The role of ultrasound and nuclear medicine methods in the preoperative diagnostics of primary hyperparathyroidism.

Primary hyperparathyroidism (PH) represents one of the most common endocrine diseases. In most cases, the disorder is caused by parathyroid adenomas. Bilateral neck exploration has been a widely used treatment method for adenomas since the 20's of the twentieth century. In the last decade, however, it has been increasingly replaced by a minimally invasive surgical treatment. Smaller extent, shorter duration and lower complication rate of such a procedure are emphasized. Its efficacy depends on a precise location of parathyroid tissue during the preoperative imaging. Scintigraphy and ultrasound play a major role in the diagnostic algorithms. The efficacy of both methods has been repeatedly verified and compared. The still-current guidelines of the European Association of Nuclear Medicine (2009) emphasize the complementary role of scintigraphy and ultrasonography in the preoperative diagnostics in patients with primary hyperparathyroidism. At the same time, attempts are made to improve both these techniques by implementing new study protocols or innovative technologies. Publications have emerged in the recent years in the field of ultrasonography, whose authors pointed out the usefulness of elastography and contrast media. Nuclear medicine studies, on the other hand, focus mainly on the assessment of new radiotracers used in the positron emission tomography (PET). The aim of this article is to present, based on literature data, the possibilities of ultrasound and scintigraphy in the preoperative diagnostics in patients with primary hyperparathyroidism. Furthermore, the main directions in the development of imaging techniques in PH patients were evaluated.

Primary hyperparathyroidism

Primary hyperparathyroidism (PH), together with type 2 diabetes and thyroid diseases, belongs to the most common endocrine disorders. The morbidity rates range from 1 to 7 per 1,000 inhabitants, depending on the given population. PH is 2–3 times more common in females. Most PH patients are over 50 years of age(.

PH is characterized by an abnormally increased synthesis and release of parathyroid hormone (PTH) in the parathyroid cells(. This leads to enhanced resorption of calcium from the skeletal system and its increased adsorption from the gastrointestinal tract, as well as increased calcium and phosphate excretion in the urine(. The spectrum of symptoms that may represent the clinical manifestation of PH is very wide. It includes, inter alia, mental disorders, gastrointestinal disorders, nephrolithiasis symptoms, as well as bone and joint pain due to a generalized or focal osteoporosis(. Despite the abundant PH symptomatology, the majority of PH cases are currently detected in asymptomatic patients based on hypercalcemia revealed by routine laboratory tests(.

PH diagnosis is based on biochemical outcomes, i.e. increased serum PTH and total or ionized calcium levels as well as hypercalciuria. The diagnosis is also based on PTH levels in the upper normal range with abnormally increased serum calcium levels, which may in some of the patients inhibit PTH release. Advanced hypercalcemia in the course of PH is very rare. It may be accompanied by sporadic, though life-threatening hypercalcemic crisis(.

Adenoma of one of the parathyroid glands is the most common cause of PH (approximately 85% of cases). About 15% of patients develop PH due to multiple adenomas or parathyroid hyperplasia. Parathyroid carcinoma accounts for less than 1% of cases. PH can occur in a sporadic or familial form (about 5% of patients), most often secondary to multiple endocrine neoplasia syndrome type 1 (MEN 1) (pituitary tumors and neuroendocrine tumors of the pancreas are also included in the syndrome) and type 2A (MEN 2A) (coexists with medullary thyroid cancer and pheochromocytoma)(.

Regardless of PH etiology, after initial asstessment of disease stage, surgical treatment is the recommended management strategy. If there are no contraindications, it should be proposed to all patients with clinical symptoms. In the case of asymptomatic patients, the current guidelines recommend surgical treatment in patients with total serum calcium levels exceeding the upper limit of normal by ≥1 mg/dL. Indications for surgical treatment further include impaired renal function (nephrolithiasis or renal parenchymal calcification in the imaging studies, creatinine clearance of <60 mL/min, hypercalciuria >400 mg/day coexisting with an increased risk of nephrolithiasis) as well as skeletal abnormalities (spinal fracture shown in the imaging study, the T-score of <–2.5 in DXA study). The age of patient (less than 50 years) is a separate indication. The urgency of the indications depends on symptom severity and biochemical disorders(.

Bilateral neck exploration (BNE), described by Mandl in 1925, has been a widely used method of surgical treatment in PH patients for many years(. Many authors emphasize that the efficacy of this procedure largely depends on the experience of the operating team(. Less importance is given to the preoperative imaging of abnormal parathyroid glands. In the recent years, minimalinvasive parathyroidectomy (MIP) has been increasingly performed due to its smaller extent, shorter duration and lower rates of complications. Its efficacy is determined by a precise location of parathyroid tissue using preoperative imaging techniques(. Parathyroid ultrasonography and scintigraphy are the main methods used for this purpose(. Complementary role of both these tests is emphasized in the literature(. At the same time, a discussion is held on improving the already existing algorithms or implementing new diagnostic tools.

Ultrasonography

Broadband, high-frequency (8–17 MHz) linear probes are used for the identification of lesions in the parathyroid glands. Probes with the frequency of 5–8 MHz may be useful in patients with obesity or large thyroid goiter(. The test should be performed in the supine position, with the patient's head tilted back(. It is recommended to obtain cross-sectional and longitudinal images of the anterior region of the neck, bilaterally in the region from the common carotid arteries to the midline as well as from the level of the common carotid artery bifurcation to the sternal notch(. If possible, the examined area should be extended to the superior part of mediastinum, by setting the probe at an appropriate angle and asking the patient to swallow own saliva(. During the test, special attention should be paid to the posterior surface of the thyroid lobes as well as the area below the lower thyroid poles(.

Typically, there are four parathyroid glands: two upper and two lower. The glands usually present the appearance of flattened oval disks; they are 5 × 3 × 1 mm in size and weigh about 40 mg(. Unchanged parathyroid glands are isoechogenic relatively to normal thyroid tissue and are not usually visible in the ultrasound image.. Pathological parathyroid tissue becomes visible due to enlargement and altered echogenicity of the gland(. Reading et al. found in their study that the weight of adenomas in 165 surgically treated patients ranged between 40 and 16,300 mg, however, 2/3 of the described lesions had a weight of less than 1,000 mg. The smallest adenoma visualized by the authors in the USG image had a weight of 75 mg and size of 7 × 3 × 3 mm. The investigators failed to identify the characteristics differentiating between parathyroid carcinoma and benign lesions(.

Parathyroid adenomas are typically visualized as solid, wellcircumscribed, oval or oblong structures with lower echogenicity compared to the surrounding thyroid tissue(. They are usually separated from the thyroid by a hyperechoic band of connective tissue. Large lesions may have a polycyclic shape and contain fluid structures (corresponding to regressive lesions) and calcifications( (Fig. 1).

Fig. 1

B-mode USG images of the right lower parathyroid adenoma: hypoechoic, inhomogeneous, well-circumscribed focal lesion located posteriorly to the right thyroid lobe. Owing to the courtesy of Prof. Iwona Sudoł-Szopińska MD, PhD, Katarzyna Dobruch-Sobczak MD, PhD., Rafał Słapa MD, PhD

The sensitivity and specificity of ultrasound in the detection of enlarged parathyroid glands were assessed by a number of authors and ranged between 69% and 90% as well as 90% and 98%, respectively(. Small size of adenomas is one of the causes of false-negative test results. In the above mentioned study by Reading et al., only 35% of lesions weighing less than 200 mg were visible on ultrasound(. The study also showed a significant correlation between the size of parathyroid lesions and the diagnostic accuracy of ultrasonography.

Ectopic parathyroid location, most often in the acoustic shadow (e.g. in the retrotracheal space or in the mediastinum), is another cause of false-negative results(.

The superior parathyroid glands, which are derived from the fourth branchial pouch, are typically located at the posterior aspect of the upper parts of both thyroid lobes; in the vicinity of the intersection of the recurrent laryngeal nerve and the lower thyroid artery in 80% of cases(. The location of the inferior parathyroid glands, which are derived from the third branchial pouch, shows greater variability. Although 60% of these glands are located in the vicinity of the lower poles of the thyroid, they may be present in the region from the mandible to pericardium(. Many cases of ectopic parathyroid glands located retrotracheally, retroesophageally, in the vicinity of carotid vessels or along the vagus nerve, also in the mediastinum, were described in the literature(. In the general population, additional parathyroid glands, which are usually located in the thymus region, are found in more than a dozen percent of patients(. Ultrasound shows low sensitivity in detecting this type of lesions. In a study by Haber et al., the sensitivity of ultrasound in the diagnosis of ectopically located adenomas of the parathyroid glands was only 25%(.

The patient's anatomic conditions can also affect medical test accuracy(. The effects of previous surgery of the neck on ultrasound sensitivity were assessed. Miller et al. described a group of PH patients with unsuccessful surgical treatment. The sensitivity of ultrasound in detecting focal lesions of the parathyroid glands was 36% in this patient population(. For comparison, as reported in the already mentioned study by Reading et al., the sensitivity and specificity of ultrasound in a subgroup of 21 patients with previous surgical treatment were 80% and 92%, respectively(.

Parathyroid adenomas located in the thyroid are another diagnostic issue. As shown in postmortem studies, the incidence of the intra-thyroid location of the parathyroid glands was estimated at less than 0.2%, and 2–5% in PH patients(. The same rate was estimated as less than 1% in a retrospective study by Goodman including more than 10,000 patients(. Intrathyroidal adenomas are difficult to distinguish from lesions that are typically visualized on ultrasound in the course of thyroid goiter. Fine needle aspiration biopsy (FNAB) is a method that allows to differentiate between the two diseases(. In a study by Owens et al., patients with identified intrathyroidal parathyroid tissue were also shown to have increased PTH levels in the needle washings compared to serum PTH levels.

With the advent of new technologies, attempts were made to increase the sensitivity and specificity of ultrasound. In one of these attempts, the possibility of vascular flow imaging was used. The parathyroid glands are usually vascularized by the thyroid artery branches, most often from the lower thyroid artery(. Color and power Doppler show an increased vascularity of parathyroid adenomas. The presence of an artery forming an arch on the adenoma periphery, which tends to branch into the adenoma with subsequent vascular amputation, is typical( (Fig. 2). The characteristic type of vascularization helps differentiate adenomas and lymph nodes supplied by vessels centrally penetrating the lymph node in the hilus region. Lane et al. showed that the visualized blood flow in the feeding artery using color or power Doppler increased the sensitivity of this method from 73% up to 83% compared to grey-scale ultrasound(.

Fig. 2

Color and power Doppler: characteristic vessels peripherally branching into the lesion. Owing to the courtesy of Prof. Iwona Sudoł-Szopińska MD, PhD, Katarzyna Dobruch-Sobczak MD, PhD., Rafał Słapa MD, PhD

There is no doubt that preoperative ultrasonographic assessment of PH patients has many advantages, such as low cost, high availability, no patient exposure to ionizing radiation, good visualization of the neck morphology.

However, it should be noted that there are some limitations to the method, including low sensitivity in the detection of focal ectopic parathyroid tissue and small lesions. Furtherthemore, nodular goiter or enlarged lymph nodes are potential causes of false-positive results. .At the same time it should be emphasized that the knowledge and experience of the examiner may contribute to decrease in the number of false diagnosis(.

Scintigraphy

In the 80's, the scintigraphic examination of the parathyroid glands was performed using thallium-201 (201Tl) and assessed combined with thyroid scintigraphy using pertechnetate (99mTc). In the next decade 201Tl was replaced with 99mTc-sestamibi and 99mTc-tetrafosmin – radiopharmaceuticals, which had been used in myocardial perfusion scintigraphy. A large number of mitochondria within parathyroid adenoma cells and the abundant vascularization in the affected tissue result in an increased uptake of both tracers(. The exceptional pharmacokinetic properties of 99mTc-sestamibi allowed to develop a method of a two-phase parathyroid scintigraphy. Following intravenous injection, 99mTc-sestamibi accumulates both in the parathyroid glands and the thyroid, however it is more rapidly washed out from the thyrocytes. Two scintigrams are performed: 10–15 minutes and 1.5–2.5 hours after radiopharmaceutical administration. The focus of increased tracer accumulation, which is maintained in the delayed phase of the test indicates the presence of parathyroid adenoma(.

While 99mTc-sestamibi and 99mTc-tetrofosmin accumulate both, in the parathyroid and thyroid tissue, the iodine-123 (123I) and 99mTc-pertechnetate are not taken up by the parathyroid cells. This phenomenon was used in the subtraction method, using two tracers. There are a few existing protocols of this method. In the final computer analysis scintigrams are fused and the images are subtracted. The focus of increased 99mTc-sestamibi or 99mTc-tetrofosmin corresponding to the absence of iodine-123 (123I) or 99mTcpertechnetate accumulation indicates the presence of parathyroid adenoma( (Fig. 3).

Fig. 3

Planar scintigraphy of the parathyroid glands performed using the subtraction method. A focus of increased 99mTc-sestamibi accumulation corresponding to a focus with no 99mTc-pertechnetate uptake in the projection of the lower right parathyroid gland.

Both scintigraphic methods were compared in a number of study protocol modifications in order to find the optimal solution. Keane et al. compared the accuracy of subtraction and two-phase method(. The percentage of non-diagnostic tests for subtraction and delayed acquisition method, respectively, after 1, 2, and 3 hours was evaluated with the obtained results of 21%, 38%, 43% and 56%, respectively, for the individual protocols. The authors emphasized that a combined use of both methods is necessary to achieve the optimal accuracy of the preoperative assessment of patients. The use of both techniques resulted in 81% accuracy (assuming the correct location of the side and pole of the thyroid, where granuloma was found) and 90% accuracy (for a correct location of the side). Interestingly, the study showed no advantage of the three-dimensional image acquisition techniques (SPECT or SPECT/CT) over planar imaging technique.

The 2015 meta-analysis included 18 studies published over the last 25 years to compare different image acquisition techniques: planar imaging, SPECT and SPECT/CT in the preoperative assessment in PH patients. The sensitivity of these methods was 63%, 66%, 84%, respectively, and the positive predictive value (PPV) was 90%, 82% and 95%, respectively((Fig. 4 and 5).

Fig. 4

Parathyroid SPECT scan. A focus of increased 99mTc-sestamibi accumulation in the lower left parathyroid gland

Fig. 5

Parathyroid SPECT/CT scan. A focus of increased 99mTc-sestamibi accumulation in the lower right parathyroid gland

The use of pinhole collimators is an interesting suggestion to increase the sensitivity of the method(. Carlier et al. showed that planar imaging with pertechnetate and 99mTc-sestamibi using SPECT and pinhole collimators allowed for an increase in the sensitivity up to 93% with 91% specificity(.

The main advantages of scintigraphy include higher sensitivity compared to ultrasound in detecting ectopic lesions. Roy et al. assessed the sensitivity of ultrasound and scintigraphy in the detection of ectopically located parathyroid adenomas: in the thymus, retroesophageally, in the thyroid, in the mediastinum, undescended (situated at least 1 cm above the upper thyroid pole) as well as in the vicinity of carotid arteries. The sensitivity of ultrasound and scintigraphy for the detection of this type of lesions was 59% and 89%, respectively. The advantage of scintigraphy over ultrasound was shown in 28 out of 59 patients, whereas ultrasound was superior in only 3 cases(.

As in the case of ultrasound, false-negative results are mostly due to the small size of adenomas whereas thyroid nodular goiter is the most common cause of false-positive results(.

The use of radiopharmaceuticals also allows to use the gamma probe for intraoperative localization of parathyroid adenomas(. It was shown, however, that this type of management cannot replace the preoperative scintigraphy in the imaging of adenomas in PH patients(.

The complementary role of ultrasound and scintigraphy of the parathyroid glands

The issue of the complementary role of ultrasound and scintigraphy in the preoperative assessment of PH patients has been repeatedly discussed in the literature during the recent years(.

In 2000, De Feo. et al. noted in their prospective study that the combined use of ultrasound and scintigraphy resulted in 96% sensitivity and 83% specificity. For comparison, the sensitivity and specificity when using only one method were 67% and 94% for ultrasound and 71% and 89% for scintigraphy, respectively. The same study additionally assessed the use of magnetic resonance imaging (MRI) both as the only diagnostic method as well as in combination with scintigraphy and ultrasound in a small group of patients. The sensitivity and specificity of MRI were 50% and 78%, respectively. No advantage of MRI/scintigraphy and/or MRI/ultrasound study protocols over ultrasound/scintigraphy protocol was shown. The retrospective part of the cited study assessed the sensitivity and specificity of computed tomography, and lower values were obtained(.

In the same year, Casara et al. presented their findings. Using a combined scintigraphic/USG protocol, focal lesions of the parathyroid glands in the course of PH were correctly localized in 20 of 21 patients (95.2%) assessed prior to a minimally invasive surgery(.

A combined use of both imaging techniques is recommended by Ozkaya et al. in one of the latest papers in the subject, based on the fact that such management allows to achieve more than 90% accuracy and equally high positive predictive value(.

The efficacy of combined use of SPECT/CT and ultrasound was assessed by Patel et al. According to the authors, ultrasound allowed for a correct detection of 64% of lesions, whereas SPECT/CT for 90% of lesions. The sensitivity and specificity for both methods were up to 95% and 91%, respectively(.

An interesting suggestion, reflecting the tendency towards a combined interpretation of both methods, was made by Bluemla et al. The authors suggested a fusion of SPECT and USG images(. However, the assessment of this type of management requires further research in larger groups of patients to compare the method against the existing standards.

The prospects for the development of parathyroid diagnostic imaging

When analyzing the developmental trends in the diagnostic imaging in PH patients, innovative studies in the field of nuclear medicine assessing the efficacy of novel radiopharmaceuticals, particularly those used in the positron emission tomography/computed tomography (PET/CT), are worth noting. In the recent years, high hopes have been associated with the use of 18F-fluorocholine and 11C-methionine.

Particularly promising observations were presented by Michaud et al., who evaluated the outcomes of PET/CT using 18F-fluorocholine. In a group of 12 patients with inconclusive USG and/or scintigraphy outcomes, the sensitivity of PET/CT was 89%, with 2 false-positive tests and 1 false-negative test(. Leizac et al. showed in their study including 24 patients that the sensitivity and specificity of PET/CT using 18F-fluorocholine were 92% and 100%, respectively(.

Less optimistic conclusions were drawn by the investigators assessing the efficacy of 11C-methionine. Hayakawa et al. showed no significant differences in sensitivity between SPECT/CT using 99mTc-sestamibi and PET using 11C-methionine(. The same method was assessed in a group of 15 patients with negative SPECT/CT by Traub-Weidinger et al. Increased focal accumulation was identified in only 5 of 11 patients(. Herrman et al. showed a decreased sensitivity of this method for the detection of parathyroid adenomas compared to USG and scintigraphy in their retrospective analysis(.

The efficacy of innovative technologies that could increase the imaging quality was also assessed in the field of ultrasonography.

The first study assessing focal lesions of the parathyroid glands using real-time elastography ultrasound technique was published in 2012. A total of 72 patients with adenomas or hyperplasia in the course of primary, secondary or tertiary hyperparathyroidism were enrolled in the study. The classification of lesions was based on a 4-grade score. All the assessed adenomas were poorly deformable (grade III and IV). Also, statistically significantly lower deformability was shown in this group compared to patients with parathyroid hyperplasia( (Fig. 6).

Fig. 6

Static elastography. Low grade of lesion deformability is noticeable. Owing to the courtesy of Prof. Iwona Sudoł-Szopińska MD, PhD, Katarzyna Dobruch-Sobczak MD, PhD., Rafał Słapa MD, PhD

In 2014, Agha et al. showed a very high, more than 95% sensitivity of contrast ultrasound in the detection of parathyroid adenomas. Even better results were obtained in patients with negative scintigraphy(.

Particular attention should be paid to an attempt of a simultaneous use of ultrasounds as both diagnostic and therapeutic method. Kovatcheva et al. described the use of ultrasound (US)-guided high-intensity focused ultrasound (HIFU) as a method for simultaneous parathyroid adenoma detection and treatment. The authors achieved a complete remission in 23% and a good disease control in 69% of patients(.

The 4D computed tomography is another imaging technique used in PH diagnostics. Day et al. achieved 89% sensitivity in detecting parathyroid focal lesions which could not be identified using ultrasound or scintigraphy(.

PET/MRI and magnetic resonance using hyperpolarized contrast agents are highly innovative diagnostic methods, which rapidly gain new applications. Unfortunately, the lack of studies evaluating their in vivo utility prevents the assessment of their diagnostic value compared to other imaging techniques used in PH patient diagnostics.