J Endocrinol Invest DOI 10.1007/s40618-016-0447-3

REVIEW

Update on parathyroid carcinoma F. Cetani1 · E. Pardi2 · C. Marcocci2 

Received: 19 January 2016 / Accepted: 12 February 2016 © Italian Society of Endocrinology (SIE) 2016

Abstract  Introduction  Parathyroid carcinoma (PC) is a rare endocrine disorder, commonly causing severe primary hyperparathyroidism (PHPT). PC is mainly a sporadic disease, but it may occur in familial PHPT. Patients with PC usually present markedly elevated serum calcium and PTH. The clinical features are mostly due to the effects of the excessive secretion of PTH rather than to the spread of tumor. At times, the diagnosis can be difficult. Purpose  The aim of this work is to review the available data on PC, and focus its molecular pathogenesis and the clinical utility of CDC73 genetic testing and immunostaining of its product, parafibromin. The pathological diagnosis of PC is restricted to lesions showing unequivocal growth into adjacent tissues or metastasis. Inactivating mutations of the cell division cycle 73 (CDC73) gene have been identified in up to 70 % of apparently sporadic PC and in one-third are germline. Loss of parafibromin immunostaining has been shown in most PC. The association of CDC73 mutations and loss of parafibromin predicts a worse clinical outcome and a lower overall 5- and 10-year survival. Conclusions  The treatment of choice is the en bloc resection of the tumor. The course of PC is variable; most patients have local recurrences or distant metastases and die from unmanageable hypercalcemia.

* F. Cetani [email protected] 1

University Hospital of Pisa, Endocrine Unit 2, Via Paradisa, 2, 56124 Pisa, Italy

2

Department of Clinical and Experimental Medicine, University of Pisa, Endocrine Unit 2, Pisa, Italy



Keywords  Primary hyperparathyroidism · Hyperparathyroidism-jaw tumor syndrome · CDC73 · HRPT2 · PRUNE2 · Parafibromin

Introduction Parathyroid carcinoma (PC) is a rare malignancy, accounting for less than <1 % of cases of primary hyperparathyroidism (PHPT) [1]. PC is commonly a sporadic disease, but it may occur in familial PHPT, namely the hyperparathyroidism-jaw tumor syndrome (HPT-JT), and, very rarely, the multiple endocrine neoplasia type 1 (MEN1) [2]. The clinical features are due primarily to the excessive secretion of PTH rather than to the spreading of tumor mass. The clinical phenotype is characterized by signs and symptoms of hypercalcemia and end-organ damage, including renal failure, bone disease, cardiac arrhythmia and neurocognitive dysfunction. Rarely, patients with PC show normal serum calcium and PTH levels (nonfunctioning PC) [3–6]. The challenge to the clinician is to distinguish PC from parathyroid adenoma (PA). Given the lack of specific biochemical and clinical features, PC is difficult to diagnose preoperatively and very often it is diagnosed postoperatively at histological examination or when the disease recurs. The treatment of choice is the en bloc resection of the tumor, which is recommended when PC is suspected. This surgical approach allows for the greatest likelihood of a cure. Up to 70 % of PC carries a somatic mutation of cell division cycle 73 (CDC73) gene (alternatively known as HRPT2) and in one-third of such cases mutations are germline. In the latter cases, genetic testing will allow to identify asymptomatic relatives at risk of PC [1].

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Fig. 1  Schematic representation of the genomic organization of the human CDC73 gene and parafibromin protein. Upper panel, CDC73 gene. The gene consists of 17 exons (boxes). The start (ATG) and stop (TGA) codons and the 3′ and 5′ untranslated regions are shown. The 5′ portion of exon 1 and the 3′ portion of exon 17 are untranslated (white). The size of coding sequences ranges from 36 to 217 bp (numbers below exons). Lower panel parafibromin. Parafibromin

shares 27 % identity to the yeast cdc73 protein within a conserved C-terminus domain (dotted area). The nuclear localization signal (NLS) and regions implicated in the binding to interacting proteins, i.e. the PAF1 complex binding domain (residues 227–413), Gli family of transcription factors (residues 200–343), β-catenin binding domain and SV40 large T antigen binding (residues 218–263) are shown. With permission from [2]

This review updates the current knowledge of PC, and focus on its molecular pathogenesis and the clinical utility of CDC73 genetic testing and immunostaining of its product, parafibromin.

kindreds with FIHP [17–27]. Somatic CDC73 mutations in sporadic PC were firstly reported by Howell [18] and Shattuck [28] in 2003 and, subsequently confirmed by Cetani, who identified CDC73 mutations in 9 of 11 PC [19, 29]. The current prevalence of CDC73 mutations in apparently sporadic PC ranges between 15 and 70 % (Table 1) [18, 19, 28–40]. The majority of these mutations is nonsense and predicts a lack/reduced parafibromin expression (see below). The mutations are scattered along the entire coding region of the gene, but most are located in exons 1, 2 and 7 [10]. In about one-third of patients the mutations are germline, suggesting that some patients with apparently sporadic PC might have the HPT-JT syndrome or a variant (Table  1). Hypermethylation of the CDC73 promoter has also been shown in 2 of 11 PC [41]. CDC73 mutation very rarely occur in sporadic PAs, indicating a limited, if any, pathogenic role in this neoplasia [17–19, 32, 42]. Parafibromin, a protein of 531 amino acids, interacts with the polymerase II/Paf1 complex and is involved in transcriptional and post-trascriptional control pathways (Fig. 1) [43– 45]. Parafibromin is mostly a nuclear protein, with a functional bipartite nuclear localization signal (NLS), critical for its nuclear localization [44–46]. Specific CDC73 mutations predicted to truncate parafibromin upstream of or within the NLS disrupt the nuclear localization [46]. Parafibromin is also localized in the nucleolus [47]. The tumor suppressor role of parafibromin arises from the observation that parathyroid tumors harbouring CDC73 mutations are frequently associated with loss of parafibromin expression. Several studies evaluated the diagnostic utility of parafibromin immunostaining. Diffuse or focal loss of nuclear staining is found in the majority of PC and, very rarely, in PAs [29, 32, 33, 48–53]. A genome-wide study of DNA methylome from benign and malignant parathyroid tumors identified several genes with altered DNA methylation independently of the tumor’s

Etiology The etiology of PC is unknown. The potential role for prior neck irradiation is less clear than in PA [2]. Rare cases of PC have been reported in patients with end-stage renal disease [7]. A retrospective population-based study in Sweden found that the risk of PC is higher in patients with thyroid cancer or PA [8]. PC is commonly a sporadic disease, but familial cases may occur [9], particularly in HPT-JT. HPT-JT is a rare autosomal dominant disease with incomplete penetrance and variable expression, characterized by multiple, usually metachronous, parathyroid tumors, with an increased prevalence of PC (15 %), ossifying fibromas of the maxilla/mandible (15 %), renal abnormalities (25–50 %)] [10], and benign or malignant uterine neoplasia (in up to 75 % of women) [11]. PC is also part of familial isolated hyperparathyroidism (FIHP) [12, 13] and, rarely MEN1 and MEN2A syndrome [14, 15]. Pathogenesis Several genes and/or their encoded proteins, especially those involved in cell cycle regulation, have been linked to PC: retinoblastoma (Rb), p53, breast carcinoma susceptibility (BRCA2), and cyclin D1/parathyroid adenoma 1 oncogene (PRAD1). Their pathogenetic role is still uncertain [16]. Major advances in the knowledge of the molecular pathogenesis of PC followed the cloning of the tumor suppressor CDC73 gene (Fig. 1) [17]. Germline mutations of CDC73 gene are responsible for HPT-JT [10, 17] and few

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J Endocrinol Invest Table 1  CDC73 mutations in sporadic parathyroid carcinomas Nucleotide nomenclature

Protein nomenclature

c.13C>T c.14C>T c.16delA c.23_26delinsGTG c.25C>T c.30delG c.32delA c.34_35insCT c.34_37delAACA

P.Leu5Phe P.Leu5Pro p.Ser6AlafsX15 p.Leu8ArgfsX13 p.Arg9stop p.Gln10HisfsX11 p.Tyr11SerfsX10 p.Asn12ThrfsX10 p.Asn12SerfsX9

c.40delC c.42delG c.60delG c.60_69del10 c.64G>T c.70G>T c.76delA c.82_85delGGGG c.85delG c.93_94insTA

p.Gln14ArgfsX7 p.Gln14GlnfsX7 p.Val20ValfsX6 p.Val20ValfsX3 p.Gly22Stop p.Glu24Stop p.Ile26SerfsX11 p.Gly28SerfsX8 p.Glu29SerfsX8 p.Trp32TyrfsX6

c.127_128insC c.128G>A c.162C>G c.165C>A c.165delC c.176C>T c.182T>A c.195dupT c.197dupA c.226C>T c.248delT c.260_261delGA c.284T>C c.343G>T c.356delA c.375dupA c.415C>T c.513-1delG c.520_523delCTCG c.539_544insA c.626_629delAACA c.664C>T c.679_680insAG c.687_688delAG c.692_693insT c.693dupG c.700C>T c.736delT c.750delT

p.Trp43SerfsX23 p.Trp43Stop p.Tyr54Stop p.Tyr55Stop p.Tyr55Stop p.Ser59Phe p.Leu61Stop p.Asn66Stop p.Asn66LysfsX16 p.Arg7Stop p.Ile83IlefSX26 p.Arg87LysfsX3 p.Leu95Pro p.Glu115Stop c.Gln119ArgfsX14 p.Arg126ThrfsX5 p.Arg139Stop ? p.Ser174LysfsX46 p.Ile182AsnfsX10 p.Lys209ArgfsX11 p.Arg222Stop p.Arg227LysfsX30 p.Arg229SerfsX28 p.Trp231CysfsX36 p.Arg232GlufsX35 p.Arg234Stop p.Ser246ProfsX11 p.Phe250LeufsX7

Exon/intron

Type

Somatic/germline

References

1 1 1 1 1 1 1 1 1

Missense Missense Frameshift Frameshift Nonsense Frameshift Frameshift Frameshift Frameshift

S S S S S G S S S

[32] [37] [28] [28] [19] [36] [36] [33] [39]

1 1 1 1 1 1 1 1 1 1

Frameshift Frameshift Frameshift Nonsense Nonsense Nonsense Frameshift Frameshift Frameshift Frameshift

S S S S S S S S S S

[28] [32] [35] [28] [35] [28, 29] [18] [28] [40] [32]

1 1 2 2 2 2 2 2 2 2 3 3 3 4 4 5 5 Intron 6 7 7 7 7 7 7 7 7 7 8 8

Frameshift Nonsense Nonsense Nonsense Nonsense Missense Nonsense Nonsense Nonsense Nonsense Frameshift Frameshift Missense Nonsense Frameshift Frameshift Nonsense Splice site Frameshift Frameshift Frameshift Nonsense Frameshift Frameshift Frameshift Frameshift Nonsense Frameshift Frameshift

G S S S S G S S S G S G S G G G G S G G G G G G G S G S S

[46] [30] [18, 28, 37] [18, 36] [18, 30] [30] [29] [19] [19] [28, 37, 40] [35] [33] [36] [31] [36] [28] [29, 32] [18] [32] [36] [33] [28, 33] [32, 33] [28] [30] [30] [19, 28, 39] [28] [28]

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Table 1  continued Nucleotide nomenclature

Protein nomenclature

c.1231delC

p.Gln411ArgfsX17

Exon/intron 14

Type

Somatic/germline

References

Frameshift

S

[28]

G

[36, 38, 69]

Whole gene deletion

Mutations are designated according the latest nomenclature recommendations of the Human Genome Variation Society

Fig. 2  Parathyroid carcinoma: histological features (hematoxylin/ eosin staining 100×). a The tumor shows a solid growth pattern associated with fibrous bands. b Tumor growth into blood vessels: true vascular invasion is defined by the attachment of the tumor cells

to the wall of a vessel lined by endothelial cells (the arrow shows endothelial cells surrounding the neoplastic thrombus). c The tumor infiltrates the surrounding adipose tissue

nature, suggesting that other genes, in addition to CDC73, are involved in parathyroid carcinogenesis [54]. Allelic loss at 11q chromosome, the most common alteration in PAs, has never been detected in PC, suggesting that PC arises de novo, rather than from a pre-existing benign lesion [55]. Aberrant expression of microRNAs (miRNAs) has also been reported in PC [56]. A significant gain of C19MC and MIR371-3 clusters was found in a substantial proportion of PC. Another study has shown that the microarray profile of 825 human miRNAs differs between PA and PC. These findings suggest that alterations in miRNA expression might have a role in the pathogenesis of PC [56].

Recently, whole-exome sequencing in 22 PC and 40 PA identified mutations of PRUNE2 gene in 18 % of PC. Alterations of mTOR, MLL2, CDKN2C, THRAP3, PIK3CA, and EZH2 genes were also reported in PC [36].

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Pathology PC is typically larger (>3 cm) than PA. Macroscopically the tumor is lobulated, grayish-white with occasional necrosis, stony-hard, often with adherence to and invasion of the surrounding neck structures [57]. Schantz and Castleman in 1973 established the criteria for the microscopic

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diagnosis of PC: sheets of cells arranged in a lobular pattern separated by thick fibrous bands, mitotic activity, and vascular and capsular invasion [58] (Fig. 2). It is important to note that some of these features are also found in benign adenoma [59]. Capsular invasion is rather common, whereas vascular invasion occurs less frequently (10–15 %) [58] (Fig. 2). Capsular invasion should be distinguished from “pseudoinvasion” (degeneration and subsequent fibrosis and “trapping” of tumor cells within the capsule) which may occur in large PAs [60, 61]. Different criteria of vascular invasion have been defined, according to whether capsular vessels or vessels in the surrounding tissues are involved [57, 60, 61] (Fig. 2) and/or attachment of neoplastic cells to blood vessel wall or thrombosis are present [61]. The diagnosis of PC based upon morphologic criteria may be difficult at surgery, unless gross local invasion and/or metastases are present [1]. Indeed, some features described earlier, like adherence to surrounding tissues, fibrous bands, trabecular growth and mitosis, can also occur in PAs. Mitotic activity is common in PC, but also detected in PA; atypical mitoses, however, usually indicate malignancy. The diagnostic accuracy largely depends upon the experience of the pathologist. Indeed, as many as 50 % of parathyroid tumors initially classified as benign developed metastases during follow-up [62]. A minority of patients with a histological diagnosis as PC has a good clinical outcome. Whether these cases represent an initial stage of PC cured by surgery is currently unknown. Other histological features have been investigated to improve the diagnostic accuracy, but none has proven to be useful [63–66]. The high prevalence of CDC73 abnormalities in PC has paved the way to develop new diagnostic tools (CDC73 mutational status and/or parafibromin immunostaining), particularly useful in equivocal cases (see below). Nonfunctioning PC is rare [3–6]. These tumors are large, mainly consisting of clear or oxyphil cells, and can be misdiagnoses as thyroid cancers. A positive immunostaining for PTH and chromogranin A, but not for thyroglobulin, calcitonin and thyroid transcription factor 1, may confirm the parathyroid nature. Rarely malignant tumors may metastasize or spread to the parathyroids [67]. Aids to diagnosis by pathological examination of tissue Immunohistochemistry may improve the diagnostic accuracy of PC. Increased labeling of cell cycle-associated proteins (Ki-67, cyclin D1) has been shown in PC as compared to PA [29, 60], but overlap among these tumors has limited the utility of this approach. Decreased expression of p27 and increased expression of Galectin-3 have also been

shown in PC [64, 66, 68] and their association with a high Ki-67 labeling may increase the likelihood of malignancy. Mutation of the CDC73 gene and loss (total/focal) of parafibromin staining are found in most PC, but very rarely in PAs [29, 32, 33, 48–50, 69] (Fig. 3). Limited data are available in equivocal cases, where this technique would have the greatest diagnostic utility [32]. Negative parafibromin staining together with a CDC73 gene mutation increases the likelihood of malignancy and also predicts the clinical outcome, namely local invasion and/or metastases and mortality [35, 53]. An increased mortality is predicted by either of these abnormality combined with down regulation of the calcium-sensing receptor (CaSR) expression [53]. We, therefore, suggest searching for alterations of the CDC73 gene not only for diagnostic purposes in tumor with uncertain diagnosis of malignancy, but also for prognostic value in unequivocal cancers. The identification of germline mutation would prompt the extension of the genetic analysis to first-degree relatives. Diagnosis Clinical features The clinical manifestations of PC overlap with those of benign PHPT, even though signs and symptoms due to moderate-to-severe hypercalcemia, renal and bone involvement dominate the clinical picture in patients with PC [1, 2]. The suspicion of PC at initial evaluation is of paramount importance, since may guide extent of the initial surgery, the major determinant of definitive cure. Several clinical findings could raise the suspicion of PC. There is no gender preference, whereas there is a female predominance (3–4:1) in benign PHPT. The average age at diagnosis of patients with PC (50 year) is about 10 year younger than that of the patients with benign PHPT [1, 2]. Physical examination is commonly unrevealing, but the finding of a palpable cervical mass and laryngeal nerve palsy may predict the presence of PC. Combined renal (nephrocalcinosis, nephrolithiasis, and impaired renal function) and bone involvement (osteitis fibrosa cystica, subperiostal resorption, “salt and pepper” skull) suggests the possibility of PC [1]. PC should be suspected in patients with acute PHPT, a condition characterized by markedly elevated serum calcium and PTH levels. Nonfunctioning PC rarely occurs in patients in the sixth or seventh decade. The clinical picture is characterized by symptoms caused by compression/invasion of adjacent structures and can be misdiagnosed as a thyroid or thymic carcinoma [3–5, 25]. We recently reported a 50-year-old

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Fig. 3  Immunohistochemistry of parafibromin (100×). a Normal parathyroid. A diffuse nuclear staining is present in most parathyroid cells. b A representative case of parathyroid carcinoma scored

as negative. The neoplastic cells are completely negative for nuclear staining. c A representative case of parathyroid carcinoma scored as positive. The majority of cells show a positive nuclear staining

man with nonfunctioning PC misdiagnosed as a thyroid follicular nodule [6].

needed to validate the clinical utility of hCG measurement in patients with PC. The combined finding of markedly elevated serum calcium [>12 mg/dl (>3 mmol/l)] and a large parathyroid lesion (>3 cm) [(the so-called >3 + >3 rule [75] should raise the suspicion of PC.

Laboratory testing Most patients with PC show markedly elevated levels of calcium (>14–15 mg/dl) and PTH (3–10 times above the upper normal limit). Conversely, most patients with PA have mild hypercalcemia and mild-moderate elevation of PTH [70]. An N-terminal PTH fragment, distinct from 1 to 84 PTH, recognized by third-generation, but not by secondgeneration, PTH immunoassays, circulates in some patients with PC [71]. A 3rd- to 2nd-generation PTH ratio >1 is found in the majority of patients with advanced PC, with a diagnostic sensitivity and specificity for PC of 83.3 and 100 %, respectively [72, 73]. Serum and urinary levels of hCG and its hyperglycosilated isoform are abnormally elevated in patients with PC, but not in those with PA [74]. Their measurements might be useful for the differential diagnosis and monitoring of selected patient with PC. Elevations of hCG might also be predictive of hip fracture and death [74]. Further studies are

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Imaging studies Non-invasive studies—ultrasound, 99mTc-labeled sestamibi scintigraphy (MIBI), computerized tomography (TC), and magnetic resonance imaging (MRI)- may be of aid in patients with a suspicion of PC and for localizing recurrences. Neck ultrasound and MIBI help to localize the abnormal parathyroid tissue prior to surgery [76]. At neck ultrasound, a size >3 cm, a lobulated non-homogeneous pattern, marked hypoechogenicity, degenerative changes, calcifications, and irregular halo sign may raise the suspicion of PC (Fig. 4) [77]. A retrospective study has shown that local infiltration and calcification have a 100 % positive predictive value of PC; conversely absence of suspicious vascularity, a thick capsule, and inhomogeneity

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operations may be required for local recurrences and/or metastases. Lymph nodes and distant metastases are rare at the initial diagnosis [1, 81–83]. Resection of the primary tumor rarely results in a definitive cure of PC and, over time, the tumor spreads to cervical nodes (30 %), lung (40 %), liver (10 %) and, very rarely, bone, pleura, pericardium, and pancreas. The disease-free interval between the initial surgery and the occurrence of metastases may be as long as 20 years [32, 62, 84]. The clinical course is indolent and when the disease progresses patients complain mostly because of the clinical manifestations of hypercalcemia and its complications, rather than because of symptoms related to the spreading of the tumor. The finding of CDC73 germline mutations in about onethird of patients with PC [19, 28–30, 32, 33, 35] suggests that these patients might have the HPT-JT syndrome or a variant, in which asynchronous multiglandular parathyroid involvement may occur. Therefore, recurrent hypercalcemia after initial surgery may suggest either recurrence and/ or metastases of the primary tumor or the involvement of an additional parathyroid. A regular surveillance for jaw and renal lesions, and uterine tumors in women, is also recommended. Finally, the CDC73 genetic analysis should be extended to first-degree relatives and mutation carriers should be monitored for the development of PC or other HPT-JT-related manifestations [25, 26]. Fig. 4  Ultrasound image of a parathyroid carcinoma. The tumor (arrows), located at the upper pole of the thyroid, shows a heterogeneous pattern, irregular shape and halo sign (longitudinal view)

Management Surgery

(100 %) showed a negative predictive, 97.6, 96.7, and 100 %, respectively [78]. These data are encouraging, but should be confirmed in prospective studies. MIBI (either planar or single-photon emission computed tomography) allows identifying eutopic and ectopic parathyroid tissue as well as recurrent disease, but there are no specific features to distinguish benign and malignant tumors. Both CT and MRI can accurately localize the primary tumor or its recurrence, their relationship with adjacent structures and lymph node metastases. Four-dimensional CT has a higher sensitivity (up to 94 %) in detecting parathyroid lesions compared to CT [79]. Few studies are available on the use of 18F-fluorodeoxyglucose positron emission tomography (FDG PET) in PC [80]. Evangelista et al. has shown that PET/CT scan, despite a low sensitivity in detecting small lesions, is a very sensitive imaging technique to define the extension of the disease at initial evaluation and identify a recurrence [80]. Natural history and surveillance Patients with PC usually have a long survival because the tumor has a low malignant potential, but multiple

Parathyroidectomy is the treatment of choice for patients with severe and symptomatic PHPT, which is the typical clinical presentation of PC [1]. The adequate surgical approach depends upon the pre-operative suspicion of PC and the experience of the surgeon. All patients with suspected PC should be referred to an experienced parathyroid surgeon [4]. The gold standard treatment is the en bloc resection of the tumor, the ipsilateral thyroid lobe with gross clear margins, and the adjacent involved structures, paying particular attention to avoid the tumor spillage [1, 2]. Tracheoesphageal, paratracheal, and upper mediastinal lymph nodes should be excised. There is no evidence that routine lymph nodes dissection of the centrocervical compartment improves the survival rate [4, 83, 85, 86], but this approach has recently been recommended by Schulte et al. at initial surgery in all patients with PC [87]. The optimal surgical approach in carriers of CDC73 germinal mutations who develop a parathyroid tumor has not yet been established. Standard cervical exploration to visualize all four parathyroid glands and en-bloc removal of any abnormal tissue has been suggested by Kelly et al.

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[26]. Autograft of parathyroid tissue in these patients is not recommended because of the risk of introducing potentially malignant tissue in an ectopic site [26]. Restoration of normocalcemia after surgery indicates that all hyperfunctioning tissue has been removed. When the diagnosis of PC is shown at pathology, as often happens, the management plan becomes more complex. If the macroscopic features are typical of PC and extensive vascular or capsular invasion is present at histology, a reoperation aimed at resecting the adjacent structures could be considered. Similarly, repeated surgery, after appropriate localization studies, should be considered in patients with persistent/relapsing hypercalcemia. If the patient is normocalcemic and the histology is equivocal, immediate reoperation is not indicated, as the complete resection of the tumor may have been curative. In the early postoperative period patients should be monitored because of the risk of symptomatic hypocalcemia due to the “hungry bone syndrome”. During follow-up serum calcium and PTH should be closely monitored (i.e., biannually for 5 years and then yearly). The follow-up of the patients with nonfunctioning PC should only rely on imaging studies. PC has a recurrence rate of >50 %. Most recurrences occur within 2–3 years after initial surgery, with a local recurrence rate between 33 and 82 % within 5 years [2, 82]. Imaging studies should be performed in all patients before reoperation. Fine-needle aspiration of equivocal lesions with measurement of PTH in the eluate could be theoretically of help, but should be avoided because of the potential seeding of malignant cells along the needle track [88]. When non-invasive imaging studies are negative, arteriography and selective venous sampling for PTH measurement may be useful. Local recurrences should be treated with wide resections [4]. Accessible distant metastases, particularly in the presence of localized metastatic disease, should also be resected, as long as possible [1, 89] and may result in periods of normocalcemia ranging from months to years [1, 31, 32]. The results of chemotherapy and radiotherapy are generally disappointing [90]. Recent reports suggest the use of irradiation as adjuvant therapy. A median disease-free survival of 60 months in 4 patients given postoperative adjuvant radiotherapy has been reported [91]. The MD Anderson Cancer Center experience suggests a benefit of adjuvant radiation given after surgery, independent of the type of operation and the stage of the disease [82, 92]. Radiofrequency ablation alone or in combination with arterial embolization has successfully been used in the treatment of hepatic and lung metastases in two patients with PC [93, 94].

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Management of hypercalcemia Medical management is the main treatment of patients awaiting surgery and in those with inoperable PC [82]. Aggressive hydration with saline infusion is the first step of management. Subsequently, loop diuretics could be administered to increase urinary calcium excretion, but, in the majority of cases bone antiresorptive drugs are needed. Pamidronate and zoledronate are transiently effective in lowering serum calcium, but patients frequently become refractory. Denosumab, a fully human monoclonal antibody against the RANK ligand, has successfully been used in three patients with PC [95]. Anti-PTH immunotherapy showed promise in early reports [96, 97], but this approach has not been further developed. Dendritic cell-immunotherapy has also shown benefit in a few patients with a short follow-up [98]. Calcimimetics have emerged as the more effective treatment in controlling hypercalcemia. Calcimimetic are allosteric modulators of the CASR, which increase the receptor’s affinity for calcium and reduce PTH secretion. Cinacalcet, a potent second-generation calcimimetic, is effective in lowering and often normalizing serum calcium and partially reducing PTH concentrations in patient with mild-moderate PHPT [99, 100]. The efficacy of cinacalcet has been demonstrated in 29 patients with inoperable PC [101]. Serum calcium levels significantly decreased, with the greatest responses seen in patients with the highest levels of serum calcium before therapy. PTH levels reached a nadir 4 h after drug administration, but the decline was not pronounced, nor was it sustained. The most common side effects were nausea and vomiting. There is no evidence that cinacalcet modifies the course of the PC. Prognosis The prognosis of PC is quite variable. Patients with complete resection of the tumor at initial surgery carry the best prognosis. The mean time to recurrence is usually 3 years [32, 62, 84]. Once the tumor recurs, a complete cure is unlike, although prolonged survival is still common with palliative surgery. A 5- and 10-year survival rate of 78.3 and 49 %, respectively, has been reported [4, 82, 85, 92]. Negative prognostic factors for survival were higher calcium level at recurrence, numbers of neck recurrences, the use of several calcium-lowering medications, simple parathyroidectomy as initial surgery, presence of lymph nodes or distant metastases, and nonfunctioning PC. In addition, patients whose tumor carries a CDC73 mutation, and/or loss of parafibromin or CASR expression have a worse survival rate [35, 53].

J Endocrinol Invest Acknowledgments  The authors thank Dr. Liborio Torregrossa for preparing the histological images. Compliance with ethical standards  Conflict of interest  The authors declare that they have no conflict of interest. Ethical approval  This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent   No need for informed consent. Funding  This study was not founded by any grant.

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