Diagnostic Applications of Nuclear Medicine: Parathyroid Tumors
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.
Keywordsparathyroid 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
Contrast-enhanced computed tomography
- DW ratio
External beam radiation therapy
Hyperparathyroidism-jaw tumor syndrome
Multiple endocrine neoplasia
Minimally invasive radioguided parathyroidectomy
Magnetic resonance imaging
Positron emission tomography
Parathyroid adenomatosis oncogene
Single photon emission computed tomography
Single photon emission computed tomography/computed tomography
Vitamin D receptor
Anatomy, Physiology, and Pathophysiology
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 . 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 .
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 . 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) . 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 .
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 .
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 .
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 . 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 . 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 .
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 .
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 . 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 . 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 .
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
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 , 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.
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 ; 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 . 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 . 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 .
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 . 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 .
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.
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) .
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 .
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 .
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%) ; 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%) .
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) . 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.
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 .
Norman and Chheda described the first protocol for minimally invasive radioguided parathyroidectomy in 1997 . 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 . 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 .
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 , 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 . 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 ), radioguidance continues to show particular clinical usefulness in diverse additional clinical conditions such as tertiary HPTH  and in pediatric patients .
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.
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  and in the HPTH-jaw tumor syndrome , 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 , while only one case of parathyroid carcinoma has been reported in the MEN2A syndrome .
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 , 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 . 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 . Controversial data have instead been reported about the presence of HRPT2 mutations in sporadic benign parathyroid adenomas [108, 130, 132].
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  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 . In these cases, the surveillance for renal and jaw lesions is recommended . 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 . 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 . During follow-up, US evaluation is useful for detecting local recurrence of parathyroid carcinoma.
PET with [18F]FDG has also shown to be very helpful for detecting metastatic parathyroid cancers , although brown tumors can be [18F]FDG avid as well, thus being possibly incorrectly interpreted as metastatic bone lesion . 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 . 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
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 . 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 .
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 . 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.
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 , external beam radiation therapy (EBRT) has little, if any, effect in invasive parathyroid cancers . 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 . 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 .
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 . A first generation calciomimetic, R-568, was used for 2 years in a patient with metastatic parathyroid carcinoma, resulting in effective control of hypercalcemia . 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 . 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].
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 . 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.
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.
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