The endocrine disorder known as hyperparathyroidism (HPT) is brought on by an excess of parathyroid hormone (PTH), which is secreted by the parathyroid glands and regulates blood levels of calcium, phosphorus, and vitamin D.^[1] Usually, this condition is associated with elevated levels of serum calcium and PTH. In some patients, the PTH levels may be within the normal range but accompanied by hypercalcemia.^[2]

Elevated levels of serum calcium as a result of excessive parathyroid hormone in blood circulation is associated with fatigue, weakness, pain in muscles and bones, polyuria, polydipsia, nocturnal urinary frequency, renal calculi, memory loss, constipation, pyrosis, and depression. Nowadays, most patients are asymptomatic and are diagnosed during routine laboratory screening.^[3]

HPT can be either primary, secondary, or tertiary. Primary HPT is a relatively common endocrine condition, with an incidence of 0.5/1000 in the general population, and it affects women nearly three times more than males. ^[4] It is typically caused by a solitary parathyroid adenoma in the majority of patients (80%–85%). Of them, 95% are sporadic, and the other 5% are associated with hereditary syndromes, for example, multiple endocrine neoplasia types 1, 2, and 4. In 15%–20% of all patients with primary hyperparathyroidism, the identified cause is either hyperplasia of the glands or multiple parathyroid adenomas. In rare cases, less than 1%, parathyroid carcinoma is the underlying cause.^[5]

An anatomical understanding of the parotid glands is needed since there are variations in their localization, justified by their embryological development, which can pose a significant challenge for nuclear medicine physicians, radiologists, and surgeons.

The parathyroid glands are small, lentil-sized glands that are normally found behind the upper and lower poles of both thyroid lobes. There are typically four of these glands.

The superior parathyroid glands arise from the dorsal wing of the 4th pharyngeal pouch. During the 7th gestational week, the glands detach from the pharynx, attach themselves to the thyroid tissue and descend with it caudally. The superior parathyroid glands have more constant location than the inferior parathyroid glands, because of their shorter migration length. Their final point of migration is usually on the dorsal surface of the upper thyroid poles, dorsally to the recurrent laryngeal nerve outside of the thyroid fibrous capsule.^[6]

The inferior parathyroid glands are more likely to vary in position because they arise from the dorsal wing of the third pharyngeal pouch, which differentiates at approximately the fifth or sixth week of pregnancy, with the ventral wing developing into the thymus. The thymus then descends together with them further inferiorly compared to the superior parathyroid glands. Their migration usually ceases close to the lower thyroid poles, at the dorsal surface of the thyroid gland, outside of the fibrous capsule anteriorly to the recurrent laryngeal nerve.^[7]

Despite the limited migration path of their embryological development, there are still, however, cases of ectopy of parathyroid glands, which is a cause of hyperparathyroidism. Ectopic parathyroid glands may be located within thymus in the anterior mediastinum, within the thyroid or along the paraesophageal space and carotid sheath.^[8]

The most favorable treatment of hyperparathyroidism is minimally invasive parathyroidectomy, but this focused approach is applicable only in those cases when the solitary adenoma is preoperatively identified.^[9]

Parathyroid scintigraphy plays a crucial role in the preoperative localization of hyperfunctioning parathyroid adenomas, multiglandular parathyroid involvement or ectopic parathyroid glands allowing the selection of personalized surgical approach.

However, the success of the appropriate parathyroid surgery does not only depend on the expertise of the surgeon, but also on the sensitivity and accuracy of the chosen preoperative imaging modality.^[10]

Our study presents the diagnostic accuracy of our dual-tracer subtraction parathyroid scintigraphy combined with SPECT/CT imaging protocol.

After reviewing the results from the dual-tracer subtraction, combined with SPECT/CT imaging of 30 patients, predominantly female 29 (96.7%) with primary hyperparathyroidism, we found positive scans in 26 patients and negative in 5 patients. Of these 30 patients, one had a previous parathyroid surgery, but still clinical and laboratory evidence of primary HPT. The positive lesions revealed by the method were visually classified as foci of high, moderate or mild uptake. All included patients were either operated or treated conservatively. In the group of operated patients, the diagnosis was confirmed histopathologically, while in the conservatively treated group, the diagnosis was based on clinical examination and biochemical results – persistent elevation of calcium serum levels and PTH. Four patients (13.33%) with clinical suspicion of primary hyperparathyroidism and positive result from the hybrid dual-tracer imaging refused surgical treatment, while a parathyroidectomy was carried out on the other 26 patients (86.67%). The results showed adenoma of the inferior parathyroid glands in 18 patients (60%) of them 10 were with adenoma of the right inferior and 8 with adenoma of the left inferior parathyroid gland (Fig. 1).

No evidence of adenoma was found in 4 patients (13.33%), ectopic parathyroid gland was found in 4 patients (13.33%) – either in the anterior mediastinum or along the paraesophageal space and carotid sheath (Fig. 2).

Adenoma of the superior parathyroid glands was found in 3 patients (10%) – in all of them in the right superior gland. In one patient (3.33%) multiglandular parathyroid involvement was observed - multifocal adenomas of the right parathyroid glands.

Planar scintigraphy was positive for presence of hyperfunctioning parathyroid in 15 patients (50%), whereas SPECT/CT imaging was positive in 26 patients (86.7%) and negative in 4 patients (13.3%). SPECT/CT was able to identify hyperfunctioning parathyroid tissue in 11 patients (36.7%) with negative planar scintigraphy, allowing appropriate surgical intervention (Fig. 3).

The findings of this study suggest that SPECT/CT enhances the diagnostic utility of dual-phase scintigraphy for the preoperative identification of hyperfunctioning parathyroid lesions in patients with primary HPT. This technique provides a less invasive means of identifying affected glands in cases where there is only one, thereby reducing the possibility of an extended intraoperative examination of the remaining parathyroid glands. The added value of 3D imaging for detection of adenomas is advocated in the medical literature. Similar results are reported in a study by Assante et al., which highlights the importance of the three-dimensional method in the selection of surgical approach and the achievement of better therapeutic outcomes. The study proves the superiority of SPECT/CT over dual-phase scintigraphy in preoperative patients with primary HPT and uncertain ultrasound findings.^[11]

SPECT/CT may give additional information in patients with ectopic parathyroid adenoma in the neck and mediastinum, providing accurate anatomical location of the pathology.^[12]

The dual-tracer method (the ^99mTc-pertechnetate/^99mTc-MIBI method in our case) is a very useful tool in patients with thyroid nodules or goiter, in whom performing a subtraction of the images allows easy visualization of the parathyroid adenoma.^[13] Another advantage of our dual-tracer protocol is its low cost for a nuclear medicine technique using ^99mTc tracers. There are many tracers (^99mTc, ¹²³I, or ¹³¹I) that could be applied in the thyroid gland mapping in the dual-tracer subtraction. However, the costs of administering 99mTc to a single patient are twenty times as low as those when ¹²³I is applied, and using a MIBI kit is 10 times cheaper than using ¹²³I.^[14]

But compared to a dual-phase single-tracer method, this technique comes with a higher radiation dose to the patient. Another disadvantage of this method is that it requires good patient compliance to stay still and relaxed in the required position during the scanning in order to avoid motion artifacts.^[13]

Possible causes of false negative results when applying our protocol include a low pathological tumor weight, a parathyroid cyst, non-steroidal anti-inflammatory drugs used by the patient, calcium channel blockers, or calcimimetics leading to low or no 99mTc-MIBI uptake.^[15] Another possible reason for a false negative result could be a low concentration of oxyphil cells in the parathyroid adenoma.^[16]

The primary limitation of our research is the limited number of patients we included. However, having in mind the trend towards minimally invasive surgery and the increased demand for hybrid parathyroid imaging, more patients should be examined in order to demonstrate the diagnostic superiority of our dual-tracer subtraction scintigraphy combined with SPECT/CT protocol, so that the collected data could make a significant contribution.

When combined with SPECT/CT, dual-radiopharmaceutical subtraction imaging offers the integration of functional and morphological data, optimizing diagnostic accuracy from a single exam and influencing surgical strategy and treatment outcome.

T.S.: corresponding author, report writing, date collection, and drafting the manuscript; S.B.S.: report writing and interpretation; B.S.R.: data collection and patient follow-ups; M.T.D: data management and analysis. All co-authors listed here have agreed to have the manuscript submitted for publication.

We have no conflicts of interest to disclose.