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Journées Klotz 2015

Parathyroid carcinoma: Challenges in diagnosis and treatment Le carcinome parathyroïdien : défis dans le diagnostic et traitement Daniela Betea ∗ , Iulia Potorac , Albert Beckers Département d’endocrinologie, université de Liège, CHU Sart Tilman, 4000 Liège, Belgium

Abstract Parathyroid carcinoma is a malignant neoplasm affecting 0.5 to 5.0% of all patients suffering from primary hyperparathyroidism. This cancer continues to cause challenges for diagnosis and treatment because of its rarity, overlapping features with benign parathyroid disease, and lack of distinct characteristics. The third/second generation PTH assay ratio provides valuable information to distinguish between benign parathyroid disease and parathyroid carcinoma. An abnormal ratio (> 1) could indicate a high suspicion regarding carcinoma and metastatic disease. Early en bloc surgical resection of the primary tumour with clear margins remains the best curative treatment. Although prolonged survival is possible with recurrent or metastatic disease, cure is rarely achievable. The efficacy of classical adjuvant therapies, such as radiotherapy and chemotherapy, in management of persistent, recurrent, or metastatic disease has been disappointing. In metastatic disease the goal of therapeutic support is to control the PTH-driven hypercalcemia that represents the primary cause of mortality. Calcimimetics, which are allosteric modulators of the calcium sensing receptor, have a sustained effect in lowering serum calcium levels. Bone anti-resorptive therapy, like intravenous bisphosphonates (pamidronate and zolendronate), or more recently denosumab (fully human monoclonal antibody with high affinity to bind RANK ligand) might be temporarily useful. In a small number of cases treated with anti-PTH immunotherapy, inducing anti-PTH antibodies, promising results have been seen with clinical improvements and decrease of calcemia. In one case metastasis shrinkage has been observed. © 2015 Elsevier Masson SAS. All rights reserved. Keywords: Parathyroid carcinoma; Hypercalcemia; PTH ratio; Surgery; Immunotherapy

Résumé Néoplasie endocrinien rarissime, le carcinome parathyroïdien affecte 0,5 à 5 % des patients souffrant d’hyperparathyroïdie primaire. Ce cancer énigmatique pose une grande difficulté diagnostique et thérapeutique du fait de sa rareté, de l’absence de signes cliniques et paracliniques caractéristiques, qui miment ceux de l’hyperparathyroïdie primaire bénigne. Le ratio entre les valeurs de la PTH dosées avec les kits de troisième/deuxième génération, fournit actuellement des informations très précieuses dans le diagnostic différentiel de l’hyperparathyroïdie primaire bénigne et le carcinome parathyroïdien. Un ratio anormal (> 1) soulève une grande suspicion de carcinome et de maladie métastatique. Le meilleur traitement, à visée curative, demeure la chirurgie avec résection « en bloc » de la tumeur primitive avec marges de sécurité oncologique. Dans le cas de la maladie métastatique, une survie assez prolongée est possible, aux prix des multiples interventions, la guérison n’étant que très rarement acquise. L’efficacité des thérapies adjuvantes classiques, comme la radiothérapie ou la chimiothérapie, dans le contrôle d’une maladie évolutive, récurrente ou métastatique, est très décevante. Dans la maladie métastatique, le but du traitement est de maîtriser l’hypercalcémie maligne PTH-induite, qui représente la première cause de mortalité. Les calcimimétiques, modulateurs allostériques du récepteur sensible au calcium, ont un effet significatif dans la réduction des taux de calcium sériques. La thérapie antiresorbtive, avec puissants bisphosponates en intraveineux (pamidronate et zolendronate), ou plus récemment le dénosumab (anticorps monoclonal humanisé, avec grande affinité pour le RANK-ligand) peut se montrer d’une utilité temporaire. Dans quelques cas, l’immunothérapie anti-PTH a montré des résultats encourageants, avec induction d’anticorps anti-PTH, suivie d’amélioration clinique et réduction de la calcémie. Dans un cas, une régression des métastases a été observée. © 2015 Elsevier Masson SAS. Tous droits réservés. Mots clés : Carcinome parathyroïdien ; Hypercalcémie ; PTH ratio ; Chirurgie ; Immunothérapie

∗

Corresponding author. E-mail address: [email protected] (D. Betea).

http://dx.doi.org/10.1016/j.ando.2015.03.003 0003-4266/© 2015 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Betea D, et al. Parathyroid carcinoma: Challenges in diagnosis and treatment. Ann Endocrinol (Paris) (2015), http://dx.doi.org/10.1016/j.ando.2015.03.003

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1. Introduction A very rare malignancy, parathyroid carcinoma represents less than 0.005% of all cancers. It is also a very rare endocrine cancer ( 3.0 mmol/L), young age, male gender, hypercalcemic crisis, concomitant renal and bone involvement, as well as the presence of a palpable neck mass (more than 3 cm) should raise the suspicion of parathyroid carcinoma [1,6,8,11,34]. Patients with this combination of symptoms have a 4.5–fold increased risk of parathyroid cancer when compared to less symptomatic patients. Hoarseness as a sign of recurrent laryngeal nerve palsy due to local invasion is highly suggestive of malignancy, since it is very uncommon in benign hyperparathyroidism.

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with these third-generation PTH kits, but not with antibodies used in the second-generation kits. PTH 7-84 represents 15–50% and amino-PTH less than 10% of the total circulating PTH. Consequently, in healthy individuals the ratio between the amounts of PTH measured with third- versus second-generation assays, will not be superior to 1. Recently it has been shown that amino-PTH is overproduced in parathyroid carcinomas [36]. In these cases, the third- to second-generation PTH ratio may be inverted (>1). In our study, in a series of 24 patients with advanced parathyroid carcinoma – a comparatively large series, considering the rarity of the disease –, an inverted third-generation to secondgeneration PTH ratio was found in 83% of patients compared with 0% of a series of 245 relevant controls. Our results, as well as those from the literature, indicate than an inverted thirdgeneration to second-generation PTH ratio is a tumor marker for parathyroid carcinoma, with a sensitivity of 78.5% and a specificity of 98.9% among patients with primary hyperparathyroidism [35–37,42]. The overproduction of non-truncated amino-PTH in patients with parathyroid cancer might be related to HRPT2/CDC73 inactivation [43].

5. Novel PTH assay 6. Imaging studies We have recently studied a new laboratory diagnostic tool that can greatly help the clinician in differentiating benign adenoma from malignant carcinoma. This is the ratio of PTH measurement, obtained by dividing third-generation to secondgeneration assay results [35–38]. PTH levels in parathyroid cancer are usually very high [39]. However, in most patients, high levels of PTH are secreted by benign lesions. The first assays used to measure PTH – an 84amino-acid peptide hormone – were radioimmunoassays. They recognized the full length of PTH 1-84, but also a large amount of various C-terminal fragments (resulting from processes of cleavage and phosphorylation). Since 1987 various routine immunoassays of so-called intact PTH became available [40]. These immunoassays (commonly termed second-generation PTH immunoassay) use a pair of antibodies that bind to the PTH 13-24 and PTH 39-85 regions of the peptide. These antibodies also cross-react with a family of large N terminal-truncated fragments, among which the most abundant form is PTH 7-84. This latter form accumulates in patients suffering from chronic kidney disease, leading to an overestimation of PTH values. In 1999 a next generation of PTH immunoassays was developed (commonly termed third-generation PTH immunoassay) [41]. These immunoassays used capture antibodies similar to the second-generation immunoassay for the PTH 39-84 region, but added anti N-terminal antibodies directed against the PTH 14 epitope. Therefore this immunoassay can recognize the entire PTH molecule, as well as the non-truncated amino-PTH, but does not measure the PTH 7-84 fragment. Amino-PTH, a recently described form of PTH, is modified in the 15-20 amino-acid region, probably by phosphorylation of a serine residue at position 17 [35]. Amino-PTH cross-reacts

After the biological diagnosis of hyperparathyroidism, almost all patients undergo imaging studies for tumour localisation. When combined, these diagnostic techniques have high sensitivity and specificity. Neck ultrasound and technetium99m sestamibi scan are the most common imaging studies used in benign disease, but they are highly informative in malignant cases as well [44–48]. Computed tomography (CT-scan), magnetic resonance imaging (MRI), 18-FDG positron emission tomography (PET-scan) and, recently, fusion imaging of single photon emission computed tomography (SPECT) and CT have a better sensitivity as compared to sestamibi scan and a similar specificity [49]. Ultrasonography (US), which is accessible, noninvasive and inexpensive, is the most widely used technique [6]. Parathyroid carcinoma appears as a large hypoechoic, lobulated lesion, with irregular borders as compared to parathyroid adenomas [50,51]. In a recent retrospective ultrasonographic study, specific criteria that predict malignancy were identified, such as infiltration and calcifications. The absence of suspicious intra-tumoral vascularisation, a thick capsule and a heterogeneous aspect has a high negative predictive value, allowing the investigator to largely exclude malignancy [47,52]. Fine needle aspiration (FNA) should be avoided as the cytology obtained with this technique is largely insufficient to differentiate between benign and malignant tumors [52,53]. Moreover, FNA risks tumor seeding on the biopsy tract [54]. Technetium-99m sestamibi scanning is used for parathyroid tumor localization, but it does not supply information regarding the benign or malignant nature of the tumor. The technique is however useful in diagnosing and localizing metastatic parathyroid carcinoma [55–57].

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Other imaging techniques such as CT scan and MRI may be useful for localizing recurrence or metastasis, most frequently in the lungs, liver and bones. The combination of at least two techniques enhances the sensitivity for detecting recurrent disease of the Tc-99m sestamibi scan, CT scan and ultrasonography to 86, 79 and 100% in a series of 14 reintervention cases [58]. Previous results obtained in a similar series of reinterventions, found a sensitivity for localizing parathyroid carcinoma recurrence using Tc-99m sestamibi scan, MRI, CT scan, ultrasound and selective venous sampling of PTH secretion of 79, 93, 69 and 83% respectively [45]. During surgery, in the absence of massive local invasion or regional metastasis, the diagnosis of carcinoma is very difficult. In a large retrospective study in 1999, for 86% of patients the diagnosis of parathyroid carcinoma could not be established during surgery, although it was performed by experienced parathyroid surgeons [1]. Frozen section analysis is of little value, since the histopathological features of carcinoma may overlap those of benign adenoma [59]. Before referring patients with suspected parathyroid cancer to the surgeon, the most reliable parameters that indicate an increased cancer risk are blood calcium levels corrected for albumin, PTH assay ratio and tumour size. The values of these parameters will orient the surgeon towards an oncological approach. 7. Histopathological diagnosis Confirmation of parathyroid cancer is histopathological. The cardinal features for the diagnosis of any cancer rely on local invasion and metastasis. However, these features are not commonly found at the first presentation in parathyroid carcinoma [60]. Many pathological criteria have been proposed to help distinguish between benign and malignant lesions, as no single histopathological feature is pathognomonic for parathyroid carcinoma. Early reports in the 1970s [61] describe a combination of criteria highly suggestive of malignancy: fibrous trabeculae, mitotic figures, capsular and vascular invasion. None of these criteria are sensitive or specific enough to confirm or recuse the diagnosis, as mitotic activity and trabecular pattern are also found in benign lesions [62,63]. More recently, the histopathological diagnosis of parathyroid cancer, according to the WHO criteria [64], is defined as the presence of minor criteria such as capsular and soft tissue invasion as a sign of infiltrative growth or a major criterion as histological proof of vascular invasion, with or without invasion of vital organs, or presence of local or distant metastasis [64,65]. In practice, capsular invasion is only found in some of the specimens, whereas vascular invasion is rarely present [32,66]. It is hence of great importance to consider the overall clinical picture, rather than any single histopathological feature [2,52,60]. Because of these difficulties, considerable efforts have been directed towards developing other methods such as immunohistochemistry and DNA analysis [67,68]. Immunohistochemical staining for parafibromin can help to avoid diagnostic errors; the absence of parafibromin is a powerful tool to diagnose

parathyroid cancer, as it is rarely observed in sporadic benign cases. Recent reports suggest using a combination of different markers including loss of parafibromin together with Rb expression and overexpression of galectin-3 and Ki-67 labelling index. This combination was found to be highly relevant in differentiating parathyroid carcinoma from atypical adenoma and other non-malignant lesions [68,69]. Moreover, a more recent study explored the value of parafibromin staining as a prognostic marker in parathyroid carcinoma. The authors found that negative staining for parafibromin was associated to a higher risk of recurrence, decreased 5-year survival rates of 59% and significantly decreased 10-year survival rates of 23% [70]. Finally, all patients with parathyroid carcinoma should be considered for germline testing for HRPT2/CDC73 because more than 20% of them have unrecognised HPT-JT syndrome even in the absence of family history [27,29,71]. 8. Management/therapeutical support 8.1. Staging Because of the rarity of the disease, there is no universally agreed-upon staging system. Several research groups have proposed possible staging systems for parathyroid cancer [8,72]. Shaha and Shah proposed a staging system based on the size of the tumour, extent of local invasion, presence of regional lymph node extension and distant metastases [72]. The other classification system proposed by Talat and Schulte focuses more on the extent and type of tumor invasion rather than tumor size [8]. They also divide parathyroid carcinoma cases into low and high risk. Low-risk disease is defined as invasion limited to the capsule and soft tissue. High-risk disease is defined as any of the following: vascular invasion, lymph node metastasis or invasion of vital organs (trachea, oesophagus or major cervical vessels). The same research group recently published an analysis of a new classification system that further subgrouped highrisk cancer. In this classification low-risk cancer corresponded to class I. The high-risk cancers were subdivided into vascular invasion alone (class II), lymph node metastasis or organ invasion (class III) and distant metastasis (class IV). A statistically significant overall survival difference was found between these different classes (98.6, 72, 71.4, 40% respectively), thereby confirming the validity of this classification system [8,73]. 8.2. Surgery The treatment of choice is undoubtedly complete surgical resection, the only technique that is potentially curative [1,3,6,32,45]. The goal is to remove the entire tumour, prevent local recurrence and eliminate the risk of distant metastasis originating from regionally persistent disease [9]. The most important factors determining patient outcome are tumour characteristics and surgical approach. Surgery is indicated in two distinct clinical scenarios: at the time of diagnosis of hyperparathyroidism, when it could be

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curative and in case of recurrent or metastatic disease, when multiple interventions are usually necessary. Complete en bloc resection with ipsilateral hemithyroidectomy and centrocervical lymphadenectomy should represent the minimum oncological approach in all patients with suspected parathyroid carcinoma. When performed by dedicated endocrine oncologic surgeons, this procedure has moderate risks [65]. It is of great importance that clear gross margins are obtained and rupture of the capsule is avoided, preventing tumour seeding and local recurrence [74,75]. If the recurrent laryngeal nerve is involved, it can be sacrificed [45]. At presentation, 15–30% of PC patients have cervical node involvement. The therapeutic ipsilateral cervical compartment lymph node dissection is indicated if preoperative or intraoperative findings indicate lymph node involvement. Prophylactic neck dissection in patients without evidence of local invasion is not indicated, because it does not improve survival, but does increase morbidity [76]. More extensive surgical resection advocated by certain investigators is usually not recommended because of increased morbidity and unimproved survival [77]. The evolution of the disease is directly influenced by the surgical approach, hence the importance of the en bloc resection. Patients who were diagnosed before or during surgery and benefited from an en bloc resection had a recurrence rate of 33%, whereas patients who were diagnosed after the initial surgery had a recurrence rate of over 50%, as only local excision was performed [1,3,76]. The use of rapid intraoperative PTH assay, when available, can be useful in the management of parathyroid carcinoma. Normalization of PTH levels postoperatively is reassuring that the tumour was most likely completely resected [37,52,78]. If PTH levels do not decrease into the normal range and the patient remains hypercalcemic, incomplete resection should be suspected and additional localisation studies and reintervention is warranted. In these cases, adequate pre-operative imaging techniques are of capital importance to help localise the disease and guide the surgeon toward the adequate intervention. Parathyroid carcinoma usually recurs two to five years after the initial surgery [74,76]. Local recurrence rates vary between 33% and 82% at five years [6,32,61,76] and are most likely due to incomplete resection. Metastases occur through lymphatic and hematogenous dissemination. The most common sites of distant metastasis are the lung, liver and bones [6,61,75]. Patients with recurrent disease or distant metastasis present with gradually increasing serum calcium along with high PTH values. At this point, management of hypercalcemia and performing appropriate imaging studies to localise the site of recurrence are essential. Combining techniques, from less to more invasive, such as selective venous sampling with PTH measurement, should be undertaken in case of inconclusive results [45]. Repeat surgery with metastasis resection has shown to decrease PTH and calcium levels, providing symptomatic relief and temporary biochemical normalisation, which is why it is always recommended when feasible. Resection of distant metastasis has been shown to improve patient survival, as the mortality

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in advanced parathyroid carcinoma is mostly related to severe hypercalcemia rather than the tumour mass [44]. The goal of metastasis resection is to remove all lesions located in the neck, mediastinum, as well as in distant sites and to obtain clear margins. In patients who have repeated recurrences, a combined treatment modality could be employed complementary to surgery: embolization, radio-frequency ablation [79]. 8.3. Chemotherapy There is no evidence supporting the efficacy of chemotherapy in parathyroid carcinoma. Due to the rarity of the disease, experience is limited to case reports [11,32,74,80]. These scattered case reports showed some benefits with regimens including dacarbazine alone or in combination with other agents in patients with advanced metastatic disease, but a survival benefit was not demonstrated [11,80]. 8.4. Radiotherapy Parathyroid carcinoma is not considered to be radiosensitive and there is no evidence for the efficacy of radiation treatment as primary therapy in local or metastatic disease. There is some evidence, however, suggesting the benefit of postoperative radiotherapy, in several case reports [11,32,81,82]. In these cases, radiotherapy reduced local recurrence and increased disease free interval. In one study, the investigators recommended adjuvant post-surgery radiation with 40-50 Gy in patients at high risk of local recurrence [82], while in another study the dosage administered was 70 Gy [81]. These results should be interpreted with great caution, as the studies were retrospective and each included a very small number of patients. 8.5. Metastatic disease For most patients with metastatic dissemination, parathyroid carcinoma becomes a chronic disease. The severe hypercalcemia is the most frequent cause of morbidity and mortality. Prolonged survival is still possible at this stage, as long as hypercalcemia is controlled. Medical intervention is required in patients with disseminated or unresectable local disease, in case of hypercalcemic crisis and also in patients selected for surgical reintervention. In such patients, severe dehydration arises because of the calcium-induced nephrogenic diabetes insipidus and the associated nausea and vomiting. Aggressive volume expansion with saline infusion and use of loop diuretics to enhance renal excretion of calcium are required on an urgent basis [56]. The use of agents interfering with osteoclast bone resorption is almost always necessary. 8.5.1. Bisphosphonates Bisphosphonates, which are potent inhibitors of osteoclastmediated bone resorption, have been shown to reduce serum calcium in patients with parathyroid cancer [6,56,83]. Potent agents such as pamidronate and zolendronate can be

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administered intravenously, but their control of hypercalcemia is only temporary, ranging from days to several months at best. 8.5.2. Denosumab Denosumab, an humanized monoclonal antibody that binds to the “receptor activator of nuclear factor kB ligand (RANKL)” was recently reported to be effective in the management of severe hypercalcemia in patients with metastatic disease [84,85]. It is effective for several months. Use of other agents such as mithramycine [6], plicamicyn and gallium nitrate is limited due to their toxicity, particularly renal. Moreover, their efficacy is only transient [86]. Calcitonin and octreotide as well as corticosteroids can also be administered, but with only temporary benefit [6,87]. 8.5.3. Calcimimetics Calcimimetics represent another class of drugs, which are allosteric modulators of the calcium sensing receptor. These drugs bind to the calcium-sensing receptor on the surface of parathyroid cells, increasing the receptor’s sensitivity to extracellular calcium. This results in a reduction of PTH secretion by parathyroid cells [83]. After encouraging results with a first-generation calcimimetic (R-568), a second-generation product, cinacalcet, proved its efficacy by decreasing serum calcium in patients with metastatic parathyroid carcinoma enrolled in a multicentric study. In this study 18 out of 29 patients responded to treatment with an average reduction in serum calcium from 15 mg/dL to 11 mg/dL. Patients with the highest calcium levels at the beginning of the study had the most significant responses. Patients tolerated total daily doses up to 360 mg, nausea and vomiting being the most common side effects. Interestingly, decreased serum calcium levels were achieved without a significant decrease in PTH levels [88,89]. 8.6. Radiofrequency ablation of metastasis In metastatic disease with unresectable disseminated lesions, alternative methods such as radiofrequency ablation were reportedly used in the management of lung metastasis [90,91]. A combination of radiofrequency ablation and transcatheter arterial embolization has been used to treat multiple metastatic lesions in the liver [92]. In these reports, improvement of serum calcium and PTH levels were obtained following treatment. 8.7. Immunotherapy The early years of immunotherapy in the treatment of solid, aggressive cancers have seen inconclusive results. Progressively the mechanisms of antigen presentation, immune tolerance and autoimmunity became more clearly understood. This raised interest in developing a variety of methods used to induce and enhance targeting of antigens expressed by cancer cells. In 1999, Bradwell and Harvey showed that it was possible to reduce hypercalcemia in a patient with terminal metastatic parathyroid carcinoma, by immunologically blocking the effects

of high PTH concentrations. This was achieved by immunisation and induction of neutralizing autoantibodies against human PTH. This procedure involved breaking normal immune tolerance to PTH by using human and bovine PTH-like immunogenic fragments in order to stimulate the production of antibodies that would cross-react with human PTH [93]. We immunised our first patient in 2001 following the same protocol [94]. We chose a combination of human, modified human and bovine peptides for the immunotherapy. The human modified peptides contained single amino-acid substitution at position 2 of each fragment, remaining more similar to human molecule than to the bovine one. These minimal structural differences are required to favour cross-recognitions of human proteins, assuring a satisfactory major histocompatibility complex presentation of antigens from B cells to T cells. Antigenicity was enhanced by synthesizing each of the PTH fragments as multi-antigenic peptides (octamers) on lysine webs connected to a lysine core. These immunogenic peptides were further mixed with whole human PTH and with Freund adjuvant and were further administrated as intradermal injections targeting cervical, axillary and inguinal lymph nodes. After the fourth immunisation, we observed a decrease and even normalisation of calcium concentrations followed by the same trend in PTH levels. Both calcemia and PTH levels were normalised at the time of the fifth immunisation and remained stable for more than 72 months [94]. Semi-quantitative dot-blot analysis was used to demonstrate the presence of antibodies against all the human and bovine PTH fragments. These were identified as early as three weeks after the first immunisation [94]. Regular surveillance of pulmonary metastases found a progressive decrease from the baseline (before starting immunotherapy) to the time of the eight immunisation of 39.2–71.4% in their size [94]. The patient remains alive and well but has required intermittent but irregular immunisations due to increases in serum calcium, Few other patients with metastatic parathyroid carcinoma were immunised by following the same protocol. A significant reduction in calcium levels was obtained and it lasted for over six months, with no change of PTH levels or metastases volume [95,96]. Almost at the same time, another immunisation method has been attempted. Dendritic cells, pulsed with patient’s tumour extract in vitro have been used in parathyroid carcinoma, as well as in medullary thyroid carcinoma, but with poor clinical results [97,98], possibly related to antigen processing. In our opinion, immunotherapy represents a promising technique. It provides significant clinical benefits in term of survival and quality of live and has fewer side effects when used as adjuvant therapy. Nevertheless, this treatment requires further validation in clinical trials, which are difficult to conceive due to the rarity of the disease. In the past decade, significant advances in the understanding of mechanisms underlying tumour immunology were achieved. Immunotherapy has become an important therapeutic strategy, with advanced phase III clinical studies demonstrating survival advantages in the treatment of melanoma, lung or prostate

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cancer. Various immunotherapy techniques have been developed recently with a wide field of application. These focus on stimulating an immune response against tumour antigen or on reducing immune tolerance to cancer cells by blocking inhibitory immune checkpoint molecules, as in the case of advanced melanoma [99]. 9. Conclusion Parathyroid carcinoma is a rare disease, usually presenting with clinical signs of severe hypercalcemia, but often disguising as apparently benign primary hyperparathyroidism. As for many other cancers, its cause is unknown, although recently mutations in the HRPT2/CDC73 gene were found to play a fundamental role in pathogenesis. Clinical suspicion prior to surgery is crucial, since specific surgical procedure is the only potentially curative therapy. The combination of high levels of serum calcium, tumour size and an inverted (>1) PTH ratio are efficient in orienting towards an oncological surgical approach. In the case of metastatic disease and when surgery is no longer indicated, combined techniques, such as powerful bisphosphonates, new antiresorbtive agents, calcimimetics, radiofrequency ablation and immunotherapy, are useful tools in controlling the complications of severe hypercalcemia. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Hundahl SA, Fleming ID, Fremgen AM, Menck HR. Two hundred eightysix cases of parathyroid carcinoma treated in the US between 1985-1995. Cancer 1999;86:538–44. [2] Obara T, Okamoto T, Kanbe M, Iihara M. Functioning parathyroid carcinoma: clinicopathologic features and rational treatment. Semin Surg Oncol 1997;13(2):134–41. [3] Koea JB, Shaw JH. Parathyroid cancer: biology and management. Surg Oncol 1999;8:155–65. [4] Lee PK, Jarosek SL, Virnig BA, Evasovich M, Tuttle TM. Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer 2007;109:1736–41. [5] De Quervain F. Parastruma maligna aberrata. Langenbecks Arch Surg 1909;100:334–53. [6] Shane E. Parathyroid carcinoma. J Clin Endocrinol Metab 2001;86:485–93. [7] Ruda JM, Hollenbeak CS, Stack BC. A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg 2005;132:359–72. [8] Talat N, Schulte KM. Clinical presentation, staging and long-term evolution of parathyroid cancer. Ann Surg Oncol 2010;17:2156–74. [9] Schulte KM, Talat N, Galata G, Gilbert J, Miell J, Hofbauer LC, et al. Oncologic resection achieving r0 margins improves disease-free survival in parathyroid cancer. Ann Surg Oncol 2014;21:1891–7. [10] Harari A, Waring A, Fernandez-Ranvier G, Hwang J, Suh I, Mitmaker E, et al. Parathyroid carcinoma: a 43-year outcome and survival analysis. J Clin Endocrinol Metab 2011;96:3679–86. [11] Wynne AG, van Heerden J, Carney JA, Fitzpatrick LA. Parathyroid carcinoma: clinical and pathologic features in 43 patients. Medicine (Baltimore) 1992;71:197–205.

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