Advertisement

Diagnostic Applications of Nuclear Medicine: Parathyroid Tumors

  • Federica Guidoccio
  • Sara Mazzarri
  • Salvatore Mazzeo
  • Giuliano MarianiEmail author
Living reference work entry

Abstract

The most common causes of hyperparathyroidism (HPTH) are of a benign nature, for either primary or secondary HPTH (as well as the tertiary form). Diagnosis of HPTH is based on clinical and biochemical findings, without any role for diagnostic imaging per se. Imaging is instead important for characterizing the disease, regarding especially number and sites of the hyperfunctioning parathyroid glands, which can be in their classical anatomic location or in ectopic locations. This information is crucial for planning surgery with a minimally invasive approach, associated or not with intraoperative guidance with the help of a handheld gamma-detecting probe – an approach that is common to other applications of radioguided surgery.

In addition to high-resolution ultrasound (US) and Magnetic resonance imaging (MRI) (and ceCT for selected applications), SPECT/CT with 99mTc-sestamibi has excellent performance for preoperative imaging of hyperfunctioning parathyroid glands. The PET tracer [11C]methionine has also been shown to possess excellent localization properties in patients with HPTH.

Parathyroid carcinoma is a very rare endocrine malignancy that occurs in <1% of primary HPTH. The initial clinical manifestations of parathyroid carcinoma are primarily linked to the effects of markedly elevated serum PTH levels. At initial presentation, very few patients have metastasis at regional lymph nodes or at distant sites. Parathyroid carcinoma tends to infiltrate adjacent structures in the neck. US, CT, and MRI have been used to localize parathyroid carcinomas and to detect mediastinal and thoracic recurrences or distant metastases. 99mTc-sestamibi scintigraphy can be successful for preoperative localization of the neoplasia and can identify metastases in lymph nodes and at distant sites. PET with [18F]FDG can also detect metastatic parathyroid cancers. Parathyroid carcinoma recurs in more than 50% of the cases and imaging studies should be performed in all patients before reoperation.

Keywords

parathyroid adenoma Parathyroid carcinoma Hyperparathyroidism Parathyroid scintigraphy 99mTc-sestamibi Single-tracer dual-phase parathyroid scintigraphy Double-tracer parathyroid scintigraphy Parathyroid PET/CT [18F]FDG [11C]methionine 18F-DOPA 18F-fluorocholine Ectopic parathyroid Minimally invasive parathyroidectomy Radioguided parathyroidectomy 

Glossary

99mTcO4-

99mTc-pertechnetate

ceCT

Contrast-enhanced computed tomography

CEUS

Contrast-enhanced ultrasound

CT

Computed tomography

DW ratio

Depth/width ratio

EBRT

External beam radiation therapy

ECG

Electrocardiogram

HPT-JT

Hyperparathyroidism-jaw tumor syndrome

HPTH

Hyperparathyroidism

MEN

Multiple endocrine neoplasia

MIRP

Minimally invasive radioguided parathyroidectomy

MRI

Magnetic resonance imaging

mRNA

Messenger RNA

PET

Positron emission tomography

PRAD

Parathyroid adenomatosis oncogene

PTH

Parathyroid hormone

RGS

Radioguided surgery

SPECT

Single photon emission computed tomography

SPECT/CT

Single photon emission computed tomography/computed tomography

US

Ultrasound

VDR

Vitamin D receptor

Anatomy, Physiology, and Pathophysiology

There are normally two pairs of parathyroid glands in adult humans, each one measuring approximately 6 × 4 × 2 mm and weighing 30–50 mg (for a total weight of approximately 130–140 mg). Supernumerary parathyroid glands can be found in 2–5% of the general population, while it is very rare to find less than four glands. The parathyroid glands are endodermal in nature and originate embryologically from the third and fourth pharyngeal pouches. From the point of view of their final anatomical location, it is important to notice that their relative position is inverted during their migration in fetal life (Fig. 1). In fact, the two glands that are originally positioned more cranially (in the third pharyngeal pouch) follow in part the descent of the thymus, to reach their final location at the posterolateral surface of the lower lobes of the thyroid; nevertheless, they can also detach from their connection to the thymus and remain located somewhere along their path of descent. The glands that are originally positioned in the fourth pharyngeal pouch (more caudally) are instead closely associated with the embryologic structure of the thyroid gland; they maintain a close association with the fetal thyroid until the descent of both structures to their final location in the neck. These parathyroid glands are positioned at the posterolateral surface of the upper poles of the thyroid lobes. The most frequent anatomo-topographic location of the upper glands is posterior to the middle and upper third of the thyroid lobe, cranially to the inferior thyroid artery and posterior to the recurrent laryngeal nerves. The inferior parathyroid glands are located in a more variable position, most likely due to their more complicated pattern of migration from and initial cranial position to a final caudal position [1]. From the surgical point of view, in approximately 50% of the cases, the lower parathyroid glands are located posteriorly or laterally to the lower pole of the thyroid lobe, within a 20 cm radius. Other less frequent locations include within the thyrothymic ligament, within the thymus in the mediastinum, or intrathyroidal [2] (Fig. 2). Enlarged adenomatous or hyperplastic parathyroid glands may change somewhat their location.
Fig. 1

Embryological origin and routes of descent of the thymus and parathyroid glands during fetal life. The parathyroid glands that originate more cranially (in the third pharyngeal pouch) migrate initially in association with the thymus, to reach their final position more caudally with respect to the parathyroid glands that originate in a lower location (fourth pharyngeal pouch). Therefore, the lower parathyroid glands follow a much longer path of descent, a feature that probably explains the greater frequency of ectopic location in adult life of these glands with respect to the upper parathyroid glands (Modified from: Sadler [171])

Fig. 2

Diagrammatic representation of the variability in anatomic location of hyperfunctioning parathyroid glands. This data refers to a total of 104 adenomas found at reoperation over a quite long time span (1930–1975) at the Massachusetts General Hospital (Harvard Medical School, Boston, MA); patients underwent second surgery because of recurrent PHPT after prior conventional four-gland exploration surgery. About 65% of all ectopic locations mirror the route of descent of the lower parathyroid glands (longer migration path) (Modified from: Wang [172])

The predominant type of cells that constitute adult parathyroid tissue is constituted by the so-called chief cells, followed by the oxyphilic cells (whose histologic appearance is linked to their abundance in mitochondria) and by the intermediate stage of transitional oxyphilic cells [3]. The parathyroid hormone (PTH) acts on different tissues and apparatuses with multifaceted functions, the combined effect of which is to increase calcium concentration in blood. In order to achieve this effect, PTH stimulates bone resorption (thereby mobilizing calcium from bone to circulating fluids) and promotes calcium resorption in the kidneys; at the same time, it decreases tubular resorption of phosphate. Moreover, PTH stimulates the synthesis of the active form of vitamin D, which in turn stimulates calcium absorption in the gastrointestinal tract [4].

Benign Causes of Hyperparathyroidism

Primary hyperparathyroidism (HPTH) is characterized by inappropriate PTH production, i.e., not as a response to reduced calcium concentration in circulating blood as it would be the physiologic function of the parathyroid glands; therefore, this inappropriate PTH secretion results in hypercalcemia [5]. The causes of primary HPTH are either a single parathyroid adenoma (80–85% of the cases), hyperplasia or multiple adenomas (10–15% of the cases), or parathyroid carcinoma (0.5–1% of the cases) [6]. Familial forms of primary HPTH include multiple endocrine neoplasia type I (MEN I) and type II (MEN II), the HPTH-jaw tumor syndrome, familial hypocalciuric hypercalcemia, and familial isolated HPTH [7].

The characteristic abnormality in hyperparathyroidism is the downregulated response of parathyroid cells to reduce PTH secretion in response to elevated calcium. In vitro and in vivo studies have focused on the receptor for calcium ions expressed by parathyroid cells (CaR) to explore the role of the calcium sensor in the development of hyperparathyroidism. Abnormalities in CaR expression or function as a consequence of some as yet unidentified genetic mutation(s) may contribute to the failure of PTH secretory regulation [4].

Also genetically linked variations of vitamin D metabolism can be associated with some forms of hyperparathyroidism. In fact, some allelic variants of vitamin D receptors (VDR) are overexpressed in patients with PHPT, combined with a reduced expression of VDR mRNA; as a consequence, the parathyroid cells are less susceptible to inhibition by active vitamin D, a condition that favors hyperplastic or adenomatous changes [4, 8, 9].

Prior irradiation of the neck and upper chest for benign diseases, including treatment of Grave’s disease with 131I-iodide, is an additional risk factor for the development of HPTH [10, 11]. Interestingly, this association has not been demonstrated after treatment with radioiodide for thyroid cancer, a condition that is usually treated with much greater amounts of radioactivity than Graves’ disease. The genetic alterations found in radiation-associated parathyroid tumors most commonly involve losses in 11q and 1p, similarly as in parathyroid adenomas linked to MEN-1 gene abnormalities; these observations suggest a certain degree of vulnerability of this gene to irradiation.

Secondary HPTH is the result of long-standing hypocalcemia, as a physiologic or pathophysiologic parathyroid response to maintain calcium homeostasis. The most frequent cause of secondary HPTH is chronic renal failure, developing in about 90% of the patients undergoing hemodialysis [12, 13]. Other causes of secondary HPTH include osteomalacia, rickets, and malabsorption.

Tertiary HPTH is r eferred to the condition of persisting HPTH after successfully treating the cause of a secondary form of HPTH, as it can happen following, e.g., correction of chronic renal failure with kidney transplantation. Tertiary HPTH is usually sustained by hyperplasia of all four glands, but in over 20% of the patients, single or double adenomas are present [12].

Parathyroid adenomas include several histologic patterns, the most frequent of which are the oncocytic variant (constituted of cells with abundant granular eosinophilic cytoplasm) (Fig. 3), the lipoadenoma variant (composed of abundant stromal cells), and the water-clear cell variant. These variants represent clonal expansions, and several molecular abnormalities have been described such as rearrangement of the cyclin-D1/PRAD1 oncogene and mutation of the tumor suppressor MEN1 gene (11q13). Loss of the chromosome 11q locus is the most frequent abnormality found in parathyroid adenomas [14, 15].
Fig. 3

Histologic pattern of a parathyroid adenoma (low magnification): nests of densely packed cells arranged in follicular and colloid-like structures mimicking the thyroid; scattered lymphocytic infiltrates are also present (Courtesy of Prof. Fulvio Basolo, Division of Pathology, Department of Surgery, University of Pisa, Pisa, Italy)

Diagnosis and Treatment of Benign Hyperparathyroidism

Besides hypercalcemia, manifestations of symptomatic primary HPTH include overt bone disease, kidney disease, as well as nonspecific gastrointestinal, cardiovascular, and neuromuscular dysfunction. The main renal manifestations include nephrolithiasis (due to hypercalciuria), nephrocalcinosis, and renal dysfunction. Bone disease includes osteopenia (with pathologic fractures) and osteitis fibrosa cystica, while altered neurologic function can manifest with obtundation and delirium [16]. Nevertheless, over 80% of the cases of primary HPTH are today asymptomatic, being only discovered during general check-up evaluations (that now routinely include measurement of the serum calcium levels); there are no clinical factors that predict prognosis of these patients [17, 18]. Diagnosis of primary HPTH is based on persistent hypercalcemia and elevated serum PTH levels. Serum phosphorus is typically low, due to decreased resorption in the kidneys.

Secondary HPTH is characterized by hypocalcemia or normocalcemia (despite increased serum PTH levels) and hyperphosphatemia, associated with decreased vitamin D levels [12]. In tertiary HPTH, there are normal or elevated serum calcium concentrations in combination with moderately elevated PTH levels, decreased vitamin D and phosphate levels, and elevated alkaline phosphatase [12].

Currently, the only promising medical therapy available for primary HPTH is based on the use of the drug “cinacalcet ” [19, 20], a novel member of the family of calcimimetics; its mechanism of action is based on direct modulation of the CaR expressed by the chief parathyroid cells, thereby the drug increases the sensitivity of the calcium sensor to extracellular calcium and thus reduces the secretion of PTH [21, 22, 23]. Management of patients with secondary HPTH is predominantly medical, and it includes calcitriol, vitamin D, calcimimetics (such as cinacalcet and new phosphate binders) [24, 25]. In tertiary HPTH, medical treatment is generally not indicated, although supplementation with vitamin D can be beneficial.

About 1–2% of patients with secondary HPTH require parathyroidectomy because of calciphylaxis, failure of medical management of hypercalcemia, hypercalciuria, serum PTH >800 pg/mL, hyperphosphatemia (with “calcium × phosphorus” product greater than 70), and associated symptoms [26, 27]. The main form of treatment for tertiary HPTH is surgery, which is indicated in case of severe or persistent hypercalcemia, severe osteopenia, and clinical symptoms [28].

Complete resection of any hyperfunctioning parathyroid tissue is crucial for surgical treatment with curative intents. Persistent or recurrent HPTH generally results from inadequate initial resection and/or from the presence of an ectopic hyperfunctioning gland that had not been recognized at surgery; this condition requires reoperation. Bilateral neck exploration, based on surgical visualization of all four parathyroid glands, achieves a high success rate with minimal morbidity, if performed by experienced endocrine surgeons [29]. During parathyroid surgery, distinguishing an adenoma from hyperplasia can be problematic, not only on visual analysis but also upon intraoperative frozen section histology.

Preoperative imaging techniques play an important role in the surgical management of patients with HPTH, in order to localize and identify abnormal glands [30]. This approach has been crucial for the development of minimally invasive parathyroidectomy [31, 32], a procedure that can be video-assisted, endoscopic, radioguided, or image-guided unilateral exploration [33, 34, 35]. Several imaging techniques are available for preoperative localization of hyperfunctioning parathyroid glands, as detailed further below.

Persistent and Recurrent Hyperparathyroidism

In 5–10% of patients who undergo surgery for primary HPTH, persistent or recurrent HPTH can occur. Hyperparathyroidism presenting after a period of >6 months of normocalcemia following surgery is defined as “recurrent hyperparathyroidism” and is usually linked to regrowth of the remaining parathyroid tissue.

Causes of the immediate failure of surgical treatment failure (inducing persistent HPTH) include inaccurate/incomplete localization of adenoma(s), the insufficient resection of easily recognized multigland disease, and (even though a rare occurrence) the presence of metastatic parathyroid carcinoma. Persistent HPTH is characterized by abnormalities in calcium metabolism in the immediate postoperative period. Surgical failure may be due to either inexperience of the surgeon or interpretation errors during intraoperative frozen section histology. Persistent HPTH is more frequent in patients with familial forms of hyperparathyroidism, especially the MEN-1 syndrome (generally in less than 25% of patients, but up to 40–60% for less-experienced surgeons [36].

Another rare situation of recurrent or persistent hyperparathyroidism is called “parathyromatosis ” which is defined as multiple remnants of hyperfunctioning parathyroid tissue scattered throughout the neck or upper mediastinum. This condition may be due either to growth of nests of parathyroid tissue left along the route of descent during embryologic development of the parathyroid glands or to accidental implantation of parathyroid tissue in the surgical bed at the time of parathyroidectomy.

Role of Preoperative Imaging

Preoperative imaging of the parathyroid glands is important to identify the parathyroid glands that are enlarged/hyperfunctioning because of hyperplasia and/or adenoma. Visualization of normal parathyroid glands using conventional imaging is virtually impossible; because of their tissue characteristics and small size and weight (less than 40 mg), they cannot be distinguished from the adjacent thyroid parenchyma. Adequate presurgical imaging not only reduces the surgical time by limiting surgical exploration to the affected side but, above all, allows the detection of parathyroid adenomas in ectopic sites. While approximately 80–85% of parathyroid adenomas are found in their normal location adjacent to the thyroid gland, 15–20% are ectopic [37]; when parathyroid adenomas are located in the mediastinum, into the thyroid gland, in or lateral to the cervical neurovascular bundle, or high in the neck, the term “major ectopy” is employed to describe the condition. Overall ectopic locations include:
  • Anterior–superior mediastinum (either within the thymus or in a juxta-thymic position)

  • Posterior–superior mediastinum along the esophagus

  • Lower thyroid lobe (2–3% of all parathyroid adenomas)

  • The middle mediastinum (very rarely)

Other ectopic locations include the carotid sheath (within or even lateral to this anatomic structure), while an undescended lower parathyroid gland is rarely found in the upper neck, anterior to the carotid bifurcation.

Hyperplasia and adenoma(s) of parathyroid glands produce increased cellularity, increased metabolic activity, and increased arterial vascular supply. These features are the basis for visualization using different imaging approaches. Imaging protocol for hyperplastic/adenomatous parathyroid glands usually consists of high-resolution ultrasound, radionuclide imaging, contrast-enhanced computed tomography (CT), and magnetic resonance imaging (MRI) [30, 38, 39, 40], used in variable combinations depending on certain patient-specific features as well as on local availability, logistics, cost, and radiation dosimetry considerations. In a recent review [39], the most frequently cited average values of sensitivity for correct localization of the adenoma are 76.1% (95% CI 70.4–81.4%) for ultrasound examination, 78.9% (70.4–90.6%) for scintigraphy with 99mTc-sestamibi, and 89.4% for CT. The corresponding average positive predictive values are 93.2% (95% CI 90.7–95.3%) for ultrasound, 90.7% (83.5–96%) for scintigraphy, and 93.5% for CT.

Non-radionuclide Imaging Techniques

High-resolution ultrasound (US) currently constitutes, in association with nuclear medicine imaging, a reliable first-line modality for preoperative localization of a parathyroid lesion. The main advantages of US are low cost, wide availability, and the noninvasive nature of the technique; furthermore, US has an important role to select patients for other imaging modalities (for instance, in case of negative US studies due to ectopic parathyroid glands located in deep cervical sites or in the mediastinum).

Optimal parameters for best diagnostic performance of US include the use of a high-frequency (7.5–13 MHz) linear array probe. The entire region of the neck including the thyroid gland, the paratracheal groves, and the carotid–jugular axis from the carotid bifurcation superiorly to the sternal notch inferiorly should be carefully explored by transverse and longitudinal scans. In patients with a large thyroid goiter and/or when the thyroid gland is partially plunging in the upper mediastinum, the use of a lower frequency US probe, with deeper penetration, can be helpful to explore the neck. The patient is lying supine and with the neck hyperextended during the US scan; right or left lateral rotation of the head is useful to better visualize the deep sites of the neck, in particular the paraesophageal or paravertebral regions (possible sites of an ectopic parathyroid adenoma/mass) are better visualized with right or left lateral rotation of the head.

A parathyroid mass typically appears on grayscale US imaging as a rather homogeneous hypoechoic mass adjacent and posterior to the thyroid gland (Fig. 4). Topographically, the mass is usually located anteriorly to the longus colli muscles, medially to the common carotid artery; occasionally the mass is located more inferiorly in the paratracheal and paraesophageal groves. It is not infrequent to detect a clear hyperechoic interface line separating the thyroid gland from the parathyroid lesion (Fig. 5). Structure of an adenomatous/hyperplasic parathyroid gland is mostly frequently constituted by a hypercellular tissue with absent or scarce fluid or stromal components, a feature that explains the hypoechoic pattern of these lesions. Nevertheless, fatty deposition and/or internal calcifications occasionally occur in adenomas, causing the appearance of nontypical inhomogeneous echographic patterns, some of which are characterized by lobulation and/or cystic changes.
Fig. 4

Ultrasound pattern of a parathyroid adenoma located behind the right thyroid. The thyroid parenchyma is well recognized in the middle part of the image, just below the superficial layers (skin and subcutaneous muscle). The parathyroid adenoma is located just beneath the thyroid tissue, well separated by a hyperechoic capsule and appearing slightly hypoechoic with respect to the thyroid parenchyma; color Doppler evaluation reveals some hypervascularization within the parathyroid adenoma

Fig. 5

Ultrasound pattern of a parathyroid adenoma more hypoechoic than the case presented in Fig. 4. Also in this case, the adenoma is located behind the right thyroid lobe of the thyroid, which is well recognized below the skin and subcutaneous muscle and separated from the parathyroid adenoma by a thin hyperechoic capsule (better detected in the upper panel). The more hyperechoic structure beneath the thyroid and the parathyroid adenoma is the transverse process of a vertebra in the cervical spine (C4–C5). Color Doppler evaluation (lower panel) reveals multiple vessels within the adenoma (Courtesy of Dr. Mario Meola, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy)

On the other hand, it is difficult in most instances to distinguish the US pattern of a hyperplasic parathyroid gland from that of a parathyroid and adenoma. In general, hyperplasic parathyroid glands most frequently have a spherical shape than adenomas and occasionally contain intraparenchymal calcifications. Furthermore, when multiple parathyroid glands are involved in a patient with chronic renal failure, it is easy to diagnose parathyroid hyperplasia. Finally, although the US appearance of a parathyroid carcinoma mimics that of an adenoma, malignancy can be recognized by an irregular shape concomitant with infiltration of the adjacent anatomic structures [41, 42].

The color Doppler pattern is also useful to correctly identify parathyroid lesions that are in general characterized by diffuse intranodular color signals or focal peripheral flow associated with variable degrees of intranodular vascularization. These features are especially useful to distinguish a parathyroid mass from a typical thyroid nodule that generally displays a regular peripheral flow pattern [43, 44, 45]. A recent addition to the imaging armamentarium for enlarged parathyroid glands is contrast-enhanced US (CEUS), based on the use of microbubble contrast and contrast-specific imaging software [46]; the underlying rationale is that the blood pool contrast so induced can depict the micro- and macro-circulation of the organ/tissue under evaluation. Both parathyroid adenomas and hyperplastic glands exhibit strong enhancement in the arterial phase, a feature related to the hyperfunctioning nature of these lesions; parathyroid lesions usually display faster washout than lesions pertaining to the thyroid gland. On the other hand, lymph nodes (whose basic US structure can be misinterpreted as a parathyroid mass) display an early central arterial and late parenchymal enhancement without early washout.

The accuracy of parathyroid’s localization with US varies as a function of the size and location of the adenoma, being lowest in the evaluation of the substernal, retrotracheal, and retroesophageal spaces [47]. Furthermore, in about 40% of the patients who have undergone prior surgery, US examination does not allow to detect the presence of parathyroid glands because of distorted anatomy and/or the presence of fibrous scar tissue. Notwithstanding these limitations, US still constitutes a reliable first-line imaging approach, in conjunction with radionuclide imaging, for preoperative localization of enlarged parathyroid glands.

CT imaging is less commonly used for preoperative localization and is usually reserved (similarly as for MRI) for detecting suspected ectopic glands in patients in whom prior parathyroidectomy has failed to cure HPTH [48]. CT should also be considered for patients in whom the first-line imaging steps (US and scintigraphy) are negative [39, 49] or for patients in whom the US examination is negative, but scintigraphy suggests an ectopic lesion [50].

CT localizes parathyroid adenomas in the retrotracheal, retroesophageal, and mediastinal spaces better than US. On the other hand, parathyroid glands located in the lower neck or close to the thyroid gland are not easily detectable by CT. The overall sensitivity of CT for preoperative identification of hyperplastic parathyroid glands ranges between 46% and 80%. Because of frequent hypervascularization of abnormal parathyroid glands, CT with contrast enhancement results in sensitivity consistently close to 80%. In fact, in patients with multigland disease, CT has high sensitivity and high positive predictive value, especially if performed with the so-called 4D modality [40, 51, 52]. When compared to 99mTc-sestamibi scintigraphy, CT has the advantage of a shorter examination time, associated with a comparable overall cost; on the other hand, dedicated acquisition protocols should be adopted in order to keep to a minimum the relatively high radiation burden of CT. Although local availability and logistics frequently dictate the sequence of imaging steps for preoperative localization of hyperfunctioning parathyroid lesions, there are some proponents for the use of CT imaging (either alone, combined with US, or combined with 99mTc-sestamibi scintigraphy) as the first-line approach rather than the combination of US with 99mTc-sestamibi scintigraphy [53, 54, 55, 56, 57].

Obvious disadvantages of CT imaging include a relatively high radiation burden to patients and the need to use an iodinated contrast to be administered i.v.; the latter feature has some associated risks and strict contraindications, for instance, in patients with prior allergic reactions to iodinated contrast agents or in patients with reduced renal function.

MRI is currently less used than CT as a second-line imaging procedure for preoperative localization of parathyroid lesions, mostly due to difficult access to this imaging modality [58]. Nevertheless, MRI is used in patients with negative or discordant localization studies, those with persistent or recurrent disease after prior surgery, or when contrast CT is contraindicated. In general, the sensitivity of MRI for localizing hyperfunctioning parathyroid glands ranges from 43% to 71%, higher when it is employed for detecting ectopic glands (88–96%) [59, 60]. Recent study showed that high-resolution MRI using a 3.0 T magnet could detect adenomas in 57% of patients with PHPT in whom both contrast CT and 99mTc-sestamibi scintigraphy failed to localize the adenoma [61].

MRI protocols involve the acquisition of multiplanar images of the neck and upper mediastinum. The standard images are obtained from the hyoid bone to the sternal notch; when a mediastinal ectopic parathyroid gland is suspected, additional ECG-gated axial images of the mediastinum are acquired. MRI scans are commonly acquired with standard T1–T2-weighted spin-echo sequences.

On MRI, enlarged parathyroid glands have considerably increased intensity on T2-weighted and proton density images, but it is not possible to distinguish parathyroid adenomas from either simple hyperplasia or carcinoma.

Parathyroid Scintigraphy

Although there are no radiopharmaceuticals concentrating specifically only in the parathyroid glands, parathyroid scintigraphy plays an important role in the preoperative localization of hyperfunctioning parathyroid glands as a guide to minimally invasive parathyroidectomy. Early radionuclide techniques were based on the subtraction scan using two imaging agents, one accumulating both in the thyroid and parathyroid parenchyma and one exclusively in the thyroid gland, respectively. The two historical approaches to parathyroid imaging with radionuclides are the use of 75Se-methionine (a radiolabeled amino acid accumulating in both tissues) coupled with 131I-iodide (accumulating solely in the thyroid gland) [62, 63, 64], and the use of 201Tl-chloride (imaging both parenchymas, similarly as 75Se-methionine) coupled with 99mTc-pertechnetate (imaging the thyroid only) [65].

However, since its first introduction for parathyroid imaging in 1989 [66], 99mTc-sestamibi has rapidly become the radiopharmaceutical of choice for parathyroid imaging, with an overall 85–95% accuracy in primary HPTH. Localization of 99mTc-sestamibi in the parathyroid tissue is a function of metabolic activity, since this agent accumulates preferentially in mitochondria-rich tissues, as typically is a hyperfunctioning parathyroid gland. Although 99mTc-sestamibi accumulates also in the normal thyroid parenchyma, its washout rate from the parathyroid glands is different from that of the thyroid tissue [67]; in fact, this radiopharmaceutical is released much faster from the thyroid than from the parathyroid tissue. This differential retention kinetics seems to be related to downregulation in the parathyroid tissue of the P-glycoprotein system, which is responsible for the efflux of various compounds (including 99mTc-sestamibi) from the intracellular to the extracellular space [68]. The so-called single-tracer, double-phase scintigraphy is based on this difference in washout rate; it is performed by acquiring early images of the neck and thorax (about 15 min postinjection) and then imaging again at 2–3 h. A hyperfunctioning parathyroid adenoma appears as an area of early radiopharmaceutical uptake that persists on late imaging [69] (Fig. 6). Thyroid nodules that concentrate 99mTc-sestamibi avidly can cause difficulties in the interpretation of images [70]. To avoid this drawback, 99mTc-pertechnetate or 123I-iodide scintigraphy can be performed in patients with thyroid nodular goiter [71]. Furthermore, some parathyroid adenomas exhibit a rapid washout of 99mTc-sestamibi, thus possibly resulting in false-negative results.
Fig. 6

Planar, single-tracer, dual-phase parathyroid scintigraphy with 99mTc-sestamibi in a patient with primary hyperparathyroidism, showing early uptake at the base of the right lobe (slightly greater than in the thyroid parenchyma), and selective retention in the delayed imaging. This area corresponded to a parathyroid adenoma that was subsequently removed with radioguided, minimally invasive surgery

Differently from earlier approaches based on the use of a single tracer, the current version of dual-tracer subtraction parathyroid scintigraphy is based on the use of 99mTc-sestamibi coupled with a second radiopharmaceutical that accumulates specifically in the thyroid gland, either 123I-iodide or 99mTc-pertechnetate [71]. The thyroid images are subtracted from the 99mTc-sestamibi image, so that residual focal uptake indicates the presence of hyperfunctioning parathyroid tissue. Due to high cost and limited availability of 123I-iodide (as well as to the relatively long acquisition time with this radionuclide), 99mTc-pertechnetate is most frequently employed as the pure thyroid imaging agent in the routine clinical practice. The 99mTc-pertechnetate image (standard activity of 185 MBq) is acquired 20 min after injection; thereafter potassium perchlorate can be administered to induce rapid washout of this agent from the thyroid gland, after which 99mTc-sestamibi is administered [72]. The 99mTcO4 -/99mTc-sestamibi technique has sensitivity around 90% and specificity close to 100%. Alternatively, administration of 99mTc-pertechnetate after the delayed 99mTc-sestamibi acquisition allows to improve the definition of equivocal area of 99mTc-sestamibi uptake [48] (Fig. 7).
Fig. 7

Dual-tracer parathyroid scintigraphy with 99mTc-sestamibi and 99mTc-pertechnetate in a patient with hyperparathyroidism and multinodular goiter. Upper left panel: planar image acquired early after injection of 99mTc-sestamibi (about 10 min), with a field of view including the neck and the whole chest as a preliminary exploration for possible ectopic locations of the adenoma. Upper right panel: image acquired about 15 min postinjection, with zoom on the neck and upper chest; there is a suspicious area of abnormal accumulation corresponding to the base of the left thyroid lobe. Lower left panel: image acquired about 2.5 h postinjection of 99mTc-sestamibi, showing partial washout from the thyroid parenchyma and persistent uptake corresponding to the base of the left thyroid lobe. Lower right panel: image acquired about 20 min after administering 99mTc-pertechnetate (digitally subtracted from residual activity in the delayed 99mTc-sestamibi acquisition), showing selective visualization of the thyroid parenchyma with inhomogeneous uptake throughout the gland due to multinodular goiter. The parathyroid adenoma was located in the area showing slow washout of 99mTc-sestamibi in the delayed acquisition

As an alternative to 99mTc-sestamibi, 99mTc-tetrofosmin is employed in some centers for parathyroid scintigraphy, although this agent exhibits slower washout from the thyroid gland than washout of 99mTc-sestamibi [73].

Parathyroid scintigraphy, either with the single-tracer, dual-phase technique or with the dual-tracer subtraction method, shows a sensitivity higher than 90% in primary PHPT, higher than that obtained with the other imaging techniques [31]. Nevertheless, sensitivity to detect hyperplastic glands in secondary HPTH is not higher than 55% [12]. 99mTc-sestamibi scintigraphy is critical in persistent or recurrent HPTH, with successful identification of the parathyroid remnant in 85% of the patients. SPECT, and especially SPECT/CT imaging, is useful especially in the detection of small or ectopic adenomas and in patients with multinodular goiter or with recurrent HPTH [74, 75] (Fig. 8).
Fig. 8

Dual-tracer parathyroid scintigraphy with 99mTc-sestamibi and 99mTc-pertechnetate in a patient with hyperparathyroidism and multinodular goiter. (a) Upper left panel: planar image acquired early after injection of 99mTc-sestamibi (about 10 min), with a field of view including the neck and the whole chest as a preliminary exploration for possible ectopic locations of the adenoma. Upper right panel: image acquired about 15 min postinjection, with zoom on the neck and upper chest; there is a suspicious area of abnormal accumulation corresponding to the apex of the left thyroid lobe. Lower left panel: image acquired about 2.5 h postinjection of 99mTc-sestamibi, showing partial washout from the thyroid parenchyma and persistent uptake corresponding to the apex of the left thyroid lobe. Lower right panel: image acquired about 20 min after administering 99mTc-pertechnetate (digitally subtracted from residual activity in the delayed 99mTc-sestamibi acquisition), showing selective visualization of the thyroid parenchyma with inhomogeneous uptake especially at the left thyroid lobe due to multinodular goiter. (b) Transaxial, coronal, and sagittal fused SPECT/CT sections defining location of the parathyroid adenoma at the apex of the left thyroid lobe

By combining the three-dimensional functional information of SPECT with the anatomic information of CT, hybrid SPECT/CT allows optimal preoperative localization of the enlarged parathyroid glands (Fig. 9), thus complementing and sometimes even clarifying negative/equivocal US findings (Fig. 10). In this regard, it has clearly been demonstrated that SPECT/CT is more accurate than SPECT alone in patients with HPTH and nodular goiter and that the combination of early SPECT/CT with any delayed imaging method (SPECT/CT, SPECT, or planar imaging) is superior to double-phase planar imaging or double-phase SPECT [76, 77, 78]. This procedure should therefore be routinely used in the preoperative evaluation of patients with HPTH in whom minimally invasive parathyroidectomy is planned.
Fig. 9

99mTc-sestamibi SPECT/CT (fused transaxial, coronal, and sagittal sections) in patient with persistent HPTH after prior parathyroidectomy (during which thyroidectomy was also performed because of concomitant multinodular goiter). Hybrid imaging defines the exact anatomic coordinates of the ectopic parathyroid adenoma located in the upper mediastinum

Fig. 10

A 62-year-old woman with clear diagnosis of primary HPTH (serum calcium 11 mg/dL, serum phosphorous 1.9 mg/dL, serum PTH 996 pg/mL). (a) An initial US scan of the neck could not reveal abnormal parathyroid lesions in the expected locations (upper panel); the lower panel shows the early and delayed 99mTc-sestamibi planar scans, with clear positivity for a hyperfunctioning parathyroid mass located below the left lower thyroid lobe. A SPECT/CT acquisition was additionally performed. (b) The left panels show the axial sections obtained with hybrid SPECT/CT imaging, confirming prolonged retention of 99mTc-sestamibi in a mass which was detectable also on the low-definition CT component of the scan (CT image above, fused SPECT/CT image below). A focused US scan was therefore repeated and confirmed the presence of a parathyroid adenoma in an unexpected location, well below the lower end of the left thyroid lobe (Courtesy of Drs. Maria Luisa De Rimini and Pietro Muto, Nuclear Medicine Service, “Monaldi” Hospital, Naples, Italy)

Similarly as has been successfully done for planar imaging, attempts have been made to apply subtraction protocols to SPECT acquisitions. In particular, Neumann et al. described a technique based on acquisition of SPECT/CT images with a dual-energy window after administration of 123I-iodide and 99mTc-sestamibi. Then, the attenuation-corrected SPECT sections were utilized to obtain SPECT subtraction images (99mTc-sestamibi SPECT subtracted of the 123I-iodide SPECT). In the authors’ experience, SPECT/CT was significantly more specific than dual-isotope subtraction SPECT for preoperative localization of parathyroid adenomas [79].

In addition to single-photon imaging with conventional gamma cameras, the use of PET/CT with different tracers has also been proposed for localizing hyperfunctioning parathyroid tissue, particularly in the setting of recurrent HPTH and/or failure of conventional radionuclide imaging. Although the performance of these newer techniques is reported to be highly promising, clinical experience is still limited to a few specialized centers. The PET tracers employed in this scenario include [18F]FDG, [11C]methionine, 18F-fluorocholine, and 18F-DOPA as the most widely employed agents [80, 81, 82, 83, 84]. On the basis of recent systematic reviews and meta-analyses, the most promising PET tracers appear to be [11C]methionine and 18F-fluorocholine. Although with a high degree of etherogeneity, the currently available clinical evidence for [11C]methionine shows an 81% pooled sensitivity (95% CI 74–86%) with 70% detection rate (95% CI 62–77%) [83]; according to these data, another analysis obtained a pooled 69% sensitivity (95% CI 60–78%) for detecting a lesion in the correct quadrant, with very high specificity (98% pooled estimate for the positive predictive value; 95% CI 96–100%) [84].

Minimally Invasive Parathyroidectomy and Radioguided Surgery

Minimally invasive parathyroidectomy has been facilitated by the introduction of the intraoperative rapid PTH test, which can be performed with the purpose of detecting any remaining abnormal glands. Since the biological half-life of PTH in the circulation is approximately 2 min, serum PTH levels reduced by more than 50% about 15–30 min after removal of a suspected parathyroid adenoma indicate that the source of abnormal production of PTH has actually been removed.

The key to success for focused parathyroidectomy employing minimally invasive approaches relies on preoperative imaging for accurate localization of the adenoma(s) and/or hyperplasia. In addition to preoperative imaging, the surgeon can rely on intraoperative procedures that can help to find the hyperfunctioning parathyroid tissue and/or to assess completeness of surgical resection of the lesion (such as, e.g., the intraoperative serum PTH assay) [85]. One of such procedures is represented by radioguided parathyroid surgery, which is performed with a handheld “gamma probe” for continuous, real-time measurements in the surgical bed after administration of 99mTc-sestamibi.

The success of radioguided surgery in HPTH patients (especially in case of primary HPTH) is based on the following considerations: (1) in most of the cases (80%) this condition is caused by a single hyperfunctioning adenoma, which is usually located adjacent to the thyroid gland [86, 87, 88, 89]; (2) avid uptake of 99mTc-sestamibi in parathyroid adenomas is the basis for their efficient identification and preoperative localization, thus making it easier to detect intraoperatively the adenoma using the gamma probe [90]. However, there are some well-defined indications for radioguided parathyroid surgery. In particular, this procedure is to be considered only in case of clear identification and localization of a solitary parathyroid adenoma in the 99mTc-sestamibi scan, as it occurs in 60–70% of the patients with primary HPTH [90]. Indications for a minimally invasive approach can be summarized as follows:
  • Both US and scintigraphy have identified only a single adenoma.

  • Uptake of 99mTc-sestamibi in the enlarged parathyroid gland is clear and unequivocal.

  • The 99mTc-sestamibi scan does not show thyroid nodules with persistent tracer uptake.

  • A familial form of the disease has been excluded.

  • The patient had not been submitted to prior irradiation of the neck.

Whereas, minimally invasive radioguided parathyroidectomy is not contraindicated in patients submitted to prior neck surgery. On the other hand, the open surgery procedure becomes mandatory in case of concomitant presence of a nodular thyroid goiter or of multigland parathyroid disease. Similarly, bilateral neck exploration is recommended when a parathyroid malignancy is suspected [90].

Norman and Chheda described the first protocol for minimally invasive radioguided parathyroidectomy in 1997 [91]. In their “single day” approach, 99mTc-sestamibi parathyroid scintigraphy was combined with radioguided surgery in the same day. In particular, radioguided surgery is performed 2–3 h after administration of 740–925 MBq of 99mTc-sestamibi and acquisition of a single-tracer, dual-phase parathyroid scintigraphy. This protocol has two main advantages: (1) the technique is cost-effective in patients with primary or recurrent hyperfunctioning parathyroid adenoma, and (2) the entire procedure (preoperative scintigraphic localization and radioguided surgery) is concentrated in a rather short time window of approximately 3–4 h.

Soon after the first reports by Norman and colleagues, the Padua group proposed a “low-dose” multiple day protocol [92, 93], which consists in performing parathyroid scintigraphy and radioguided surgery in two different days. In particular, the patient is first submitted to a classical dual-tracer parathyroid scintigraphy using full diagnostic activities; surgery is planned based on the findings of this scan. Thereafter, on the day of surgery (which is scheduled according to general logistic and organizational needs), the patient is injected with only 37 MBq of 99mTc-sestamibi just before starting the radioguided surgery procedure. At variance with the Norman’s protocol, the radiation exposure for personnel in the operating room derived from such low radioactivity amount is minimal; furthermore, the surgical approach can be planned and optimized in advance based on the results of the prior full-dose parathyroid scintigraphy [48, 94, 95].

The intraoperative detection rate of parathyroid adenomas is very high with both protocols (over 95%); thus, choice of the method depends on local logistic/organizational considerations. However, the “low-dose protocol” is more suited for patient populations in iodine-deficient geographic areas, where there is a high prevalence of nodular goiter. In fact, thyroid nodules can occasionally be 99mTc-sestamibi avid and with slow tracer washout, an occurrence that could cause false-positive scintigraphic results if relying solely on a single-tracer, dual-phase imaging protocol. In these conditions, dual-tracer parathyroid scintigraphy has better specificity than the dual-phase scintigraphy adopted in the Norman protocol, therefore allowing better selection of patients meeting for radioguided surgery [96]. More recently, the low-dose protocol has been shown to be highly effective also in patients with secondary HPTH, with clear advantages versus the high-dose protocol [97].

Despite the excellent performance of radioguided surgery reported by several groups around the world, there seems to be a prevailing trend within the USA for parathyroid surgery to shift away from intraoperative radioguidance [98], despite the fact that the fear of exposure to significant levels of radiation for the personnel involved in the procedure has been cleared by recent careful dosimetric measurements demonstrating that the maximum allowed radiation exposure to the surgeon would not be reached until over 5,600 radioguided parathyroidectomies are performed by the same personnel per year [99]. In fact, in most centers surgeons tend to rely on accurate preoperative localization imaging alone, especially if combined with the intraoperative PTH assay. Nevertheless, considerable interest is continuing to focus on radioguided parathyroid surgery [32, 100, 101, 102], thanks also to the introduction of newer intraoperative detection/imaging techniques [103, 104], as reported in better details in chapter “Radioguided Surgery – Novel Applications” of this book. In addition to primary and secondary HPTH (including primary multigland disease [105]), radioguidance continues to show particular clinical usefulness in diverse additional clinical conditions such as tertiary HPTH [106] and in pediatric patients [107].

Parathyroid Carcinoma

Pathology

Less than 1% of the cases of primary HPTH are sustained by a parathyroid carcinoma [108], a very rare endocrine malignancy (no more than 400 cases had been reported in the literature up to 1997) [109]. Since histology of parathyroid tumors can be equivocal or frankly misleading, the differential diagnosis between a parathyroid carcinoma and an adenoma is often made only when local recurrence or metastases occur [110, 111]. The histologic features of parathyroid carcinoma are not very specific and difficult to be defined. Generally, neoplastic cells (usually chief cells) are arranged in a lobular pattern partitioned by dense trabeculae (Fig. 11). The more typical features are a high mitotic activity, vascular and capsular invasion, and the presence of thick fibrous bands. Gross infiltration of adjacent structures also strongly suggests the diagnosis of carcinoma; from the clinical point of view, this feature corresponds to a firm mass adherent to surrounding tissues and with very irregular margins. Mean size of the primary tumor at presentation is usually >2–3 cm, and color of the cutting surface is grayish-white [112, 113]. However, many of these features are not specific for malignancy, since they can also be found in parathyroid adenomas. Only the detection of metastatic lesions makes the diagnosis of malignancy certain, but metastasis is rare at presentation [114, 115]. For all these reasons, distinguishing a benign from a malignant parathyroid tumor is very difficult and rarely made at initial histologic evaluation. Immunohistochemistry makes diagnosis of parathyroid carcinoma easier. Since parathyroid carcinoma usually has an elevated mitotic activity, increased expression of cell cycle-associated antigens, such as Ki-67 and cyclin D1, can make the diagnosis of parathyroid carcinoma more likely than that of adenoma [116, 117]; nevertheless, there is some overlap between benign and malignant forms. Decreased expression of p27, an inhibitor of cyclin-dependent kinase, and abnormal galectine-3 expression have also been demonstrated in parathyroid carcinomas, while evaluation of HRPT2 gene abnormalities constitutes a promising diagnostic tool as well [118]. Finally, loss of heterozygosity and loss (total or focal) of parafibromin expression have been reported in the large majority of parathyroid carcinomas but very rarely in adenomas [119, 120, 121, 122].
Fig. 11

Histologic pattern of a parathyroid carcinoma (low magnification): nests of densely packed cancer cells with trabecular arrangement (also occasionally arranged in follicular-like structures) separated by fibrous bands incompletely dividing the tumor into lobules. Initial invasion of the tumor capsule is seen at the upper edge of the tumor (Courtesy of Prof. Fulvio Basolo, Division of Pathology, Department of Surgery, University of Pisa, Pisa, Italy)

Epidemiology

In contrast to parathyroid adenomas, wh ere women predominate over men by a ratio of 3–4:1, parathyroid cancer occurs with equal frequency in the two sexes. The mean age at diagnosis is 40 years, which is 10 years earlier than the typical age of onset age for parathyroid adenomas.

Etiology

The etiology of parathyroid carcinoma remains largely unknown. Neck irradiation and a long-standing secondary HPTH might be considered as risk factors for parathyroid carcinoma, but, indeed, this relationship has been demonstrated only for parathyroid adenomas [10, 11]. Most parathyroid carcinomas are sporadic, although a few cases have also been reported in familial isolated HPTH [123] and in the HPTH-jaw tumor syndrome [124], a rare autosomal disorder where a parathyroid malignancy has been reported in as many as 15% of the patients. Parathyroid carcinoma has been reported also in MEN1 syndrome and with somatic MEN1 mutations [125], while only one case of parathyroid carcinoma has been reported in the MEN2A syndrome [126].

Pathogenesis

Several oncogenes and tumor suppressor genes, especially t hose involved in the control of the cell cycle, such as retinoblastoma (Rb), p53, breast carcinoma susceptibility (BRCA2), and the cyclin Dl/parathyroid adenomatosis gene 1 oncogene (PRAD1) genes [127], have been linked to parathyroid carcinomas. However, none of these genes play a primary role in the pathogenesis of parathyroid carcinoma.

Instead, a strong correlation has been demonstrated between the HPTH-jaw tumor syndrome and mutation of the HRPT2 gene (alias CDC73 and Clorf 28). This gene encodes a 531-amino acid protein called parafibromin which plays a central role in the control of the cell cycle, and subsequently in determining cell fate and promoting tumorigenesis [128]. HRPT2 is frequently mutated both in HPTH-jaw tumor syndromes and in many parathyroid carcinomas [129, 130]. In particular, parathyroid carcinoma occurs with higher frequency in the HPTH-jaw tumor syndrome than in sporadic PHPT (15% versus less than 1%). Similar germline mutations occur in a subset of kindreds with familial isolated HPTH [128, 129]. Most of these mutations are “nonsense” point mutations and result in lack of or reduced protein expression of the encoded parafibromin protein. The prevalence of HRPT2 mutations in sporadic parathyroid carcinomas may be as high as 76.6%. Therefore, HRPT2 mutations are considered one of the most significant molecular events involved in the pathogenesis of most sporadic parathyroid carcinomas. Another mechanism of HRPT2 gene inactivation, methylation of the promoter, has been reported in 2 out of 11 parathyroid carcinomas [131]. Controversial data have instead been reported about the presence of HRPT2 mutations in sporadic benign parathyroid adenomas [108, 130, 132].

Clinical Presentation

The initial clinical manifestations of parathyroid carcinoma are primarily linked to the effects of markedly elevated serum PTH levels (i.e., hypercalcemia) rather than to local infiltration or distant metastases. From the clinical point of view, parathyroid carcinomas are usually indolent, though progressive. At initial presentation, very few patients have metastasis at regional lymph nodes (<5%) or at distant sites (<2%) [108, 133]. Parathyroid carcinoma tends to recur locally and to infiltrate adjacent structures in the neck. Metastases occur late in the course of the disease, involving cervical lymph nodes (30%) and/or lungs (40%) and/or liver (10%). Distant metastases in the bone, pleura, pericardium, and pancreas are more rare. Severe hypercalcemia with renal involvement (nephrocalcinosis and nephrolithiasis) is present in up to 80% of the patients, while bone involvement (osteitis fibrosa cystica, subperiosteal resorption, “salt and pepper” skull, and diffuse osteopenia) occurs in up to 90% of the patients. In about 80% of the patients with parathyroid carcinoma, a palpable neck mass is present at physical examination. Besides symptoms linked to nephrolithiasis, patients may complain of muscle weakness, fatigue, depression, nausea, polydipsia and polyuria, bone pain, and fractures. Recurrent severe pancreatitis, peptic ulcer disease, and anemia can also occur. However, none of these features are specific for malignancy. A few parathyroid carcinomas do not produce excess PTH [134] and can therefore be confused with thyroid or thymic carcinoma because of locally advanced disease (palpable neck mass, dysphagia, hoarseness due to laryngeal nerve palsy). The correct diagnosis can be defined by immunohistochemistry for PTH (positive staining), while staining for thyroglobulin, thyroid transcription factor 1, and calcitonin is negative. The features that might raise the suspicion of a parathyroid carcinoma in a patient with PHPT include male gender, age <50 years, serum calcium >14–15 mg/dL, markedly elevated serum PTH levels, bone and renal clinical involvement, and tumor size >3 cm.

The identification of HRPT2 gene mutations in patients with apparently sporadic parathyroid cancers as germline events suggests that a subset of these patients might have the HPT-JT syndrome or variant thereof [135]. In these cases, the surveillance for renal and jaw lesions is recommended [130]. Moreover, the relatives of a patient carrying a germline HRPT2 mutation are susceptible to develop a parathyroid cancer or other manifestation of the HPT-JT syndrome. Monitoring of family members with serum calcium determinations and neck US is therefore warranted.

Imaging of Parathyroid Carcinoma

Although not extensively discussed in the literature because of the relative rarity of this tumor, the same imaging techniques as those used for localizing benign parathyroid disease are helpful also for imaging parathyroid cancers. They include US evaluation of the neck, 99mTc-sestamibi scintigraphy, CT, and MRI, as well as PET [136, 137]. The accuracy of imaging depends on the size and site of the parathyroid carcinoma, while the suspected tissue always requires histologic confirmation [138, 139].

US examination of the neck is useful especially for detecting a space-occupying lesion, while it can also help to distinguish a parathyroid carcinoma from an adenoma, as well as invasion in the surrounding tissue and metastasis in local lymph nodes [140]. Although the US findings are not exquisitely specific for parathyroid cancer, large size, inhomogeneous appearance, and/or irregular borders with a depth/width (DW) ratio >1 are observed in 94% of the cases [141]. During follow-up, US evaluation is useful for detecting local recurrence of parathyroid carcinoma.

CT and MRI have been variously used to localize parathyroid carcinomas and to detect mediastinal and thoracic recurrences or distant metastases [142]. Nevertheless, in the postoperative status artifacts due to surgical clips may make the interpretation of cervical CT scans difficult; in this condition, T1-weighted MRI with gadolinium contrast may be more useful to detect residual locoregional parathyroid carcinoma [143]. Invasive diagnostic procedures, such as selective venous catheterization with measurement of PTH concentration in the effluent blood, may also be used to localize lesions when noninvasive imaging studies have been noncontributory [144]. 99mTc-sestamibi scintigraphy can be successful for preoperative localization of a parathyroid malignancy (with 80–90% sensitivity). However, it cannot distinguish a parathyroid adenoma from a carcinoma [145, 146], since 99mTc-sestamibi localizes in both parathyroid adenomas and parathyroid carcinoma as well as in any other non-tumor hyperfunctioning tissue(s) and in different types of malignancy. The National Cancer Database Report by the American Cancer Society estimates that 15–17% of parathyroid carcinomas, which look identical to parathyroid adenomas on 99mTc-sestamibi scintigraphy, have concomitant lymph node metastasis at the time of diagnosis [113]. Once parathyroid carcinoma has been diagnosed and resected, 99mTc-sestamibi scintigraphy can identify recurrences in the surgical bed, as well as metastases in the contralateral neck lymph nodes (Fig. 12) and metastasis at distant sites such as the lung and bone [147]. The evaluation of bone lesions can be challenging from the diagnostic point of view, because skeletal brown tumors (a possible consequence of HPTH) accumulate 99mTc-sestamibi as well, thus mimicking metastatic parathyroid carcinoma [148]. When performed for surgical planning in patients with recurrent disease, 99mTc-sestamibi scintigraphy correctly identifies 67% of the recurrences; this compares well with 53% for CT imaging. Although discordant results between the two techniques are reported in 78% of the cases [149], both imaging studies are recommended for optimal preoperative planning [150].
Fig. 12

A 75-year-old patient previously submitted to surgery because of primary HPTH initially thought to be caused by an adenoma of the lower right parathyroid gland. Histology revealed instead parathyroid carcinoma. About 18 months later, local recurrence was treated with a second surgery, after which the PTH levels in blood normalized for several months then started to rise again. (a) Planar scan of the neck and chest obtained about 10 min after administration of 99mTc-sestamibi, suggesting some ill-defined abnormal uptake of the radiopharmaceutical at the base of the neck (slightly right sided). (b) Tridimensional volume rendering of fused SPECT/CT of the neck and upper chest clearly identifies the site of abnormal 99mTc-sestamibi uptake in the right paramedian suprasternal space; the lesion corresponds to a previously unrecognized metastasis in a lymph node, as subsequently confirmed histologically

PET with [18F]FDG has also shown to be very helpful for detecting metastatic parathyroid cancers [151], although brown tumors can be [18F]FDG avid as well, thus being possibly incorrectly interpreted as metastatic bone lesion [152]. Overexpression of the P-glycoprotein, a plasma membrane mechanism involved in multidrug resistance through an ATP-dependent drug efflux pump, seems to be involved in the false-negative results at either 99mTc-sestamibi scintigraphy or [18F]FDG PET [153]. Due to the rarity of parathyroid carcinoma, there is very limited experience with the use of PET agents other than [18F]FDG, occasional reports being usually included in case study populations of HPTH patients in general. Similarly as for benign forms of HPTH, the performance of [11C]methionine PET/CT is expected to be especially promising in patients with parathyroid carcinoma.

Management of Parathyroid Carcinoma

Surgery

Complete resection of the primary lesion at the time of initial operation is the only curative treatment for parathyroid carcinoma; this is possible when the cancer is diagnosed at an early stage, when the tumor is small and intraparathyroidal. Patients who present with features suggestive of parathyroid carcinoma warrant thorough exploration of all four parathyroid glands, as parathyroid carcinoma has been reported to coexist along with benign adenomas or hyperplasia.

The most effective surgical approach is en bloc resection with curative intents [154]. Tracheoesophageal, paratracheal, and upper mediastinal lymph nodes should be excised, but extensive lateral neck dissection is indicated only when there is metastasis in the anterior cervical lymph nodes. Despite early diagnosis and a potentially curative resection, parathyroid carcinoma recurs in more than 50% of the cases. Most recurrences occur 2–3 years after the initial operation, although disease-free intervals as long as 20 years have been reported [155].

Imaging studies should be performed in all patients before reoperation. FNA of a suspicious lesion (with measurement of PTH in the needle washing) should be used with caution, if at all, to avoid seeding of malignant cells along the needle track [156]. If noninvasive imaging is negative, arteriography and selective venous sampling for PTH measurement may be useful. The management of recurrent or metastatic lesions is primarily surgical. Recurrences in the neck should be treated with wide resections, including the regional lymph nodes and other involved structures. Accessible distant metastases, particularly in the presence of localized metastatic disease, should also be excised, if possible. Even a small tumor may produce a sufficient amount of PTH to cause hypercalcemia. Although resection of a single metastasis or other foci of malignant tissue is rarely curative, their removal may result in periods of normocalcemia ranging from months to years. Decreasing the tumor burden may also render the patient’s hypercalcemia more amenable to medical treatment.

Chemotherapy

Although several chemotherapy regimens have been tried (such as nitrogen mustard, vincristine, cyclophosphamide, actinomycin D, and adriamycin alone or in combination with cyclophosphamide and 5-fluorouracil), none of them has proved to be effective either by themselves or combined [157, 158]. Therefore, chemotherapy has currently no role in the management of patients with parathyroid carcinoma.

External Beam Radiation Therapy

With the exception of a single report of apparent cure (10 years) in a patient with infiltration of the trachea [157], external beam radiation therapy (EBRT) has little, if any, effect in invasive parathyroid cancers [155]. Nevertheless, recent reports suggest the benefit of EBRT as adjuvant therapy. In fact, a median disease-free survival of 60 months has been reported in four patients who received postoperative adjuvant EBRT [159]. Furthermore, a reduced rate of local recurrence has been observed when adjuvant EBRT is given after surgery, irrespective of the type of surgery and stage of the disease [160].

Management of Hypercalcemia

When parathyroid carcinoma has become widely metastatic and no surgical options are available, the control of hypercalcemia becomes the primary medical objective. Hydration with i.v. infusion of saline and loop diuretics is often beneficial in the short term, although drugs that inhibit bone resorption are needed in the longer run. Intravenous bisphosphonates (pamidronate and zoledronate) can be used for transient control of hypercalcemia. Also plicamycin is effective, but the response is transient, and repeated courses may be associated with toxicity. New promising therapies include anti-PTH immunotherapy and dendritic cell immunotherapy [161, 162]. Calcimimetics and allosteric modulators of the calcium receptors reduce PTH secretion by enhancing sensitivity of the parathyroid cells to extracellular calcium [163]. A first generation calciomimetic, R-568, was used for 2 years in a patient with metastatic parathyroid carcinoma, resulting in effective control of hypercalcemia [164]. Cinacalcet, a more potent second-generation agent with a longer half-life and more predictable hepatic metabolism, has recently replaced R-568. In benign PHPT, cinacalcet normalizes serum calcium and partially reduces PTH levels for up to 3 years [165]. Cinacalcet therefore represents an important new option for managing severe hypercalcemia, especially in patients with inoperable disease. A highly effective approach to the treatment of severe hypercalcemia (that represents the primary cause of mortality in these patients) is based on the use of the monoclonal antibody denosumab against the RANK ligand, with a mechanism involving inhibition of receptor activation of the nuclear factor kB ligand [166, 167, 168, 169].

Prognosis

The prognosis of parathyroid carcinoma is quite variable and, although complete cure is unlikely, prolonged survival is common with palliative surgery and medical therapy. The mean time to recurrence is usually 3 years, although periods as long as 20 years have been reported [170]. Once the tumor recurs, 5-year survival rates vary from 40% to 86%. The most favorable prognostic factor is early diagnosis and the complete excision of the tumor at initial surgery.

Concluding Remarks on Preoperative Parathyroid Imaging When Planning Minimally Invasive Parathyroidectomy

There are advantages and limitations in each of the imaging modalities described in this chapter, and various combinations are used to achieve accurate and reliable preoperative localization of the parathyroid lesion(s) for which surgery is planned. Final choice of the patient-specific imaging sequence often depends on local availability and attitudes rather than on strictly designed algorithms.

A practical algorithm has recently been proposed as a guide to imaging in patients with primary HPTH [30] (Fig. 13). The underlying condition is that the diagnosis of primary HPTH has been firmly established on the basis of biochemical parameters, that is, increased serum calcium levels with inappropriately increased PTH levels. High-resolution US examination of the neck is generally the first imaging test in these conditions, since this procedure is widely available, easy to perform and, in experienced hands, frequently enables to identify an orthotopically located parathyroid adenoma (i.e., adjacent to thyroid tissue); furthermore, US-guided FNA cytology can be performed in equivocal/inconclusive cases. On the other hand, the mediastinum and the para-tracheoesophageal space (possible sites of ectopy) cannot be explored with US, and the diagnostic performance is reduced in patients previously submitted to surgery; furthermore, US examination is a highly operator-dependent technique.
Fig. 13

Flowchart diagram showing an algorithm proposed for noninvasive preoperative imaging of patients with PHPT. The gray-shaded path in the right lower portion indicates the goal of reducing the use of contrast-enhanced CT in favor of MRI. The dotted gray path in the upper right portion demonstrates the patient who undergoes focused surgery directly on the basis of unequivocal localization of a parathyroid lesion by US, as in the case of a negative 99mTc-sestamibi scintigraphy after unequivocal US localization of parathyroid lesion(s) (indicated with “-*” in the path after scintigraphy). Ce-MDCT contrast-enhanced multi-detector computed tomography, qPTH intraoperative quick PTH assay, RGS-MIRP radioguided surgery minimally invasive radioguided parathyroidectomy

Unequivocal identification/localization of a parathyroid adenoma by high-resolution US would in principle be sufficient to guide a minimally invasive surgical approach, possibly associated with intraoperative quick PTH assay for assessing correct resection of the parathyroid lesion (see dotted path in the upper left portion of Fig. 13). Nevertheless, localization of the adenoma is generally confirmed in these patients with 99mTc-sestamibi scintigraphy, which is useful also to exclude and possible additional, ectopic hyperfunctioning glands (especially if performed with hybrid SPECT/CT imaging). Fused SPECT/CT images yield extremely useful functional and anatomic information for preoperative planning. Furthermore, in case of a positive 99mTc-sestamibi scan, radioguided surgery can be performed, as indicated by the RGS-MIRP acronym in Fig. 13 (RGS, “radioguided surgery”; MIRP, “minimally invasive radioguided parathyroidectomy”).

99mTc-sestamibi scintigraphy (which entails a much smaller radiation burden than contrast-enhanced CT) is mandatory as a second-line imaging procedure in patients with a negative or inconclusive US examination. Patients with negative US but with positive scintigraphy may undergo a focused surgical approach, especially if radioguided surgery is to be employed. Nevertheless, such discordant findings should be clarified with third-line imaging, such as CT and/or MRI).

Further investigation with either CT or MRI is recommended for patients in whom both US and 99mTc-sestamibi scintigraphy are negative. To this purpose, the current practice in most centers is to rely on contrast-enhanced CT, unless there are clear contraindications to administration of the iodinated contrast medium. Since access to MRI is generally more limited than that to CT imaging, MRI is currently reserved for selected cases only, although the use of MRI is to be recommended in the perspective of reducing the radiation burden to patients (especially to the thyroid); this is the reason why the CT path in Fig. 13 is shaded in gray.

In patients with unequivocal localization of parathyroid lesion(s) by either CT or MRI, a minimally invasive procedure (combined with intraoperative PTH assay for) can safely be performed. Finally, a classical bilateral surgical exploration is justified when all the imaging techniques employed have failed to identify the hyperfunctioning parathyroid gland(s) or have provided inconclusive findings.

References

  1. 1.
    Baloch ZW, Livolsi VA. Parathyroids – morphology and pathology. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 23–36.Google Scholar
  2. 2.
    Rao SD, Bhadada SK, Parfitt AM. Parathyroid growth: normal and abnormal. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 255–78.Google Scholar
  3. 3.
    Carlson D. Parathyroid pathology: hyperparathyroidism and parathyroid tumors. Arch Pathol Lab Med. 2010;134:1639–44.PubMedGoogle Scholar
  4. 4.
    Brown EM. Control of parathyroid hormone secretion by its key physiological regulators. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 101–18.Google Scholar
  5. 5.
    Arnold A, Levine MA. Molecular basis of primary hyperparathyroidism. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 279–96.Google Scholar
  6. 6.
    Madkhali T, Alhefdhi A, Chen H, Elfenbein D. primary hyperparathyroidism. Ulus Cerrahi Derg. 2016;32:58–66.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Thakker RV. Familial and hereditary forms of primary hyperparathyroidism. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 341–64.Google Scholar
  8. 8.
    Bouillon R, Bollersley J, Silverberg SJ. Vitamin D and primary hyperparathyroidism. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 481–8.Google Scholar
  9. 9.
    Heaney RP. Vitamin D, and parathyroid hormone. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 633–40.Google Scholar
  10. 10.
    Christmas TJ, Chapple CR, Noble JG, Milroy EJ, Cowie AG. Hyperparathyroidism after neck irradiation. Br J Surg. 1988;75:873–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Rasmuson T, Damber L, Johansson L, Johansson R, Larsson LG. Increased incidence of parathyroid adenomas following X-ray treatment of benign diseases in the cervical spine in adult patients. Clin Endocrinol (Oxf). 2002;57:731–4.CrossRefGoogle Scholar
  12. 12.
    Pitt SC, Sippel RS, Chen H. Secondary and tertiary hyperparathyroidism, state of the art surgical management. Surg Clin North Am. 2009;89:1227–39.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Salusky IB, Wesseling-Perry K. The parathyroids in renal disease: pathophysiology and systemic consequences. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 641–52.Google Scholar
  14. 14.
    Hadar T, Shvero J, Yaniv E, Ram E, Shvili I, Koren R. Expression of p53, Ki-67 and Bcl-2 in parathyroid adenoma and residual normal tissue. Pathol Oncol Res. 2005;11:45–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Szende B, Farid P, Vegso G, Perner F, Kopper L. Apoptosis and P53, Bcl-2 and Bax gene expression in parathyroid glands of patients with hyperparathyroidism. Pathol Oncol Res. 2004;10:98–103.PubMedCrossRefGoogle Scholar
  16. 16.
    Bandeira F, Correia A. Clinical presentation of primary hyperparathyroidism: a global perspective. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 309–16.Google Scholar
  17. 17.
    Bilezikian JP, Potts Jr JT, Fuleihan Gel H, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab. 2002;87:5353–61.PubMedCrossRefGoogle Scholar
  18. 18.
    Silverberg SJ, Bilezikian JP. Asymptomatic primary hyperparathyroidism. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 317–30.Google Scholar
  19. 19.
    Joy MS, Kshirsagar AV, Franceschini N. Calcimimetics and the treatment of primary and secondary hyperparathyroidism. Ann Pharmacother. 2004;38:1871–80.PubMedCrossRefGoogle Scholar
  20. 20.
    Khan A, Bilezikian J, Bone H, Gurevich A, Lakatos P, Misiorowski W, et al. Cinacalcet normalizes serum calcium in a double-blind randomized, placebo-controlled study in patients with primary hyperparathyroidism with contraindications to surgery. Eur J Endocrinol. 2015;172:527–35.PubMedCrossRefGoogle Scholar
  21. 21.
    Barman Balfour JA, Scott LJ. Cinacalcet hydrochloride. Drugs. 2005;65:271–81.PubMedCrossRefGoogle Scholar
  22. 22.
    Mingione A, Verdelli C, Terranegra A, Soldati L, Corbetta S. Molecular and clinical aspects of the target therapy with the calcimimetic cinacalcet in the treatment of parathyroid tumors. Curr Cancer Drug Targets. 2015;15:563–74.PubMedCrossRefGoogle Scholar
  23. 23.
    Rodríguez M, Goodman WG, Liakopoulos V, Messa P, Wiecek A, Cunningham J. The use of calcimimetics for the treatment of secondary hyperparathyroidism: a 10 year evidence review. Semin Dial. 2015;28:497–507.PubMedCrossRefGoogle Scholar
  24. 24.
    Martin KJ, Gonzalez EA, Gellens M, Hamm LL, Abboud H, Lindberg J. 19-Nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol. 1998;9:1427–32.PubMedGoogle Scholar
  25. 25.
    Slatopolsky EA, Burke SK, Dillon MA. RenaGel, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. RenaGel Study Group Kidney Int. 1999;55:299–307.CrossRefGoogle Scholar
  26. 26.
    Triponez F, Clark OH, Vanrenthergem Y, Evenepoel P. Surgical treatment of persistent hyperparathyroidism after renal transplantation. Ann Surg. 2008;248:18–30.PubMedCrossRefGoogle Scholar
  27. 27.
    Girotto JA, Harmon JW, Ratner LE, Nicol TL, Wong L, Chen H. Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery. 2001;130:645–50.PubMedCrossRefGoogle Scholar
  28. 28.
    Milas M, Weber CJ. Near-total parathyroidectomy is beneficial for patients with secondary and tertiary hyperparathyroidism. Surgery. 2004;136:1252–60.PubMedCrossRefGoogle Scholar
  29. 29.
    Irvin 3rd GL, Carneiro DM. Management changes in primary hyperparathyroidism. JAMA. 2000;284:934–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Mariani G, Mazzeo S, Rubello D, Bartolozzi C. Preoperative localization of abnormal parathyroid glands. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 499–518.Google Scholar
  31. 31.
    Johnson NA, Tublin ME, Ogilvie JB. Parathyroid imaging: technique and role in the preoperative evaluation of primary hyperparathyroidism. AJR Am J Roentgenol. 2007;188:1706–15.PubMedCrossRefGoogle Scholar
  32. 32.
    Desiato V, Melis M, Amato B, Bianco T, Rocca A, Amato M, et al. Minimally invasive radioguided parathyroid surgery: a literature review. Int J Surg. 2016;28 Suppl 1:S84–93.PubMedCrossRefGoogle Scholar
  33. 33.
    Harvey A, Bohacek L, Neumann D, Mihaljevic T, Berber E. Robotic thoracoscopic mediastinal parathyroidectomy for persistent hyperparathyroidism: case report and review of the literature. Surg Laparosc Endosc Percutan Tech. 2011;21:e24–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Garas G, Holsinger FC, Grant DG, Athanasiou T, Arora A, Tolley N. Is robotic parathyroidectomy a feasible and safe alternative to targeted open parathyroidectomy for the treatment of primary hyperparathyroidism? Int J Surg. 2015;15:55–60.PubMedCrossRefGoogle Scholar
  35. 35.
    Brunaud L, Li Z, Van Den Heede K, Cuny T, Van Slycke S. Endoscopic and robotic parathyroidectomy in patients with primary hyperparathyroidism. Gland Surg. 2016;5:352–60.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Metz D, Jensen R, Allen B, et al. Multiple endocrine neoplasia type 1: clinical features and management. In: Bilezikian J, Levine M, Marcus R, editors. The parathyroids. New York: Raven Press; 1994. p. 591–647.Google Scholar
  37. 37.
    Noussios G, Anagnostis P, Natsis K. Ectopic parathyroid glands and their anatomical, clinical and surgical implications. Exp Clin Endocrinol Diabetes. 2012;120:604–10.PubMedCrossRefGoogle Scholar
  38. 38.
    Shah S, Win Z, Al-Nahhas A. Multimodality imaging of the parathyroid glands in primary hyperparathyroidism. Minerva Endocrinol. 2008;33:193–202.PubMedGoogle Scholar
  39. 39.
    Kunstman JW, Kirsch JD, Mahjan A, Udelsman R. Parathyroid localization and implications for clinical management. J Clin Endocrinol Metab. 2013;98:902–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Boury S. New methods for parathyroid imaging: sonography, 4D CT, MRI. Ann Endocrinol (Paris). 2015;76:148–52.CrossRefGoogle Scholar
  41. 41.
    Harari A, Waring A, Fernandez-Ranvier G, et al. Parathyroid carcinoma: a 43-year outcome and survival analysis. J Clin Endocrinol Metab. 2011;96:3679–86.PubMedCrossRefGoogle Scholar
  42. 42.
    Sidhu PS, Talat N, Patel P, Mulholland NJ, Schulte K-M. Ultrasound features of malignancy in the preoperative diagnosis of parathyroid cancer: a retrospective analysis of parathyroid tumours larger than 15 mm. Eur Radiol. 2011;21:1865–73.PubMedCrossRefGoogle Scholar
  43. 43.
    Mazzeo S, Caramella D, Lencioni R, Viacava P, De Liperi A, Naccarato AG, et al. Usefulness of echo-color Doppler in differentiating parathyroid lesions from other cervical masses. Eur Radiol. 1997;7:90–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Mohammadi A, Moloudi F, Ghasemi M. Preoperative localization of parathyroid lesion: diagnostic usefulness of color Doppler ultrasonography. Int J Clin Exp Med. 2012;5:80–6.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Devcic Z, Jeffrey RB, Kamaya A, Desser TS. The elusive parathyroid adenoma – techniques for detection. Ultrasound Q. 2013;29:179–87.PubMedCrossRefGoogle Scholar
  46. 46.
    Agha A, Hornung M, Rennert J, Uller W, Lighvani H, Schlitt HJ, Jung EM. Contrast-enhanced ultrasonography for localization of pathologic glands in patients with primary hyperparathyroidism. Surgery. 2012;151:580–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Uden P, Aspelin P, Berglund J, Lilja B, Nyman U, Olsson LE, Zederfeldt B. Preoperative localization in unilateral parathyroid surgery. A cost-benefit study on ultrasound, computed tomography and scintigraphy. Acta Chir Scand. 1990;156:29–35.PubMedGoogle Scholar
  48. 48.
    Mariani G, Gulec SA, Rubello D, Boni G, Puccini M, Pellizzo MR, et al. Preoperative localization and radioguided parathyroid surgery. J Nucl Med. 2003;44:1443–58.PubMedGoogle Scholar
  49. 49.
    Phillips CD, Shatzkes DR. Imaging of the parathyroid glands. Semin Ultrasound CT MR. 2012;33:123–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Harari A, Zarnegar R, Lee J, Kazam E, Inabnet III WB, Fahey III TJ. Computed tomography can guide focused exploration in select patients with primary hyperparathyroidism and negative sestamibi scanning. Surgery. 2008;144:970–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Kelly HR, Hamberg LM, Hunter GJ. 4D-CT for preoperative localization of abnormal parathyroid glands in patients with hyperparathyroidism: accuracy and ability to stratify patients by unilateral vs bilateral disease in surgery-naive and re-exploration patients. AJNR Am J Neuroradiol. 2014;35:176–81.PubMedCrossRefGoogle Scholar
  52. 52.
    Chazen JL, Gupta A, Dunning A, Phillips CD. Diagnostic accuracy of 4D-CT for parathyroid adenomas and hyperplasia. Am J Neuroradiol. 2012;33:429–33.PubMedCrossRefGoogle Scholar
  53. 53.
    Lumachi F, Tregnaghi A, Zucchetta P, Marzola MC, Cecchini D, et al. Technetium-99m sestamibi scintigraphy and helical CT together in patients with primary hyperparathyroidism: a prospective clinical study. Br J Radiol. 2004;77:100–3.PubMedCrossRefGoogle Scholar
  54. 54.
    Rodgers SE, Hunter GJ, Hamberg LM, Schellingerhout D, Doherty DB, Ayers GD, et al. Improved preoperative planning for directed parathyroidectomy with 4D dimensional computed tomography. Surgery. 2006;140:932–41.PubMedCrossRefGoogle Scholar
  55. 55.
    Starker F, Mahajan A, Björklund P, Sze G, Udelsman R, Carling T. 4D Parathyroid CT as the initial localization study for patient with de novo primary hyperparathyroidism. Ann Surg Oncol. 2011;18:1723–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Gafton AR, Glastonbury CM, Eastwood JD, Hogan JK. Parathyroid lesions: characterization with dual-phase arterial and venous enhanced CT of the neck. Am J Neuroradiol. 2012;33:949–52.PubMedCrossRefGoogle Scholar
  57. 57.
    Madorin CA, Owen R, Coakley B, Lowe H, Nam K, Wewber K, et al. Comparison of radiation exposure and cost between dynamic computed tomography and sestamibi scintigraphy for preoperative localization of parathyroid lesions. JAMA Surg. 2013;148:500–3.PubMedCrossRefGoogle Scholar
  58. 58.
    Gotway MB, Reddy GP, Webb WR, Morita ET, Clark OH, Higgins CB. Comparison between MR imaging and 99mTc MIBI scintigraphy in the evaluation of recurrent of persistent hyperparathyroidism. Radiology. 2001;218:783–90.PubMedCrossRefGoogle Scholar
  59. 59.
    Wakamatsu H, Noguchi S, Yamashita H, Yamashita H, Tamura S, Jinnouchi S, et al. Parathyroid scintigraphy with 99mTc-MIBI and 123I subtraction: a comparison with magnetic resonance imaging and ultrasonography. Nucl Med Commun. 2003;24:755–62.PubMedCrossRefGoogle Scholar
  60. 60.
    Ruf J, Lopez Hanninen E, Steinmuller T, Rohlfing T, Bertram H, Gutberlet M, et al. Preoperative localization of parathyroid glands. Use of MRI, scintigraphy, and image fusion. Nuklearmedizin. 2004;43:85–90.PubMedGoogle Scholar
  61. 61.
    Grayev AM, Gentry LR, Hartman MJ, Chen H, Perlman SB, Reeder SB. Presurgical localization of parathyroid adenomas with magnetic resonance imaging at 3.0 T: an adjunct method to supplement traditional imaging. Ann Surg Oncol. 2012;19:981–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Goodwin DA, Crowley LG, Camargo CA. Localization of a mediastinal adenoma by selenomethionine Se 75 scanning. JAMA. 1969;208:2333–5.PubMedCrossRefGoogle Scholar
  63. 63.
    DiGiulio W, Morales JO. The value of the selenomethionine Se 75 scan in preoperative localization of parathyroid adenomas. JAMA. 1969;209:1873–80.PubMedCrossRefGoogle Scholar
  64. 64.
    Waldorf JC, van Heerden JA, Gorman CA, Grant CS, Wahner HW. 75Se-Selenomethionine scanning for parathyroid localization should be abandoned. Mayo Clin Proc. 1984;59:534–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Samanta A, Wilson B, Iqbal J, Burden AC, Walls J, Cosgriff P. A clinical audit of thallium-technetium subtraction parathyroid scans. Postgrad Med J. 1990;66:441–5.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Coakley AJ, Kettle AG, Wells CP, O’Doherty MJ, Collins RE. 99Tcm sestamibi – a new agent for parathyroid imaging. Nucl Med Commun. 1989;10:791–4.PubMedCrossRefGoogle Scholar
  67. 67.
    Hetrakul N, Civelek AC, Stagg CA, Udelsman R. In vitro accumulation of technetium-99m-sestamibi in human parathyroid mitochondria. Surgery. 2001;130:1011–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Mitchell BK, Cornelius EA, Zoghbi S, Murren JR, Ghoussoub R, Flynn SD, Kinder BK. Mechanism of technetium 99m sestamibi parathyroid imaging and the possible role of p-glycoprotein. Surgery. 1996;120:1039–45.PubMedCrossRefGoogle Scholar
  69. 69.
    Rubello D, Gross MD, Mariani G, AL-Nahhas A. Scintigraphic techniques in primary hyperparathyroidism: from pre-operative localisation to intra-operative imaging. Eur J Nucl Med Mol Imaging. 2007;34:926–33.PubMedCrossRefGoogle Scholar
  70. 70.
    Taillefer R, Boucher Y, Potvin C, Lambert R. Detection and localization of parathyroid adenomas in patients with hyperparathyroidism using a single radionuclide imaging procedure with technetium-99m-sestamibi (double-phase study). J Nucl Med. 1992;33:1801–17.PubMedGoogle Scholar
  71. 71.
    Weber CJ, Vansant J, Alazraki N, Christy J, Watts N, Phillips LS, et al. Value of technetium 99m sestamibi iodine 123 imaging in reoperative parathyroid surgery. Surgery. 1993;114:1011–8.PubMedGoogle Scholar
  72. 72.
    Rubello D, Saladini G, Casara D, Borsato N, Toniato A, Piotto A, et al. Parathyroid imaging with pertechnetate plus perchlorate/MIBI subtraction scintigraphy: a fast and effective technique. Clin Nucl Med. 2000;25:527–31.PubMedCrossRefGoogle Scholar
  73. 73.
    Okamura T. Imaging the parathyroid glands using 99mTc-tetrofosmin: current status. Intern Med. 2000;39:85–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Spanu A, Schillaci O, Madeddu G. 99mTc labelled cationic lipophilic complexes in malignant and benign tumors: the role of SPET and pinhole-SPET in breast cancer, differentiated thyroid carcinoma and hyperparathyroidism. Q J Nucl Med Mol Imaging. 2005;49:145–69.PubMedGoogle Scholar
  75. 75.
    Yip L, Pryma DA, Yim JH, Carty SE, Ogilvie JB. Sestamibi SPECT intensity scoring system in sporadic primary hyperparathyroidism. World J Surg. 2009;33:426–33.PubMedCrossRefGoogle Scholar
  76. 76.
    Lavely WC, Goetze S, Friedman KP, Leal JP, Zhang Z, Garret-Mayer E, et al. Comparison of SPECT/CT, SPECT, and planar imaging with single and dual-phase 99mTc-sestamibi parathyroid scintigraphy. J Nucl Med. 2007;48:1084–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Eslamy HK, Ziessman HA. Parathyroid scintigraphy in patients with primary hyperparathyroidism: 99mTc sestamibi SPECT and SPECT/CT. Radiographics. 2008;28:1461–76.PubMedCrossRefGoogle Scholar
  78. 78.
    Pata G, Casella C, Besuzio S, Mittempergher F, Salerni B. Clinical appraisal of 99m technetium-sestamibi SPECT/CT compared to conventional SPECT in patients with primary hyperparathyroidism and concomitant nodular goiter. Thyroid. 2010;20:1121–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Neumann DR, Obuchowski NA, Difilippo FP. Preoperative 123I/99mTc-sestamibi subtraction SPECT and SPECT/CT in primary hyperparathyroidism. J Nucl Med. 2008;49:2012–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Rubello D, Fanti S, Nanni C, Farsad M, Castellucci P, Boschi S, et al. 11C-Methionine PET/CT in Technnetium-99m Sestamibi negative hyperparathyroidism in patients with renal failure on chronic hemodialysis. Eur J Nucl Med Mol Imaging. 2006;33:453–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Michaud L, Burgess A, Huchet V, Lefèvre M, Tassart M, Ohnona J, et al. Is 18F-fluorocholine-positron emission tomography/computerized tomography a new imaging tool for detecting hyperfunctioning parathyroid glands in primary or secondary hyperparathyroidism? J Clin Endocrinol Metab. 2014;99:4531–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Michaud L, Balogova S, Burgess A, Ohnona J, Huchet V, Kerrou K, et al. A pilot comparison of 18F-fluorocholine PET/CT, ultrasonography and 123I/99mTc-sestaMIBI dual-phase dual-isotope scintigraphy in the preoperative localization of hyperfunctioning parathyroid glands in primary or secondary hyperparathyroidism: influence of thyroid anomalies. Medicine (Baltimore). 2015;94(41):e1701. doi:10.1097/MD.0000000000001701.CrossRefGoogle Scholar
  83. 83.
    Caldarella C, Treglia G, Isgrò MA, Giordano A. Diagnostic performance of positron emission tomography using 11C-methionine in patients with suspected parathyroid adenoma: a meta-analysis. Endocrine. 2013;43:78–83.PubMedCrossRefGoogle Scholar
  84. 84.
    Kluijfhout WP, Pasternak JD, Drake FT, Beninato T, Gosnell JE, Shen WT, et al. Use of PET tracers for parathyroid localization: a systematic review and meta-analysis. Langenbecks Arch Surg. 2016;401:925–35.Google Scholar
  85. 85.
    Harrison BJ, Triponez F. Intraoperative adjuncts in surgery for primary hyperparathyroidism. Langenbeck’s Arch Surg. 2009;394:799–809.CrossRefGoogle Scholar
  86. 86.
    Greenspan BS, Dillehay G, Intenzo C, et al. SNM practice guideline for parathyroid scintigraphy 4.0. J Nucl Med Technol. 2012;40:111–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Rubello D, Pelizzo MR, Boni G, et al. Radioguided surgery of primary hyperparathyroidism using the low 99mTc-Sestamibi dose protocol: multi-institutional experience from the Italian Study Group on Radioguided Surgery and ImmunoScintigraphy (GISCRIS). J Nucl Med. 2005;46:220–6.PubMedGoogle Scholar
  88. 88.
    Rubello D, Giannini S, De Carlo E, Mariani G, Muzzio PC, Rampin L, Pelizzo MR. Minimally invasive 99mTc-sestamibi radioguided surgery of parathyroid adenomas. Panminerva Med. 2005;47:99–107.PubMedGoogle Scholar
  89. 89.
    Rubello D, Mariani G, Pelizzo MR, Italian Study Group of Radioguided Surgery and ImmunoScintigraphy. Minimally invasive radio-guided parathyroidectomy on a group of 452 primary hyperparathyroid patients: refinement of preoperative imaging and intraoperative procedure. Nuklearmedizin. 2007;46:85–92.PubMedGoogle Scholar
  90. 90.
    Grassetto G, Rubello D. The increasing role of minimal invasive radioguided parathyroidectomy for treating single parathyroid adenoma. J Postgrad Med. 2013;59:1–3.PubMedCrossRefGoogle Scholar
  91. 91.
    Norman J, Chheda H. Minimally invasive parathyroidectomy facilitated by intraoperative nuclear mapping. Surgery. 1997;122:998–1003. discussion 1003-4.PubMedCrossRefGoogle Scholar
  92. 92.
    Casara D, Rubello D, Piotto A, Carretto E, Pelizzo MR. 99mTc-MIBI radioguided surgery for limited invasive parathyroidectomy. Tumori. 2000;86:370–1.PubMedGoogle Scholar
  93. 93.
    Casara D, Rubello D, Piotto A, Pelizzo MR. 99mTc-MIBI radio-guided minimally invasive parathyroid surgery planned on the basis of a preoperative combined 99mTc-pertechnetate/99mTc-MIBI and ultrasound imaging protocol. Eur J Nucl Med. 2000;27:1300–4.PubMedCrossRefGoogle Scholar
  94. 94.
    Rubello D, Al-Nahhas A, Mariani G, Grosso MD, Rampin L, Pelizzo MR. Feasibility and long-term results of focused radioguided parathyroidectomy using a “low” 37 MBq (1 mCi) 99mTc-Sestamibi protocol. Intern Semin Surg Oncol. 2006;3:30.CrossRefGoogle Scholar
  95. 95.
    Hindié E, Zanotti-Fregonara P, Tabarin A, Rubello D, Morelec I, Wagner T, et al. The role of radionuclide imaging in the surgical management of primary hyperparathyroidism. J Nucl Med. 2015;56:737–44.PubMedCrossRefGoogle Scholar
  96. 96.
    Ikeda Y, Takayama J, Takami H. Minimally invasive radioguided parathyroidectomy for hyperparathyroidism. Ann Nucl Med. 2010;24:233–40.PubMedCrossRefGoogle Scholar
  97. 97.
    Gencoglu EA, Aktas A. The efficacy of low and high dose 99mTc-MIBI protocols for intraoperative identification of hyperplastic parathyroid glands in secondary hyperparathyroidism. Rev Esp Med Nucl Imagen Mol. 2014;33:210–4.PubMedGoogle Scholar
  98. 98.
    Greene AB, Butler RS, McIntyre S, Barbosa GF, Mitchell J, Berber E, et al. National trends in parathyroid surgery from 1998 to 2008: a decade of change. J Am Coll Surg. 2009;209:332–43.PubMedCrossRefGoogle Scholar
  99. 99.
    Oltmann SC, Brekke AV, Macatangay JD, Schneider DF, Chen H, Sippel RS. Surgeon and staff radiation exposure during radioguided parathyroidectomy at a high-volume institution. Ann Surg Oncol. 2014;21:3853–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Denmeade KA, Constable C, Reed WM. Use of 99mTc 2-methoxyisobutyl isonitrile in minimally invasive radioguided surgery in patients with primary hyperparathyroidism: a narrative review of the current literature. J Med Radiat Sci. 2013;60:58–66.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Ilgan S, Ozbas S, Bilezikci B, Sengezer T, Aydin OU, Gursoy A, et al. Radioguided occult lesion localization for minimally invasive parathyroidectomy: technical consideration and feasibility. Nucl Med Commun. 2014;35:1167–74.PubMedCrossRefGoogle Scholar
  102. 102.
    Livingston CD. Radioguided parathyroidectomy is successful in 98.7% of selected patients. Endocr Pract. 2014;20:305–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Rahbar K, Colombo-Benkmann M, Haane C, Wenning C, Vrachimis A, Weckesser M, et al. Intraoperative 3-D mapping of parathyroid adenoma using freehand SPECT. EJNMMI Res. 2012;2(1):51. doi:10.1186/2191-219X-2-51.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Casella C, Rossini P, Cappelli C, Nessi C, Nascimbeni R, Portolani N. Radioguided parathyroidectomy with portable mini gamma-camera for the treatment of primary hyperparathyroidism. Int J Endocrinol. 2015;2015:134731. doi:10.1155/2015/134731. Epub 2015 Sep 15.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Tobin K, Ayers RR, Rajaei M, Sippel RS, Balentine CJ, Elfenbein D, et al. Use of the gamma probe to identify multigland disease in primary hyperparathyroidism. Int J Endocrinol Oncol. 2016;3:13–9.CrossRefGoogle Scholar
  106. 106.
    Soimnay YR, Weinlander E, Alfhefdi A, Schneider D, Sippel RS, Chen H. Radioguided parathyroidectomy for tertiary hyperparathyroidism. J Surg Res. 2015;195:406–11.CrossRefGoogle Scholar
  107. 107.
    Burke JF, Jacobson K, Gosain A, Sippel RS, Chen H. Radioguided parathyroidectomy effective in pediatric patients. J Surg Res. 2013;184:312–7.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Cetani F, Pardi E, Marcocci C. Update on parathyroid carcinoma. J Endocrinol Invest. 2016;39:595–606.PubMedCrossRefGoogle Scholar
  109. 109.
    Shane E. Parathyroid carcinoma. Curr Ther Endocrinol Metab. 1997;6:565–8.PubMedGoogle Scholar
  110. 110.
    Shane E. Clinical review 122: parathyroid carcinoma. J Clin Endocrinol Metab. 2001;86:485–93.PubMedCrossRefGoogle Scholar
  111. 111.
    Asare EA, Sturgeon C, Winchester DJ, Liu L, Palis B, Perrier ND, et al. Parathyroid carcinoma: an update on treatment outcomes and prognostic factors from the National Cancer Data Base (NCDB). Ann Surg Oncol. 2015;22:3990–5.PubMedCrossRefGoogle Scholar
  112. 112.
    Wang CA, Gaz RD. Natural history of parathyroid carcinoma. Diagnosis, treatment, and results. Am J Surg. 1985;149:522–7.PubMedCrossRefGoogle Scholar
  113. 113.
    Hundahl SA, Fleming ID, Fremgen AM, Menck HR. Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985–1995: a National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1999;86:538–44.PubMedCrossRefGoogle Scholar
  114. 114.
    Smith JF, Coombs RR. Histological diagnosis of carcinoma of the parathyroid gland. J Clin Pathol. 1984;37:1370–8.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Sandelin K, Tullgren O, Farnebo LO. Clinical course of metastatic parathyroid cancer. World J Surg. 1994;18:594–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Abbona GC, Papotti M, Gasparri G, Bussolati G. Proliferative activity in parathyroid tumors as detected by Ki-67 immunostaining. Hum Pathol. 1995;26:135–8.PubMedCrossRefGoogle Scholar
  117. 117.
    Vargas MP, Vargas HI, Kleiner DE, Merino MJ. The role of prognostic markers (MiB-1, RB, and bcl-2) in the diagnosis of parathyroid tumors. Mod Pathol. 1997;10:12–7.PubMedGoogle Scholar
  118. 118.
    Rubin MR, Silverberg SJ. Editorial: HRPT2 in parathyroid cancer: a piece of the puzzle. J Clin Endocrinol Metab. 2005;90:5505–7.PubMedCrossRefGoogle Scholar
  119. 119.
    Cetani F, Ambrogini E, Viacava P, Borsari S, Lemmi M, Cianferotti L, et al. Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma? Eur J Endocrinol. 2007;156:547–54.PubMedCrossRefGoogle Scholar
  120. 120.
    Rubin MR, Bilezikian JP, Birken S, Silverberg SJ. Human chorionic gonadotropin measurements in parathyroid carcinoma. Eur J Endocrinol. 2008;159:469–74.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Tan MH, Morrison C, Wang P, et al. Loss of parafibromin immunoreactivity is a distinguishing feature of parathyroid carcinoma. Clin Cancer Res. 2004;10:6629–37.PubMedCrossRefGoogle Scholar
  122. 122.
    Cetani F, Marcocci C. Parathyroid carcinoma. In: Bilezikian JP, Marcu R, Levine MA, Marcocci C, Silverberg SJ, Potts Jr JT, editors. The parathyroids – basic and clinical concepts. 3rd ed. Oxford, UK: Elsevier; 2015. p. 409–21.Google Scholar
  123. 123.
    Wassif WS, Moniz CF, Friedman E, Wong S, Weber G, Nordenskjöld M, et al. Familial isolated hyperparathyroidism: a distinct genetic entity with an increased risk of parathyroid cancer. J Clin Endocrinol Metab. 1993;77:1485–9.PubMedGoogle Scholar
  124. 124.
    Chen JD, Morrison C, Zhang C, Kahnoski K, Carpten JD, Teh BT. Hyperparathyroidism-jaw tumour syndrome. J Intern Med. 2003;253:634–42.PubMedCrossRefGoogle Scholar
  125. 125.
    Agha A, Carpenter R, Bhattacharya S, Edmonson SJ, Carlsen E, Monson JP. Parathyroid carcinoma in multiple endocrine neoplasia type 1 (MEN1) syndrome: two case reports of an unrecognised entity. J Endocrinol Invest. 2007;30:145–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Jenkins PJ, Satta MA, Simmgen M, Drake WM, Williamson C, Lowe DG, et al. Metastatic parathyroid carcinoma in the MEN2A syndrome. Clin Endocrinol (Oxf). 1997;47:747–51.CrossRefGoogle Scholar
  127. 127.
    Arnold A, Shattuck TM, Mallya SM, Krebs LJ, Costa J, Gallagher J, et al. Molecular pathogenesis of primary hyperparathyroidism. J Bone Miner Res. 2002;17 Suppl 2:N30–6.PubMedGoogle Scholar
  128. 128.
    Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet. 2002;32:676–80.PubMedCrossRefGoogle Scholar
  129. 129.
    Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, et al. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. J Med Genet. 2003;40:657–63.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Cetani F, Pardi E, Borsari S, Viacava P, Dipollina G, Cianferotti L, et al. Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J Clin Endocrinol Metab. 2004;89:5583–91.PubMedCrossRefGoogle Scholar
  131. 131.
    Hewitt KM, Sharma PK, Samowitz W, Hobbs M. Aberrant methylation of the HRPT2 gene in parathyroid carcinoma. Ann Otol Rhinol Laryngol. 2007;116:928–33.PubMedCrossRefGoogle Scholar
  132. 132.
    Krebs LJ, Shattuck TM, Arnold A. HRPT2 mutational analysis of typical sporadic parathyroid adenomas. J Clin Endocrinol Metab. 2005;90:5015–7.PubMedCrossRefGoogle Scholar
  133. 133.
    Dudney WC, Bodenner D, Stack Jr BC. Parathyroid carcinoma. Otolaryngol Clin North Am. 2010;43:441–53.PubMedCrossRefGoogle Scholar
  134. 134.
    Fernandez-Ranvier GG, Jensen K, Khanafshar E, Quivey JM, Glastonbury C, Kebebew E, et al. Nonfunctioning parathyroid carcinoma: case report and review of literature. Endocr Pract. 2007;13:750–7.PubMedCrossRefGoogle Scholar
  135. 135.
    Shattuck TM, Valimaki S, Obara T, Gaz RD, Clark OH, Shoback D, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med. 2003;349:1722–9.PubMedCrossRefGoogle Scholar
  136. 136.
    Naji M, Hodolic M, El-Refai S, Khan S, Marzola MC, Rubello D, et al. Endocrine tumors: the evolving role of positron emission tomography in diagnosis and management. J Endocrinol Invest. 2010;33:54–60.PubMedCrossRefGoogle Scholar
  137. 137.
    Deandreis D, Terroir M, Al Ghuzlan A, Berdelou A, Lacroix L, Bidault F, et al. 18Fluorocholine PET/CT in parathyroid carcinoma: a new tool for disease staging? Eur J Nucl Med Mol Imaging. 2015;42:1941–2.PubMedCrossRefGoogle Scholar
  138. 138.
    Kebebew E, Clark OH. Parathyroid adenoma, hyperplasia, and carcinoma: localization, technical details of primary neck exploration, and treatment of hypercalcemic crisis. Surg Oncol Clin N Am. 1998;7:721–48.PubMedGoogle Scholar
  139. 139.
    Fang SH, Lal G. Parathyroid cancer. Endocr Pract. 2011;17 Suppl 1:36–43.PubMedCrossRefGoogle Scholar
  140. 140.
    Daly BD, Coffey SL, Behan M. Ultrasonographic appearances of parathyroid carcinoma. Br J Radiol. 1989;62:1017–9.PubMedCrossRefGoogle Scholar
  141. 141.
    Hara H, Igarashi A, Yano Y, Yashiro T, Ueno E, Aiyoshi Y, et al. Ultrasonographic features of parathyroid carcinoma. Endocr J. 2001;48:213–7.PubMedCrossRefGoogle Scholar
  142. 142.
    Mortenson MM, Evans DB, Lee JE, Hunter GJ, Shellingerhout D, Vu T, et al. Parathyroid exploration in the reoperative neck: improved preoperative localization with 4D-computed tomography. J Am Coll Surg. 2008;206:888–95.PubMedCrossRefGoogle Scholar
  143. 143.
    Kebebew E, Arici C, Duh QY, Clark OH. Localization and reoperation results for persistent and recurrent parathyroid carcinoma. Arch Surg. 2001;136:878–85.PubMedCrossRefGoogle Scholar
  144. 144.
    Obara T, Fujimoto Y. Diagnosis and treatment of patients with parathyroid carcinoma: an update and review. World J Surg. 1991;15:738–44.PubMedCrossRefGoogle Scholar
  145. 145.
    Aigner RM, Fueger GF, Lax S. A case of parathyroid carcinoma visualized on Tc-99 m-sestamibi scintigraphy. Nuklearmedizin. 1997;36:256–8.PubMedGoogle Scholar
  146. 146.
    Singhal T, Jacobs M, Mantil JC. Tc-99 m pertechnetate/sestamibi subtraction scan in a case of parathyroid carcinoma. Clin Nucl Med. 2008;33:196–7.PubMedCrossRefGoogle Scholar
  147. 147.
    Al-Sobhi S, Ashari LH, Ingemansson S. Detection of metastatic parathyroid carcinoma with Tc-99m sestamibi imaging. Clin Nucl Med. 1999;24:21–3.PubMedCrossRefGoogle Scholar
  148. 148.
    Santiago Chinchilla A, Ramos Font C, Murosde Fuentes MA, Navarro-Pelayo Láinez M, Palacios Gerona H, Moreno Caballero M, Liamas Elvira JM. False negative of the scintigraphy with 99mTc-sestamibi in parathyroid carcinoma with associated brown tumors. Contributions of the 18F-FDG-PET/CT. Rev Esp Med Nucl. 2011;30:174–9.PubMedCrossRefGoogle Scholar
  149. 149.
    Clark P, Wooldridge T, Kleinpeter K, Perrier N, Lovato J, Morton K. Providing optimal preoperative localization for recurrent parathyroid carcinoma: a combined parathyroid scintigraphy and computed tomography approach. Clin Nucl Med. 2004;29:681–4.PubMedCrossRefGoogle Scholar
  150. 150.
    Favia G, Lumachi F, Polistina F, D’Amico DF. Parathyroid carcinoma: sixteen new cases and suggestions for correct management. World J Surg. 1998;22:1225–30.PubMedCrossRefGoogle Scholar
  151. 151.
    Arslan N, Rydzewski B. Detection of a recurrent parathyroid carcinoma with FDG positron emission tomography. Clin Nucl Med. 2002;27:221–2.PubMedCrossRefGoogle Scholar
  152. 152.
    Kemps B, van Ufford HQ, Creyghton W, de Haas M, Baarslag HJ, Rinkes IB, de Klerk J. Brown tumors simulating metastases on FDG PET in a patient with parathyroid carcinoma. Eur J Nucl Med Mol Imaging. 2008;35:850.PubMedCrossRefGoogle Scholar
  153. 153.
    Sun SS, Shiau YC, Lin CC, Kao A, Lee CC. Correlation between P-glycoprotein (P-gp) expression in parathyroid and Tc-99 m MIBI parathyroid image findings. Nucl Med Biol. 2001;28:929–33.PubMedCrossRefGoogle Scholar
  154. 154.
    Koea JB, Shaw JH. Parathyroid cancer: biology and management. Surg Oncol. 1999;8:155–65.PubMedCrossRefGoogle Scholar
  155. 155.
    Sandelin K, Auer G, Bondeson L, Grimelius L, Farnebo LO. Prognostic factors in parathyroid cancer: a review of 95 cases. World J Surg. 1992;16:724–31.PubMedCrossRefGoogle Scholar
  156. 156.
    Marcocci C, Mazzeo S, Bruno-Bossio G, Picone A, Vignali E, Ciampi M, et al. Preoperative localization of suspicious parathyroid adenomas by assay of parathyroid hormone in needle aspirates. Eur J Endocrinol. 1998;139:72–7.PubMedCrossRefGoogle Scholar
  157. 157.
    Wynne AG, van Heerden J, Carney JA, Fitzpatrick LA. Parathyroid carcinoma: clinical and pathologic features in 43 patients. Medicine (Baltimore). 1992;71:197–205.CrossRefGoogle Scholar
  158. 158.
    Rao SR, Shaha AR, Singh B, Rinaldo A, Ferlito A. Management of cancer of the parathyroid. Acta Otolaryngol. 2002;122:448–52.PubMedCrossRefGoogle Scholar
  159. 159.
    Munson ND, Foote RL, Northcutt RC, et al. Parathyroid carcinoma: is there a role for adjuvant radiation therapy? Cancer. 2003;98:2378–84.PubMedCrossRefGoogle Scholar
  160. 160.
    Clayman GL, Gonzalez HE, El-Naggar A, Vassilopoulou-Sellin R. Parathyroid carcinoma: evaluation and interdisciplinary management. Cancer. 2004;100:900–5.PubMedCrossRefGoogle Scholar
  161. 161.
    Bradwell AR, Harvey TC. Control of hypercalcaemia of parathyroid carcinoma by immunisation. Lancet. 1999;353:370–3.PubMedCrossRefGoogle Scholar
  162. 162.
    Betea D, Bradwell AR, Harvey TC, Mead GP, Schmidt-Gayk H, Ghaye B, et al. Hormonal and biochemical normalization and tumor shrinkage induced by anti-parathyroid hormone immunotherapy in a patient with metastatic parathyroid carcinoma. J Clin Endocrinol Metab. 2004;89:3413–20.PubMedCrossRefGoogle Scholar
  163. 163.
    Nemeth EF, Steffey ME, Hammerland LG, Hung BC, Van Wagenen BC, DelMar EG, Balandrin MF. Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci U S A. 1998;95:4040–5.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Collins MT, Skarulis MC, Bilezikian JP, Silverberg SJ, Spiegel AM, Marx SJ. Treatment of hypercalcemia secondary to parathyroid carcinoma with a novel calcimimetic agent. J Clin Endocrinol Metab. 1998;83:1083–8.PubMedCrossRefGoogle Scholar
  165. 165.
    Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D. Cinacalcet hydrochloride maintains long-term normo-calcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2005;90:135–41.PubMedCrossRefGoogle Scholar
  166. 166.
    Vellanki P, Lange K, Elaraj D, Kopp PA, El Muayed M. Denosumab for management of parathyroid carcinoma-mediated hypercalcemia. J Clin Endocrinol Metab. 2014;99:387–90.PubMedCrossRefGoogle Scholar
  167. 167.
    Betea D, Potorac I, Beckers A. Parathyroid carcinoma: challenges in diagnosis and treatment. Ann Endocrinol (Paris). 2015;76:169–77.CrossRefGoogle Scholar
  168. 168.
    Fountas A, Andrikoula M, Giotaki Z, Limniati C, Tsakiridou E, Tigas S, et al. The emerging role of denosumab in the long-term management of parathyroid carcinoma-related refractory hypercalcemia. Endocr Pract. 2015;21:468–73.PubMedCrossRefGoogle Scholar
  169. 169.
    Jumpertz von Schwartzenberg R, Elbelt U, Ventz M, Mai K, Kienitz T, Maurer L, et al. Palliative treatment of uncontrollable hypercalcemia due to parathyrotoxicosis: denosumab as rescue therapy. Endocrinol Diabetes Metab Case Rep. 2015;2015:150082. doi:10.1530/EDM-15-0082. Epub 2015 Oct 29.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Busaidy NL, Jimenez C, Habra MA, Schultz PN, El-Naggar AK, Clayman GL, Asper JA, et al. Parathyroid carcinoma: a 22-year experience. Head Neck. 2004;26:716–26.PubMedCrossRefGoogle Scholar
  171. 171.
    Sadler TW. Langman’s medical embryology (Italian ed. of 8th United States’ ed.). Baltimore: Lippincott Williams & Wilkins; 2000. p. 370.6.Google Scholar
  172. 172.
    Wang CA. Parathyroid re-exploration. Ann Surg. 1977;186:140–5.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Federica Guidoccio
    • 1
  • Sara Mazzarri
    • 1
  • Salvatore Mazzeo
    • 2
  • Giuliano Mariani
    • 1
    Email author
  1. 1.Regional Center of Nuclear MedicineUniversity of PisaPisaItaly
  2. 2.Department of Diagnostic and Interventional RadiologyUniversity of PisaPisaItaly

Personalised recommendations