Four-gland parathyroid exploration has been the gold standard for parathyroid surgery until recently. Emphasis is now placed on minimally invasive and focused parathyroidectomy. In conjunction with functional sestamibi scanning, ultrasonography permits accurate localization of enlarged parathyroid glands in the vast majority of patients with hyperparathyroidism. Consequently, ultrasound technology applied to parathyroid pathology facilitates directed surgical therapy and minimally invasive applications. As such, ultrasonography holds great promise as a tool that enables cost-effective and advanced patient care.
Parathyroid workup
Four-gland parathyroid exploration has been the gold standard for parathyroid surgery until recently. Emphasis is now placed on minimally invasive and focused parathyroidectomy. Given this objective, there is a need for sensitive and accurate localization of parathyroid pathology. Effective imaging techniques are instrumental in achieving these ends, particularly in the midst of heightened awareness of cost containment.
A thorough medical workup identifies the cause underlying hypercalcemia in the vast majority of patients. Hyperparathyroidism accounts for most cases of hypercalcemia and is categorized as primary, secondary, or tertiary. Primary hyperparathyroidism is the most common cause of hypercalcemia, affecting an estimated 0.2% to 0.5% of the US population. There are approximately 100,000 new cases each year. One in 500 women and one in 2000 men usually in their fifties to seventies are affected. Clinical manifestations of hypercalcemia include fatigue, hypertension, bone pain, muscle weakness, renal stones, peptic ulcers, and psychiatric illness. Laboratory abnormalities include hypercalcemia, hypophosphatemia, elevated parathyroid hormone levels, and increased urine calcium excretion. Secondary hyperparathyroidism is usually found in patients with renal insufficiency marked by hypocalcemia and hyperphosphatemia or in the setting of vitamin D deficiency. Tertiary hyperparathyroidism occurs with the development of autonomously hyperfunctioning parathyroid glands of secondary hyperparathyroidism with resultant hypercalcemia.
Primary hyperparathyroidism may be sporadic or hereditary, with sporadic being much more common. Spontaneous primary hyperparathyroidism is most often due to solitary parathyroid adenomas (85 to 90%), 4-gland hyperplasia (10 to 15%) or multiple adenomas, or asymmetric hyperplasia (2 to 3%) but rarely due to parathyroid carcinoma (less than 1%). Hereditary primary hyperparathyroidism may be isolated, associated with jaw tumor syndrome or other endocrine neoplasia. In hereditary primary hyperparathyroidism, multigland disease (multiple endocrine neoplasia 1 or 2a) is the rule rather than the exception.
Identification and localization of parathyroid adenomas is crucial for selective parathyroid surgery. Previously, the predominant localization technique involved sestamibi scanning. Its limitations have prompted investigations for more effective tools, including ultrasound technology. Unlike sestamibi scanning, ultrasonography offers more precise anatomic localization with concomitant facilitation of surgical planning.
Ultrasonography in the parathyroid workup
In the setting of primary hyperparathyroidism, one study found that ultrasonography had a sensitivity, specificity, and positive predictive value of 60%, 91%, and 92%, respectively, in detecting adenomas. In the authors’ experience of surgically proven adenomas, ultrasound sensitivity was 90%, better than sestamibi (70%). Ultrasonography is a much less sensitive tool for identifying hyperplasia. In the setting of secondary hyperparathyroidism, ultrasound had a sensitivity of 60% and accuracy of 64% in localizing enlarged parathyroid glands, missing as many as 30% of patients with multigland disease. Furthermore, patients with negative localization by scintigraphy and ultrasound were more likely to have 4-gland hyperplasia.
The accuracy of ultrasonography is also affected by thyroid disease, because its sensitivity dropped from 100% to 84% to 93% and positive predictive value decreased from 100% to 84%. Nodular thyroid disease may also contribute to false-positive or negative results. Infrathyroidal lymph nodes associated with thyroiditis may result in a false-positive interpretation as inferior adenomas. Decreased sensitivity is often a consequence of poor echogenic differentiation of parathyroid tissue.
Ultrasonography in the parathyroid workup
In the setting of primary hyperparathyroidism, one study found that ultrasonography had a sensitivity, specificity, and positive predictive value of 60%, 91%, and 92%, respectively, in detecting adenomas. In the authors’ experience of surgically proven adenomas, ultrasound sensitivity was 90%, better than sestamibi (70%). Ultrasonography is a much less sensitive tool for identifying hyperplasia. In the setting of secondary hyperparathyroidism, ultrasound had a sensitivity of 60% and accuracy of 64% in localizing enlarged parathyroid glands, missing as many as 30% of patients with multigland disease. Furthermore, patients with negative localization by scintigraphy and ultrasound were more likely to have 4-gland hyperplasia.
The accuracy of ultrasonography is also affected by thyroid disease, because its sensitivity dropped from 100% to 84% to 93% and positive predictive value decreased from 100% to 84%. Nodular thyroid disease may also contribute to false-positive or negative results. Infrathyroidal lymph nodes associated with thyroiditis may result in a false-positive interpretation as inferior adenomas. Decreased sensitivity is often a consequence of poor echogenic differentiation of parathyroid tissue.
Anatomy & embryology
Most individuals have 4 parathyroid glands (80%), 2 superior and 2 inferior. Supernumerary fifth or sixth glands may be found in 13% to 25% of the population, whereas 3% to 5% of the population has fewer than 4 parathyroid glands. Approximately 1% to 3% of parathyroid glands are ectopic.
The superior parathyroid glands arise from the fourth branchial pouch. They descend the neck in an inferoposterior direction to reside posterior to the recurrent laryngeal nerve, a sixth arch derivative. Most superior parathyroid glands are located posterior to the middle or upper portion of the thyroid gland in the vicinity of the cricothyroid junction. Less commonly, they may be located inferior to the midportion of the thyroid lobe (4%) or above the superior pole of the thyroid gland (3%). Occasionally, superior parathyroid glands may migrate toward the tracheoesophageal groove or the posterior mediastinum. Such ectopic adenomas account for less than 3% and may be found in the retropharyngeal, retroesophageal, posterior paratracheal, or intrathyroidal spaces.
The inferior parathyroid glands arise from the third branchial pouch. They descend the neck in an inferoanterior direction, often in close association with the thymus, and eventually reside anterior to the recurrent laryngeal nerve. Because the inferior parathyroid glands travel a greater distance, there is more variability in their final position. They may be found anywhere from the hyoid bone to the pericardium. More often, they are located inferior or just posterior to the lower pole of the thyroid, near the inferior thyroid artery (45%–60%).
Ectopic inferior parathyroid glands may be found in the cervical thymus (26%), anterosuperior mediastinum within the thymus (2%), or inferior to the thymus deep in the mediastinum (0.2%). Alternatively, the inferior parathyroid glands may fail to adequately descend and consequently remain cephalad to the superior glands. Ectopic glands within the carotid sheath may be surrounded by thymic fat. They may also be recognized within the inferior pole of the thyroid gland.
Sonographic appearance of the parathyroid glands
Normal parathyroid glands are rarely visualized, because of their small size and insufficient acoustic difference from surrounding tissue. The average size of a normal parathyroid gland is 5×3×1 mm, with a range of 2 to 12 mm. Each gland usually weighs an average of 40 mg with a range of 10 to 78 mg. In contrast, parathyroid adenomas, hyperplasia, and carcinomas exhibit a relatively hypoechogenic pattern, because of their compact cellularity relative to thyroid tissue. Hyperplastic glands in primary hyperparathyroidism are often 2 to 4 times larger than normal. However, hyperplastic parathyroids are difficult to detect unless they exhibit a significant increase in total gland volume. Microcalcifications may be present in hyperplasia, particularly in patients with secondary hyperparathyroidism. Enlarged parathyroids with indistinct borders suggest a carcinoma.
Parathyroid adenomas are usually well-circumscribed ovoid, bilobed, polygonal, triangular, or longitudinal in shape. They tend to be solid and homogenously hypoechoic relative to echogenic thyroid tissue. Overall, the ability to detect a parathyroid adenoma is a function of its size. The smaller the adenoma, the more difficult the task of localizing it radiographically. The lower limit of detection was reported to be 4 to 8 mm, with a 90% accurate rate of diagnosis in glands weighing more than 500 mg, although the authors often detect small adenomas down to 100 to 200 mg. The average mass of parathyroid adenomas is 10 times greater than normal parathyroid glands. Rarely, cystic changes or calcifications may be seen in adenomas undergoing complete or partial cystic degeneration. Seldom encountered, lipoadenomas appear hyperechoic because of increased fat content within the parathyroid adenoma.
Sonographic technique
To begin the ultrasonographic examination, the patient is placed in a comfortable, semireclined position facing midline, with the neck mildly extended. Neck extension allows slight elevation of mediastinal structures out of the thoracic inlet and may be exaggerated for mediastinal imaging. In most patients, a high frequency linear transducer may be used (8 to 15 MHz). Examination of larger patients may require a lower frequency to allow adequate sonographic penetration.
The proper frequency setting should allow optimal spatial resolution while also enabling adequate tissue penetration to visualize deep structures, such as the prevertebral musculature. Increasing the far-field or overall gain may also improve detection of deep parathyroid glands by facilitating the sonographic difference between prevertebral musculature and parathyroid tissue.
Ultrasonographic examination ideally follows a routine pathway, focusing on one side of the neck at a time in a slow and deliberate fashion. Initial evaluation involves the central neck compartment, focusing between the carotid arteries laterally and trachea medially. Starting in the transverse plane at the level of the innominate vessels inferiorly, scanning can progress superiorly to the superior pole of the thyroid or hyoid. The transducer is then moved in a lateral to medial direction for longitudinal scanning. Although longitudinal scanning is initially more challenging, it is necessary to corroborate abnormalities detected in the transverse plane and to detect adenomas missed with transverse scanning.
Skin and subcutaneous fat is first encountered by sound waves. Beneath these layers, the strap muscles (sternohyoid, omohyoid, and sternothyroid) centrally and sternocleidomastoid muscle laterally are visualized.
Muscle tissue may be distinguished by its fibrillar hypoechoic appearance compared with the echogenic texture of thyroid tissue. The thyroid gland may be assessed for nodules and microcalcifications among other features.
The esophagus may be found to the left side of the trachea. It has a hypoechoic peripheral muscular layer and an echogenic central mucosa. It may be better identified on dynamic imaging while observing the patient swallow. The prevertebral musculature is seen posterior to the thyroid gland.
Laterally in the neck, the contents of the carotid sheath may be seen adjacent to the thyroid gland. A distinction between the artery and vein can be made based on the compressibility of venous structures and more anterior and lateral position of the internal jugular vein.
The central neck is first evaluated for orthotopic parathyroid glands, with particular attention to the common locations aforementioned. The superior gland is commonly found posterior to the middle third of the thyroid gland and sometimes in the trachea-esophageal groove, ( Fig. 1 ) demonstrate the location of an orthotopic superior parathyroid gland. The inferior gland usually lies near the inferior pole of the thyroid gland, ( Fig. 2 ) demonstrate the location of an orthotopic inferior parathyroid gland.
If an adenoma is not identified after scanning the central neck in the transverse and longitudinal planes, then a systematic search for common ectopic locations is conducted. Common ectopic locations for superior parathyroid glands are retroesophageal, deep inferior mediastinum, and, occasionally, posterior intrathyroidal.
Common ectopic locations for inferior parathyroid glands are inferior intrathyroidal, intrathymic, carotid sheath, or anterior mediastinum. Intrathyroidal parathyroid glands may be differentiated from thyroid nodules or thyroid parenchyma by their relatively hypoechoic signal; however, differentiation may require ultrasound-guided fine-needle aspiration (FNA) for cytology, staining, and parathyroid hormone assay of needle-wash contents.
An enlarged gland in the paraesophageal region may pop into view by having patients turn their head away from the side being examined and then swallowing. A hypoechoic mass will be visible along a backdrop of a longitudinally directed muscle. Also, aiming the transducer medially aids in the evaluation of the retrotracheal or paratracheal region; however, retrotracheal ectopic glands may be difficult to detect because of the poor acoustic window caused by the tracheal air column.
A more lateral position of the transducer may decrease the shadow artifact related to the carotid artery and trachea, when examining the central compartment posterior to the carotid artery and trachea.
Tilting the transducer probe is a good adjunct technique to moving the transducer during scanning. To assist in visualization of deeply inferior parathyroid glands, the patient swallows while the ultrasound probe is aimed inferiorly underneath the clavicles. Despite swallowing maneuvers, visualization of mediastinal glands is often difficult because of poor penetration by sound waves.
The distinction between superior and inferior parathyroid glands can be occasionally difficult. The key distinguishing feature is based on embryologic origin. Superior parathyroid glands lie in a deeper plane than inferior parathyroid glands. Superior parathyroid glands lie posterior to the plane of the recurrent laryngeal nerve. The posterior surface of the common carotid artery or the inferior thyroid artery may be used as surrogate markers for the recurrent laryngeal nerve. Hence, an adenoma located entirely deep to these landmarks is most likely a superior parathyroid gland, even if located more inferiorly from its usual orthotopic location.
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