Abstract
As more patients present with the incidental diagnosis of primary hyperparathyroidism due to biochemical screening, treatment guidelines have been developed for the treatment of hyperparathyroidism. Management of primary hyperparathyroidism has evolved in recent years, with considerable interest in minimally invasive approaches. Successful localization of the diseased gland(s) by nuclear imaging and anatomical studies, along with rapid intraoperative parathyroid hormone assay, has allowed for focused and minimally invasive surgical approaches. Patients in whom the localization studies have identified single-gland adenoma or unilateral disease are candidates for such focused approaches instead of the traditional approach of bilateral exploration. These imaging techniques have also been critical in the successful management of patients with persistent or recurrent disease.
1
Introduction
Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia, the treatment of which is primarily surgical resection. It is characterized by hypercalcemia due to overproduction of parathyroid hormone (PTH). In the Western countries, as a result of increasing biochemical screening, PHPT has evolved from the disease of “bones, moans stones and groans” to a disorder that is most commonly asymptomatic in many patients . Primary hyperparathyroidism is a common disease occurring in about 1% of the adults, and its incidence rises to 2% or more in population older than 55 years . It is 2 to 3 times more common in women than in men and peaks around the fourth and fifth decades of life .The traditional approach to parathyroid surgery consists of bilateral neck exploration with the goal of identifying and visually inspecting all 4 parathyroid glands. The success of this approach exceeds 90% to 95%. However, cervical exploration requires a larger incision and longer operating time and potentially can have higher morbidity. Because more than 85% of patients with PHPT have a single-gland adenoma, 4-gland exploration may not be necessary in most patients if the enlarged parathyroid gland can be identified and localized preoperatively. There has been considerable interest in localization studies of the abnormal parathyroid gland(s) since the 1980s. The goal of this approach is to allow the surgeon to perform minimally invasive parathyroidectomy. The minimally invasive approach includes small incision parathyroidectomy, outpatient parathyroidectomy, endoscopic or video-assisted parathyroidectomy, and parathyroidectomy under local anesthesia. Various invasive and noninvasive localizing tests are available for evaluating PHPT. The traditional noninvasive imaging modalities include ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI); however, more recently, technetium-99m ( 99m Tc) sestamibi scan and 99m Tc sestamibi single-emission CT have been used for localizing the pathologic or enlarged parathyroid glands.
In this article, we will review the pertinent anatomy, pathophysiology of the parathyroid glands, and diagnosis of PHPT. The indications for the management of hyperparathyroidism and treatment options will be reviewed. Furthermore, we will discuss various surgical approaches to parathyroid surgery. In detail, we will review the role of various preoperative localization techniques and the sensitivity and specificity of each technique in localizing the abnormal parathyroid gland and the concordance of this identification with the operative and pathologic findings. In addition, we will evaluate the role of intraoperative parathormone assay in determining the success of the image-guided minimally invasive approach.
2
Anatomy and embryology of parathyroid glands
The parathyroid glands are endodermal in origin and develop from the dorsal wing of the third and fourth pharyngeal pouches . The first detailed anatomical description of the parathyroid glands was published by Welsh in 1898 and subsequently by Halsted and Evans in 1907, making a distinction between the superior and the inferior glands. They produce PTH, which regulates the circulating level of calcium through intestinal and renal absorption and bone remodeling. There are typically 4 parathyroid glands; however, supernumerary glands and less than 4 glands have been reported. In a reported series of 428 cases, 0.5% had 6 glands, 25% had 5 glands, 87% had 4 glands, and 6.1% of the cases had 3 glands . Most supernumerary glands were either rudimentary or divided, weighing as little as less than 5 mg and near a normal gland. The normal weight of each parathyroid gland is about 35 to 40 mg and measuring about 3 to 8 mm . The inferior thyroid artery is the predominant vascular supply to both upper and lower parathyroid glands in 76% to 86% of the cases .
The superior parathyroid glands originate from the fourth pharyngeal pouch. As they lose their attachment with the pharyngeal wall, they attach to the posterior surface of the inferiorly migrating thyroid . They have a much shorter migration distance compared with the inferior parathyroid glands accounting for their more predictable location. They are generally at the level of the upper two thirds of the thyroid. In an autopsy study of 503 cases, 80% of the superior glands were located on the posterior aspect of the thyroid gland within a circumscribed area of 2 cm in diameter about 1 cm above the crossing point of the recurrent laryngeal nerve and inferior thyroid artery . In this study, the ectopic superior parathyroid glands were found at the level of the upper pole of the thyroid and above the pole in 2% and 0.8% of the subjects, respectively. Other ectopic positions of superior parathyroid glands such as in the posterior neck, retropharyngeal, retroesophageal space, and intrathyroidal position are quite rare and reported in up to 1% of the cases .
Although the dorsal wing of the third pharyngeal pouch gives rise to the inferior parathyroid glands, the ventral wing gives rise to the thymus during the fifth week of gestation . Both primitive glands lose their connection with the pharyngeal wall and join the thymus as it travels caudally and medially to its final position in the mediastinum . This migration of the inferior parathyroid glands with the thymus results in the inferior parathyroid gland to be in a plane that is usually ventral to that of the superior parathyroid glands . For the same reason, ectopic inferior parathyroid glands can be found anywhere along this large area of descent up to the superior border of the pericardium . In a study of 645 parathyroid glands from 160 postmortem subjects, the inferior glands were evenly distributed between the lower pole of the thyroid and isthmus . In this study, 42% of the inferior parathyroid glands were found on the anterior or the posterolateral surface of the lower pole of the thyroid, whereas 39% were located in the lower neck in proximity to the thymic tissue, 15% lateral to the thyroid, and only 2% within the mediastinal thymic tissue. The persistence of the primitive attachment of the inferior parathyroid glands to the thymus, during the thymic migration, may result in a more inferior placement of the parathyroid glands. In this situation, the inferior parathyroid glands may be found at the level of the anterior superior mediastinum near the upper pole of thymic remnants . Exploration of the superior mediastinum becomes important during 4-gland exploration when the inferior parathyroid glands cannot be identified in the neck.
A rare ectopic location that could be a source of pitfall during parathyroid surgery for hyperparathyroidism is the intrathyroid location of the parathyroid glands. The embryologic origin of this ectopic location has been controversial, but it has been reported to originate from either the superior or the inferior gland . The incidence of intrathyroid parathyroid gland is reported between 0.7% and 3.6% in the literature . Because of their rarity, the intrathyroid parathyroid glands can be missed by preoperative imaging. This must be kept in mind when meticulous bilateral neck exploration fails to identify the hyperfunctioning gland. However, most of the time, the enlarged parathyroid glands are in the capsule of the thyroid or in the crypts of the thyroid tissue and are missed as intrathyroid parathyroid. In most cases, parathyroid glands are located in a symmetrical position in the neck. In one study, the symmetrical position of the superior and inferior glands was found in 80% and 70% of the cases, respectively, with a relative symmetry of 60% for all 4 glands .
2
Anatomy and embryology of parathyroid glands
The parathyroid glands are endodermal in origin and develop from the dorsal wing of the third and fourth pharyngeal pouches . The first detailed anatomical description of the parathyroid glands was published by Welsh in 1898 and subsequently by Halsted and Evans in 1907, making a distinction between the superior and the inferior glands. They produce PTH, which regulates the circulating level of calcium through intestinal and renal absorption and bone remodeling. There are typically 4 parathyroid glands; however, supernumerary glands and less than 4 glands have been reported. In a reported series of 428 cases, 0.5% had 6 glands, 25% had 5 glands, 87% had 4 glands, and 6.1% of the cases had 3 glands . Most supernumerary glands were either rudimentary or divided, weighing as little as less than 5 mg and near a normal gland. The normal weight of each parathyroid gland is about 35 to 40 mg and measuring about 3 to 8 mm . The inferior thyroid artery is the predominant vascular supply to both upper and lower parathyroid glands in 76% to 86% of the cases .
The superior parathyroid glands originate from the fourth pharyngeal pouch. As they lose their attachment with the pharyngeal wall, they attach to the posterior surface of the inferiorly migrating thyroid . They have a much shorter migration distance compared with the inferior parathyroid glands accounting for their more predictable location. They are generally at the level of the upper two thirds of the thyroid. In an autopsy study of 503 cases, 80% of the superior glands were located on the posterior aspect of the thyroid gland within a circumscribed area of 2 cm in diameter about 1 cm above the crossing point of the recurrent laryngeal nerve and inferior thyroid artery . In this study, the ectopic superior parathyroid glands were found at the level of the upper pole of the thyroid and above the pole in 2% and 0.8% of the subjects, respectively. Other ectopic positions of superior parathyroid glands such as in the posterior neck, retropharyngeal, retroesophageal space, and intrathyroidal position are quite rare and reported in up to 1% of the cases .
Although the dorsal wing of the third pharyngeal pouch gives rise to the inferior parathyroid glands, the ventral wing gives rise to the thymus during the fifth week of gestation . Both primitive glands lose their connection with the pharyngeal wall and join the thymus as it travels caudally and medially to its final position in the mediastinum . This migration of the inferior parathyroid glands with the thymus results in the inferior parathyroid gland to be in a plane that is usually ventral to that of the superior parathyroid glands . For the same reason, ectopic inferior parathyroid glands can be found anywhere along this large area of descent up to the superior border of the pericardium . In a study of 645 parathyroid glands from 160 postmortem subjects, the inferior glands were evenly distributed between the lower pole of the thyroid and isthmus . In this study, 42% of the inferior parathyroid glands were found on the anterior or the posterolateral surface of the lower pole of the thyroid, whereas 39% were located in the lower neck in proximity to the thymic tissue, 15% lateral to the thyroid, and only 2% within the mediastinal thymic tissue. The persistence of the primitive attachment of the inferior parathyroid glands to the thymus, during the thymic migration, may result in a more inferior placement of the parathyroid glands. In this situation, the inferior parathyroid glands may be found at the level of the anterior superior mediastinum near the upper pole of thymic remnants . Exploration of the superior mediastinum becomes important during 4-gland exploration when the inferior parathyroid glands cannot be identified in the neck.
A rare ectopic location that could be a source of pitfall during parathyroid surgery for hyperparathyroidism is the intrathyroid location of the parathyroid glands. The embryologic origin of this ectopic location has been controversial, but it has been reported to originate from either the superior or the inferior gland . The incidence of intrathyroid parathyroid gland is reported between 0.7% and 3.6% in the literature . Because of their rarity, the intrathyroid parathyroid glands can be missed by preoperative imaging. This must be kept in mind when meticulous bilateral neck exploration fails to identify the hyperfunctioning gland. However, most of the time, the enlarged parathyroid glands are in the capsule of the thyroid or in the crypts of the thyroid tissue and are missed as intrathyroid parathyroid. In most cases, parathyroid glands are located in a symmetrical position in the neck. In one study, the symmetrical position of the superior and inferior glands was found in 80% and 70% of the cases, respectively, with a relative symmetry of 60% for all 4 glands .
3
Etiology
The most challenging aspect of managing patients with PHPT is the recognition of the pathologic process that gives rise to the disorder. The appropriate treatment choice is directly dependent on the underlying etiology of the disorder. Primary hyperparathyroidism could be due to adenoma and 4-gland hyperplasia and rarely due to carcinoma. Most adults (80%–85%) with PHPT have single benign parathyroid adenoma, and up to 4% to 5%% are reported to have double adenomas . Four-gland hyperplasia is reported in up to 15% of patients with PHPT and parathyroid carcinoma in 0.8% to 2% of the cases . In the Multiple Endocrine Neoplasia Type 1 (MEN-1) and Endocrine Neoplasia Type 2 (MEN-2) and the familial syndromes, hyperplasia is the primary etiology of the hyperparathyroidism. Classically, an adenoma is defined as a pathologically enlarged gland with a rim of normal tissue that is most commonly solitary. Many surgeons and pathologists agree that differentiating adenoma from hyperplasia on frozen section is extremely difficult, and it can primarily be used to distinguish parathyroid tissue from other tissue; however, routine biopsy of the parathyroid glands is not recommended . In addition, criteria, such as gland size, shape, and cell density and type, have been shown to be of little help in distinguishing between adenoma and hyperplasia .
4
Pathophysiology
Parathyroid glands secrete PTH, which is the key regulator of calcium homeostasis. Parathyroid hormone is secreted as an 84-amino-acid peptide with a short plasma half-life (2–4 minutes). It is metabolized to biologically active N-terminal and inactive C-terminal fragments. The major regulator of PTH levels is the extracellular calcium through a feedback mechanism control of the calcium receptor . Calcitriol, or 1,25-dihydroxyvitamin D (1,25-(OH)2D), is the other essential mediator of calcium homeostasis, the synthesis of which is regulated by PTH. Calcitriol production begins when cholecalciferol (vitamin D) is generated in the skin exposed to ultraviolet light or absorbed through the intestine. In the liver, vitamin D is hydroxylated to 25-(OH)D and converted 1,25-(OH)2D3 (calcitriol) in the kidneys. This last step is tightly regulated by PTH . Parathyroid hormone and calcitriol act through the gastrointestinal tract, bone, and the kidney to maintain circulating ionized calcium concentrations. It increases serum calcium by acting indirectly on the osteoclasts in the skeleton to promote bone resorption and, thus, release of calcium into extracellular fluid. In addition to regulating calcitriol production, PTH also enhances calcium resorption at the distal nephron of the kidney. Through this series of checks and balances, extracellular calcium concentration is carefully maintained in the body and at times at the expense of skeletal calcium stores .
5
Diagnosis
Primary hyperparathyroidism is usually diagnosed by the physician because of hypercalcemia found on routine laboratory evaluation with an inappropriately elevated or normal levels of PTH . Patients with PHPT typically have low phosphorus because elevated PTH levels decrease the resorption of phosphorus in the kidneys. Most commonly, these patients are asymptomatic; however, a careful history and physical examination is necessary to rule out other causes of hypercalcemia. Although PHPT is the most common cause of hypercalcemia in the ambulatory setting, the differential diagnosis of hypercalcemia is complex and includes conditions such as metastatic cancer, multiple myeloma, sarcoidosis and other granulomatous diseases, ingestion of calcium or vitamin D, milk-alkali syndrome, and other less common causes. In addition to PHPT, other disorders such as familial hypocalciuric hypercalcemia will result in elevated levels of PTH and calcium. However, 24-hour urine calcium will show abnormally low levels of calcium in the urine in patients with familial hypocalciuric hypercalcemia. Medications such as thiazides and lithium can result in the elevation of PTH and calcium levels. Patients with tertiary hyperparathyroidism who had a history of renal failure and subsequent renal transplantation will also have elevated levels of PTH and calcium.
Parathyroid hormone levels are measured using immunoradiometric assays. The intact PTH assay that measures the PTH 1–84 and the non–PTH 1–84 and the bioactive assay that measures the PTH 1–84 and N-terminal PTH can be used for the diagnosis of PHPT with excellent correlation . Plasma total calcium levels are more commonly measured compared with ionized calcium levels; however, the superiority of one test over the other has been debated. If the total serum calcium level is used, it needs to be corrected based on the patient’s albumin level. This correction is made by adding 0.8 mg/dL to the total serum calcium measurement for every 1 g/dL below the serum albumin concentration of 4 g/dL.
6
Indications for treatment
The clinical presentation of PHPT has changed from patients with symptomatic disease to those with only biochemical evidence of disease incidentally found on routine laboratory examination. Asymptomatic PHT has spurred investigation into the natural history of this disease and indications for treatment. It is accepted that surgery is indicated in patients who present with symptomatic PHPT such as nephrolithiasis, nephrocalcinosis, renal dysfunction, osteopenia with fractures, osteitis fibrosa cystica, and altered neurologic function with obtundation, delirium, or coma . However, the management of patients with asymptomatic PHPT has been controversial. The National Institutes of Health organized a consensus development conference in 1990 that made recommendations for the management of patients with asymptomatic PHPT. These recommendations were subsequently updated in the 2002 National Institutes of Health Workshop on Asymptomatic PHPT . The summary of these recommendations for the surgical management of patients with PHTP is presented in Table 1 . Under these guidelines, the indications for surgery include a serum calcium concentration of 1.0 mg/dL above the upper limit of the normal level, urinary calcium excretion of greater than 400 mg/24 h, a reduction in the creatinine clearance of more than 30%, a bone mineral density with a t score below 2.5 at any site, age younger than 50 year, or those who cannot participate in appropriate follow-up . Some authorities, however, recommend a more liberal guidelines in the management of these patients owing to the inability to predict whether the complications or progression of disease will develop in a specific patient . The 2002 guidelines for monitoring patients with asymptomatic PHPT who do not undergo parathyroid surgery are measurement of serum calcium level every 6 months, annual measurement of serum creatinine concentration, and annual bone density measurement at all 3 sites (the lumbar spine, the hip, and the distal third of the radius) .
| 1. Significant bone, renal, gastrointestinal, or neuromuscular symptoms typical of primary hyperparathyroidism | |
| In asymptomatic patients | |
| 2. Serum calcium | Elevation by ≥1 mg/dL above the reference range (ie, ≥11.5 mg/dL in most laboratories) |
| 3. 24-h urine calcium excretion | Marked elevation (eg, >400 mg) |
| 4. Creatinine clearance | Decreased levels (eg, reduced by ≥30% compared with age-matched healthy persons) |
| 5. Bone density | Reduction in bone density of >2.5 standard deviations below peak bone mass at any measured site (hip, lumbar spine, wrist; ie, “T score” approximately <2.5 at any of these sites) |
| 6. Age | younger than 50 years |
7
Localizing studies
The treatment of hyperparathyroidism involves the removal of abnormally enlarged parathyroid gland(s) with the goal of rendering the patient with normal PTH levels and who is eucalcemic. Four-gland parathyroid exploration has been the criterion standard for parathyroid surgery until recently. Doppman made a classic statement in 1986 that “the only localization study indicated in a patient with untreated primary hyperparathyroidism is the localization of an experienced parathyroid surgeon.” However, minimally invasive and focused parathyroidectomy has become a widely accepted approach for the treatment of PHPT. The major limitation of this approach is the imperfection of the preoperative localization techniques. A summary of various localization techniques is provided in Table 2 . Through the use of combined preoperative and intraoperative techniques, this approach has achieved cure rates of greater than 95% with low morbidity . The success of the localization studies also depends on the experience of the institution. Invasive localizing studies, such as angiography and selective venous sampling, are rarely used now because of the high success rate of noninvasive approaches. However, if preoperative noninvasive studies are inconclusive, intraoperative or preoperative office-based ultrasound (US)-guided jugular venous sampling can be helpful in lateralizing the most hyperfunctioning parathyroid gland(s) .
| Noninvasive | Invasive |
|---|---|
| High-resolution US | Selective venous sampling |
| 99m Tc-Sestamibi scan | Angiogram |
| CT scan | Digital subtraction |
| MRI | US-guided FNA |
| SPECT/CT | US-guided jugular venous sampling |
| 4D-CT |
8
Ultrasound
Among anatomical imaging modalities, US is the most frequently used imaging modality with the lowest cost and has the advantage of not using ionizing radiation in this setting. It is, however, highly user-dependent and does not enable retromanubrial or mediastinal visualization. Normal parathyroid glands are rarely visualized by ultrasonography because of their small size and insufficient acoustic difference compared with adjacent thyroid tissue. However, parathyroid adenomas, hyperplasia, and carcinomas exhibit a relatively hypoechogenic pattern because of their compact cellularity relative to thyroid tissue .Parathyroid adenomas are usually well-circumscribed ovoid, are longitudinal in shape, and tend to be solid and homogenously hypoechoic relative to echogenic thyroid tissue ( Fig. 1 ) . Overall, the ability to detect a parathyroid adenoma is a function of its size and the pathology of the adjacent thyroid tissue . Ultrasound is inexpensive and highly sensitive in experienced hands. The sensitivity of US for detecting enlarged parathyroid glands ranges from 70% to 100% . False-positive or false-negative sonographic diagnosis may be due to thyroid nodules, prominent blood vessels, cervical lymph nodes, esophagus, and longus colli muscle . The smaller the adenoma, the more difficult it is to localize radiographically, and in the setting of multinodular goiter, parathyroid adenomas may be over looked due to poor sonographic penetration. In the presence of thyroid gland abnormalities, the sensitivity of US to identify abnormal parathyroid glands decreases, ranging from 47% to 84% . The identified concurrent thyroid disease should be addressed preoperatively by fine-needle aspiration or intraoperatively in these patients. Ectopically located glands, particularly intrathyroidal or retroesophageal glands, make the sonographic detection of the parathyroid glands more challenging and difficult. The US sensitivity also decreases in patients with persistent or recurrent hyperparathyroidism. This sensitivity is reported between 36% and 63% . The sensitivity of surgeon-performed US is reported to be comparable with radiologist-performed US in localizing parathyroid adenomas, and this may be advantageous for experienced endocrine surgeons . An advantage of this technique is that it provides dynamic imaging in the hands of the surgeon who has an intimate knowledge of the cervical anatomy. If the US findings are inconclusive, additional localizing techniques such as Tc-sestamibi scan should be used.
9
Sestamibi scan
The thallium technetium scintigraphy was popular in the late 1980s for the diagnosis of cervical and mediastinal parathyroid adenomas . However, sestamibi ( 99m Tc-methoxyisobutyl isonitrile), which was used for evaluation of myocardial perfusion, was noted to have selective affinity for abnormal parathyroid glands . Sestamibi has become the radiopharmaceutical of choice for parathyroid nuclear localization studies. Two different techniques are used to differentiate sestamibi uptake by abnormal parathyroid glands from uptake by the thyroid gland. The first uses sestamibi as a substitute to Tl-201 in a dual-radionuclide approach with subtraction imaging (with either radioactive iodine-123 [ 123 I] or 99m Tc pertechnetate), and the second approach uses sestamibi alone (single radiotracer) with early and delayed imaging (dual-phase study). Subtraction imaging is performed with the coadministration of a thyroid imaging agent, such as 123 I or 99m Tc pertechnetate and sestamibi as a thyroid-parathyroid agent . The thyroid images generated are then digitally subtracted from the sestamibi image, and the residual signal after subtraction of the thyroid image is indicative of parathyroid uptake . Various protocols have been described based on the type of the thyroid imaging tracer used and the sequence of tracer administration. 123 I/ 99m Tc-sestamibi and 99m TcO 4 − / 99m Tc-sestamibi dual-tracer subtraction techniques, have used in parathyroid imaging with limitations such as long imaging time or high thyroid counts . The use of a pinhole collimator in the neck can increase the imaging resolution; however, it will increase the image acquisition time. Regional perfusion, gland size and functional activity, cell cycle phase, and prevalence of mitochondria-rich cells are some of the factors affecting the diagnostic accuracy of 99m Tc-sestamibi imaging of parathyroid glands .
In the dual-phase technique, the net retention of sestamibi in thyroid decreases significantly more rapidly than in parathyroid adenoma over time (1–3 hours postinjection). This technique relies on the differential washout of sestamibi from thyroid tissue than from abnormal parathyroid glands . Images are obtained after the administration of sestamibi and then, again, approximately 2 hours later ( Fig. 2 ). A greater number of mitochondria in parathyroid tissue sequester sestamibi intracellularly. The patient’s neck immobilization is an essential step in double-tracer subtraction scintigraphy that is not required for dual-phase imaging. Technical simplicity of dual-phase MIBI scintigraphy is a major advantage of this technique. Conversely, a major limitation of dual-phase MIBI scan in detecting parathyroid gland pathology is the association of HPT with thyroid nodular disease. In a study of 39 patients undergoing dual-phase MIBI scintigraphy, 41% of the patients with positive MIBI scan had thyroid carcinoma . Thyroid pathology, such as hyperplastic nodules, chronic thyroiditis, Hürthle cell lesions, and adenomas can increase sestamibi uptake and retention, resulting in a false-positive study, and high washout from the parathyroid tissue can result in false-negative findings . Correlation with anatomical imaging and the use of subtraction techniques are important in these cases. Regardless of which technique is used, sestamibi scanning as a single modality for identifying adenomas has a reported sensitivity of 54% to 100%, with most series in the 80% or 90% range . Many studies looked at the sensitivity of US compared with sestamibi scanning and found no significant difference in the sensitivity of the 2 techniques in detecting abnormal parathyroid glands . In 1 recent study of 516 patients undergoing surgery for PHPT, surgeon-performed US accurately localized adenomas in 87% of patients, and MIBI correctly identified their locations in 76% ( P < .001) . In patients who underwent US first, MIBI provided no additional information in 92%. The authors concluded that in experienced hands, US is more accurate than MIBI in predicting the location of abnormal parathyroid glans in PHPT patients.
