared with sestamibi.
Traditional contrast-assisted CT scans are sometimes used for adenoma localization, especially in settings where ultrasound and sestamibi are nonlocalizing.
However, limitations exist with smaller adenomas, which often remain invisible on traditional CT scanning. In 2006, Rodgers described a technique known as “4D-computed tomography,” in which differential perfusion of iodinated contrast over time is used to improve diagnostic yield.
Hyperfunctioning parathyroid tissue has rapid uptake and washout of iodinated contrast, and a parathyroid protocol CT involves obtaining images at multiple times (noncontrast, arterial phase, and delayed venous phase). Sensitivity for identifying the correct side of an adenoma in this protocol ranges from 88%-92%, and for correct quadrant, it is 70%. It is particularly used in patients who are unable to be localized with sestamibi or sonography
The utility of 4-dimensional computed tomography for preoperative localization of primary hyperparathyroidism in patients not localized by sestamibi or ultrasonography.
Figure 6Axial cut of parathyroid CT scan. Arrow shows lucency in R inferior thyroid lobe. On surgical exploration, the patient was found to have intrathyroidal parathyroid adenoma, with resolution of hypercalcemia after R hemithyroidectomy.
Addition of ultrasound with subsequent parathyroid protocol CT may push sensitivity to 94%-99% for correct side of the neck and 82%-90% for correct quadrant, as the advantage of ultrasound for anterior adenomas is combined with that of CT for posterior adenomas.
Parathyroid CT may be particularly helpful in areas where traditional imaging has difficulties, such as in localizing small adenomas and in the reoperative neck, with sensitivities upward of 88% in these difficult cases.
When compared with other imaging modalities, a recent meta-analysis suggests that sensitivities are approximately 76% for ultrasound, 79% for sestamibi, and 89% for parathyroid CT.
Of note, recent work suggests that by decreasing the number of scans within the CT protocol, reduced radiation exposure without reduced sensitivity may be possible.
The use of modified four-dimensional computed tomography in patients with primary hyperparathyroidism: An argument for the abandonment of routine sestamibi single-positron emission computed tomography (SPECT).
Weaknesses of parathyroid CT include high degrees of radiation exposure from multiple scans, lack of experience with the protocol at most centers, and continued poor sensitivity for multigland disease. However, it provides good anatomical detail and is less dependent on operator experience compared with ultrasound. Thus, parathyroid CT may be especially helpful in areas where high-volume ultrasound is not performed, as it is less operator dependent than ultrasound while providing excellent anatomical detail for surgical planning.
Magnetic resonance imaging
MRI is based on the principle that different tissues in the body have unique responses to an applied magnetic field. These signals are processed to form an anatomical image without the use of ionizing radiation, making MRI a valuable imaging technique. Unfortunately, MRI is not sensitive for the evaluation of the central neck owing to motion artifact with swallowing and respiration because of longer scan times compared with CT or ultrasound.
Owing to these disadvantages, it is uncommonly used in parathyroid imaging.
Selective venous sampling
Selective venous sampling is an invasive test performed in the interventional radiology suite. The procedure involves venipuncture of the femoral vein, and a baseline PTH level from the iliac vein is obtained. A catheter is then advanced under fluoroscopic guidance to the superior vena cava, and blood from various neck and mediastinal veins is sampled. Blood samples are sent for PTH levels, and gradients between sampled sites are calculated. In general, a 50% rise in the PTH level of a sampled vein compared with a control sample is considered a supportive case for a parathyroid adenoma draining into the sampled vein.
Sensitivity for localization of parathyroid adenomas ranges from 75%-90%, and a sensitivity of 70% is noted in patients with nonlocalizing planar sestamibi scans.
Prospective evaluation of selective venous sampling for parathyroid hormone concentration in patients undergoing reoperations for primary hyperparathyroidism.
It is also possible to sample the inferior internal jugular veins bilaterally, under ultrasound guidance in the office or under direct visualization in the operating room. Under this protocol, the side with a lower PTH level is considered a control and a 10% difference in PTH level is considered a supportive case for a parathyroid adenoma on the side with a higher PTH.
In practice, the gradient is often a >50% difference in our experience. Disadvantages of selective venous sampling include a limited experience with the procedure at most centers, high expense, need for an additional invasive procedure requiring femoral venipuncture, use of contrast, and use of ionizing radiation for fluoroscopy. Owing to these drawbacks, selective venous sampling is uncommonly used as a first-line parathyroid imaging study.
Conclusions
Parathyroid imaging has rapidly advanced over the past few decades, making preoperative localization and targeted surgery possible in most of the patients with sporadic primary HPT. In patients with biochemical diagnosis of primary HPT and suspected sporadic etiology, our institutional protocol begins with surgeon-performed ultrasound in the office. If the ultrasound localizes a clear single adenoma, the patient is taken for focused removal of the adenoma, with resolution confirmed by frozen section and intraoperative PTH. If the ultrasound is equivocal, nonlocalizing, or suggests multiple gland disease, a SPECT/CT sestamibi scan is performed before surgical treatment. If localization is obtained by SPECT/CT, focused exploration with intraoperative PTH is performed. If the surgical findings are consistent with an adenoma, and PTH drops appropriately, the case is terminated. If intraoperative findings are consistent with multigland disease, a bilateral exploration is performed. In patients with hereditary primary HPT, secondary or tertiary HPT, multigland disease is common, and the imaging paradigm shifts slightly. Similar to sporadic primary HPT, these patients first receive an office ultrasound. However, all of these patients also receive a SPECT/CT to evaluate for ectopic mediastinal glands or supernumerary glands before planned multigland exploration or excision.
Parathyroid CT is reserved for patients who do not show localization on ultrasound or SPECT/CT, especially in reoperative cases. In these cases, decreasing the rates of bilateral exploration is highly cost-effective, and using parathyroid CT scans for patients with suspected adenomas unable to be identified by US or SPECT/CT was found to be cost-effective in a recent cost-utility analysis.
Despite this, in some patients, localization remains difficult, and these patients must be treated with bilateral neck exploration by experienced parathyroid surgeons. Preoperative imaging is an essential step in the treatment of parathyroid disease, and advances in ultrasound, CT, and nuclear medicine have allowed us to treat our patients in a focused manner, decreasing both morbidity and operative time.
Disclosure
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
References
Institutes of Health
NIH conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus development conference statement.
Single photon emission computed tomography (SPECT) should be routinely performed for the detection of parathyroid abnormalities utilizing technetium-99m sestamibi parathyroid scintigraphy.
The utility of 4-dimensional computed tomography for preoperative localization of primary hyperparathyroidism in patients not localized by sestamibi or ultrasonography.
The use of modified four-dimensional computed tomography in patients with primary hyperparathyroidism: An argument for the abandonment of routine sestamibi single-positron emission computed tomography (SPECT).
Prospective evaluation of selective venous sampling for parathyroid hormone concentration in patients undergoing reoperations for primary hyperparathyroidism.
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