Parathyroid Cancer

Abstract

Parathyroid cancer is an uncommon malignancy and rare cause of primary hyperparathyroidism with a high morbidity and patient death in advanced cases usually resulting from intractable hypercalcemia. Inactivation of the HRPT2/CDC73 gene, encoding the putative tumor suppressor protein parafibromin and discovered in the context of the hyperparathyroidism-jaw tumor syndrome (HPT-JT), is a common, somatic genetic event in most parathyroid cancers. Some 25% of patients with apparently sporadic parathyroid cancer carry germline HRPT2/CDC73 mutation. Germline DNA analysis for HRPT2/CDC73 mutation is recommended in all patients with parathyroid cancer because of the potential benefit for offspring and other first-degree relatives. The histopathologic diagnosis of parathyroid cancer is non-specific unless vascular, lymphatic, capsular or soft tissue invasion are seen, or metastases are clinically evident. Immunohistochemical analysis of parathyroid tumors for loss of parafibromin expression offers promise as a diagnostic tool. En bloc tumor resection offers the highest chance of cure in patients with suspected parathyroid carcinoma. No adjuvant chemotherapy regimen has yet proven effective, and the role of local adjuvant radiotherapy is being evaluated. Metastatic disease can be palliated with surgical debulking. Medical therapy with the calcimimetic cinacalcet and bisphosphonates can ameliorate hypercalcemia in patients with inoperable disease.

Introduction

Parathyroid carcinoma is a rare malignancy and an uncommon cause of primary hyperparathyroidism (HPT). Although most parathyroid carcinomas secrete parathyroid hormone and cause hypercalcemia, a small fraction are non-functional. The malignant character of these tumors can be difficult to diagnose preoperatively, and is sometimes only recognized months to years later when the disease recurs. Parathyroid carcinoma is associated with higher serum calcium and PTH levels than primary HPT due to benign adenoma, and is more likely to be symptomatic at the time of presentation. Most of the histological features of parathyroid carcinoma are not specific, and the diagnosis may depend on demonstration of either local invasion, or metastases to regional lymph nodes or distant sites. The prevalence of parathyroid carcinoma is higher in kindreds with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Germline mutation of the HRPT2/CDC73 gene can be demonstrated in most patients with HPT-JT as well as in about a quarter of patients with apparently sporadic parathyroid cancer. Somatic loss or mutation of HRPT2/CDC73 is present in the majority of sporadic parathyroid cancers as well.

The best opportunity for cure is complete surgical resection at the initial operation. Although findings of a fibrous capsule and tissue invasion may offer clues to the diagnosis, often the affected gland is grossly indistinguishable from a benign atypical adenoma. Adequate surgical approach is therefore dependent on pre-operative suspicion and the experience of the surgeon. Parathyroid carcinoma usually follows an indolent but progressive course, manifested by local recurrence initially and distant metastases later. Metastatic disease most commonly affects the lung or bone. The major morbidity of parathyroid carcinoma is due to complications of hypercalcemia, such as neuropsychiatric symptoms, cardiac arrhythmias, renal failure and pathologic fractures. Surgical resection of local recurrences and distant metastases is not curative, but may relieve symptoms and reduce serum calcium levels with effects lasting months to years depending on the extent of disease. Chemotherapy and radiation are generally not effective, but newer modalities such as transcatheter arterial embolization and radiofrequency ablation are promising palliative therapies in selected patients. Medical therapy with the calcimimetic cinacalcet and intravenous bisphosphonates are useful adjuncts for control of hypercalcemia.

Epidemiology and Demographics

Parathyroid carcinoma is a rare cause of primary HPT. Early single institution case series suggested that it was responsible for 2–5% of all cases,^1–3 but these figures are likely overestimates resulting from referral and publication biases, and/or the use of variable diagnostic criteria. Data from the largest single-institution study, a comprehensive literature review and recent tumor registries indicate that it accounts for less than 1% of all cases in most of the world.^4–6 The incidence of parathyroid carcinoma was 5.1% of cases of primary HPT in a national survey in Japan in 1981, indicating that there may be significant regional variation.⁷

It is an extraordinarily uncommon malignancy, with an annual incidence of approximately 3.5–5.7 per 10 million population.⁸ It accounted for 0.005% of all malignancies in the National Cancer Database from 1985–1995.⁹ Males account for approximately 50% of all cases.^2,3,8,9 The mean age at diagnosis compiled from published reports is 44–48 years^1–3 with a range of 12–90. Classically the disease is described as occurring about 10 years earlier than benign primary HPT, but this was not confirmed by the findings of the two largest registry studies to date, in which the mean age at diagnosis was between 54 and 56 years.^8,9

Etiology and pathophysiology

The etiology of parathyroid cancer, like that of other malignancies, likely involves the interaction of multiple environmental and genetic factors. Exposure to radiation, especially during childhood, increases the risk of benign parathyroid disease^10–12 as well as concurrent thyroid and parathyroid neoplasia,^13–15 but whether such exposure plays an etiologic factor in parathyroid carcinoma remains unclear. Case reports and retrospective identification of several cases of parathyroid carcinoma in patients exposed to radiation have appeared in the literature in the last three decades but, because of the paucity of cases involved and the variable diagnostic criteria employed, a clear inference of causality is not possible.^3,16–18

Recent understanding of the genetics of parathyroid cancer has resulted mainly from the clinical and molecular genetic characterization of HPT-JT, a rare autosomal dominant familial cancer syndrome in which affected individuals may develop primary HPT due to benign or malignant parathyroid tumors, cemento-ossifying fibrous tumors of the maxilla and/or mandible, and less commonly renal cysts or tumors and/or uterine tumors.^19–22 Parathyroid carcinoma is present in approximately 15% of those with primary HPT due to HPT-JT. The trait has variable and incomplete penetrance since some 10% of gene carriers have no clinical manifestations (Fig. 1).

Figure 1.

The variable penetrance of germline HRPT2/CDC73 mutation results in a spectrum of different clinical phenotypes. Some 25% of patients with apparently sporadic parathyroid cancer have germline mutation of HRPT2/CDC73 (2), while 10% of known or obligate mutation carriers may be asymptomatic (1). Other manifestations of germline HRPT2/CDC73 mutation include familial isolated hyperparathyroidism, with or without individuals in the kindred with parathyroid cancer (3), and the hyperparathyroidism-jaw tumor syndrome with primary hyperparathyroidism due to benign adenomas (85%) or parathyroid cancer (15%), cemento-ossifying tumors of the maxilla or mandible, renal cysts or tumors, and uterine tumors (4).

In a majority of kindreds with classic HPT-JT manifestations an inactivating mutation of the HRPT2/CDC73 gene, located at 1q31, can be demonstrated.²³ The HRPT2/CDC73 gene contains 17 exons that encode the protein parafibromin, a putative tumor suppressor protein consisting of 531 amino acids with weak homology to the yeast transcriptional regulatory protein CDC73p.²⁴ Mutations are scattered throughout the coding region, and most are predicted to cause inactivation or premature truncation of the protein product.²⁵ A subset of kindreds with familial isolated primary HPT (FIHP) also harbor germline HRPT2/CDC73 mutation indicating this condition may be a forme fruste of HPT-JT^26–34 (Fig. 1).

Because of the high incidence of parathyroid carcinoma in HPT-JT and in germline HRPT2/CDC73 mutation-positive FIHP kindreds,^26,31–33 mutation in HRPT2/CDC73 was investigated in sporadic cases of parathyroid cancer. Mutational analyses of tumors from patients with no family history and histologically confirmed parathyroid carcinoma demonstrates HRPT2/CDC73 somatic mutations in 60–100% of cases.^35–37 In many parathyroid cancers analyzed, two distinct HRPT2/CDC73 mutations or a single mutation in combination with 1q31 LOH can be demonstrated, consistent with a tumor suppressor mechanism and providing evidence that HRPT2/CDC73 mutation is an early event in malignant transformation.^35,37 Molecular genetic analysis of parathyroid carcinomas reveals mutations in HRPT2/CDC73 that are also present in the germline DNA in as many as 20–30% of cases, suggesting that a significant percentage of apparently sporadic carcinomas may, like a subset of FIHP, represent incomplete expressions of HPT-JT (Fig. 1).^28,37,38 Because of the potential benefit for offspring and other first-degree relatives, germline DNA analysis for HRPT2/CDC73 mutation is recommended in all patients with parathyroid cancer.^28,37,38

Biallelic mutational inactivation of HRPT2/CDC73 cannot be demonstrated in all parathyroid cancers, even when those tumors lack parafibromin expression, making epigenetic gene silencing by promoter hypermethylation or histone acetylation a potentially relevant mechanism: hypermethylation is not frequently observed however.^39,40 Recent studies suggest that dysregulation of several microRNAs may contribute to the pathogenesis of parathyroid cancers harboring HRPT2/CDC73 mutation.⁴¹

Mutational inactivation of HRPT2/CDC73 appears to be a specific marker of parathyroid malignancy. Although reported, HRPT2/CDC73 mutation or 1q31 LOH in parathyroid adenomas is quite uncommon.^23,35,42 Gene profiling studies⁴³ and analysis of chromosomal imbalances in parathyroid tumors⁴⁴ also suggest that the molecular changes leading to malignancy are distinct from those leading to benign parathyroid neoplasia.

Parafibromin, the product of the HRPT2/CDC73 gene, is a ubiquitously expressed protein whose function as a tumor suppressor is not well understood. It is the human homolog of the yeast Cdc73 protein which is a component of a transcriptional-regulatory Paf1 complex.²⁴ Mammalian parafibromin is part of a homologous PAF1 complex and appears to have roles in RNA polymerase II-mediated gene transcription and histone methylation in the promoter and coding regions of specific genes.⁴⁵ A posttranscriptional role for parafibromin in the maturation and processing of mRNA 3’-ends has also been proposed.^46,47 A role for parafibromin in the repression of cyclin D1 expression has been explored^48–50, but studies of parathyroid tumors found no correlation between HRPT2/CDC73 mutation or loss of parafibromin expression with cyclin D1 upregulation.^51,52

Parathyroid carcinoma has been only rarely linked to the genes implicated in the familial HPT syndromes, apart from those syndromes associated with HRPT2/CDC73 mutation. Several cases of parathyroid carcinoma have been reported in multiple endocrine neoplasia type 1 (MEN1) patients both with^53,54 and without^55,56 documented germline MEN1 mutation. In addition somatic MEN1 mutation has been reported in a small subset of parathyroid carcinomas.³⁸ Metastatic parathyroid carcinoma has been reported in a patient with multiple endocrine neoplasia type 2A (MEN2A) and a germline RET mutation.⁵⁷

Alterations of other genes besides HRPT2/CDC73 have been studied for possible roles in the malignant transformation of parathyroid tissue. Loss of function of the retinoblastoma (RB1) tumor suppressor has been considered in the etiology of parathyroid cancer since a study that found LOH at the RB1 locus on chromosome 13q and/or abnormal RB1 expression in a majority of parathyroid cancers.⁵⁸ In a follow-up study however, direct RB1 gene sequencing in parathyroid carcinomas failed to identify any somatic mutations suggesting RB1 loss was not a frequent event in the progression to parathyroid cancer.⁵⁹ In other studies RB1 protein expression alone was not found to help distinguish benign from malignant parathyroid tumors,⁶⁰ although it may be useful in conjunction with other markers.^61,62 Somatic mutations in the exons representing the conserved regions of the P53 tumor suppressor gene were not found in parathyroid carcinomas,^63,64 even though allelic loss at the P53 locus and/or abnormal P53 protein expression were found in a minority of parathyroid cancers.⁶⁴

The loss or gain of specific regions of chromosomal DNA detected by techniques such as comparative genomic hybridization (CGH) suggests the existence of currently unidentified parathyroid tumor suppressors and oncogenes relevant to parathyroid cancer. Investigators have found loss of DNA on chromosomes 1p, 9p, 13q and/or 17 in malignant parathyroid tumors indicating the potential presence of novel parathyroid tumor suppressor genes at these loci.^44,65 The presence of currently unknown oncogenes on chromosome 5 or at loci 1q, 19p, and Xq is suggested by the demonstration of specific chromosomal gain in parathyroid cancer.^44,65

There have been several case reports of parathyroid carcinoma developing in the context of secondary or tertiary HPT due to chronic kidney disease (CKD) or other conditions. Several cases of parathyroid carcinoma in the context of CKD have had distant metastases documented by surgical pathologic analysis.^66–68 Interestingly, the expression of HRPT2/CDC73 was preserved in the majority of primary and metastatic tumors from 5 patients with CKD-associated parathyroid carcinoma, suggesting a pathway to malignancy in this setting that does not involve biallelic HRPT2/CDC73 inactivation ⁶⁹.

Clinical presentation of parathyroid cancer

The clinical presentation of parathyroid carcinoma is usually related to symptoms caused by the effects of markedly elevated serum PTH and hypercalcemia, rather than mass effects due to local infiltration or distant metastases. Systemic symptoms of hypercalcemia include fatigue, weakness, weight loss, anorexia, nausea, vomiting, polyuria, polydipsia and depression. Manifestations of hyperparathyroid bone disease include osteitis fibrosa cystica, subperiostial bone resorption, “salt and pepper” skull, absence of the lamina dura, diffuse osteopenia, osteoporosis, bone pain, or pathological fractures,⁷⁰ and is present in in 22–91% of patients with parathyroid carcinoma at the time of diagnosis.^{1–4,6,71,72} Formerly a common manifestation of all types of primary HPT, bone involvement is now rare in benign disease, which is more commonly asymptomatic at presentation, and detected incidentally from routine laboratory studies.⁷³ Renal complications such as nephrolithiasis, nephrocalcinosis, reduced glomerular filtration rate, or renal colic are diagnosed in 32–60% of parathyroid carcinoma patients.^{1–4,6,71,72} Renal involvement alone is not specific for malignancy. Concomitant bone and kidney disease is seen in 40-50% of patients at presentation,^2,4,6 and is very unusual in benign primary HPT.⁷⁰ Other associated clinical signs of HPT may also be seen in malignant disease, including anemia and peptic ulcer disease.^70,74 Pancreatitis is reported in 4–6%.^2,3,6,71 Carcinoma must be considered in the differential diagnosis of any patient presenting with acute primary HPT or parathyroid crisis.⁷⁰ Almost unheard of prior to the advent of the multichannel chemistry autoanalyzer in 1974, asymptomatic disease at presentation has been reported in about 2% of patients with parathyroid cancer in the larger subsequent literature reviews,^2,3,6 and may actually be increasing in frequency. Two more recent single-institution series reported asymptomatic presentation of parathyroid cancer in 7 and 30% of their patients.^4,71 Few signs on physical examination are specific to differentiate parathyroid carcinoma from benign adenoma or multigland disease. A palpable neck mass, which is reported in 15–50% of patients with parathyroid carcinoma is extremely rare in benign conditions.^{1–3,6,71,72} Hoarseness can be a sign of recurrent laryngeal nerve palsy due to local invasion. It is very uncommon in benign primary HPT, and highly suggestive of malignancy.⁷⁰

Laboratory testing and imaging in parathyroid cancer

No single laboratory finding is diagnostic of parathyroid carcinoma, but certain findings may offer clues that it ought to be included in the differential diagnosis of a patient presenting with primary HPT. The mean serum calcium in parathyroid cancer patients reported in the last three decades is 14.6–15.0 mg/dL^3,4,72 and about 60–65% of patients present with a calcium level greater than 14 mg/dL.^3,4,72 A subset of functional parathyroid cancers demonstrate normal serum calcium despite elevations of PTH at the time of diagnosis.⁷⁵ Intact PTH levels in parathyroid cancer are on average 5–10 times the upper limit of the normal range,^2–4,72,76 but no threshold level for malignancy has been defined. Alkaline phosphatase is usually elevated, and serum phosphorus is often low normal, but can be below the normal reference range. Severe primary HPT associated with benign disease is uncommon, but it can be difficult to distinguish on clinical grounds from parathyroid carcinoma.

Identification of new laboratory markers that may help differentiate malignant from benign primary HPT is an ongoing area of research. Elevated plasma human chorionic gonadotropin (HCG) has been documented in parathyroid carcinoma,⁷⁷ but also can be seen in benign primary HPT. Urinary HCG, specifically the hyperglycosylated HCG fraction, is elevated in some patients with parathyroid carcinoma, but normal in benign disease.⁷⁸ The recently identified N-terminal PTH immunoreactive species, less hydrophobic than intact PTH 1-84 on reverse-phase liquid chromatography, is overproduced in some parathyroid cancers.⁷⁹

Preoperative imaging is frequently helpful for tumor localization but in the evaluation of primary parathyroid tumors cannot reliably distinguish benign from malignant disease. Ultrasonographic features of parathyroid tumors including inhomogeneity, hypoechogenicity, and irregularity of borders have been reported to correlate with malignancy (Fig. 2),⁸⁰ but such characteristics are not always present in parathyroid cancers.⁸¹ Fine needle aspiration of cervical masses should be avoided in patients with suspected parathyroid cancer because of the documented risk of cutaneous or subcutaneous seeding along the needle track.^82,83

Figure 2.

Neck ultrasound in a patient with recurrent parathyroid carcinoma. The lesion shows typical features associated with parathyroid carcinoma (inhomogeneity, hypoechogenicity, and irregularity of borders).

Surgical findings

The diagnosis of parathyroid carcinoma is often suspected due to characteristic findings at the time of initial surgery. The tumor usually has a firm or hard consistency, is sometimes lobulated, and is usually surrounded by a dense fibrous capsule that gives it a white, grey-white or grey-brown hue. Parathyroid carcinoma often adheres to and infiltrates adjacent structures.^1,84,85 The most common sites of local invasion are the ipsilateral thyroid gland, strap muscles, ipsilateral recurrent laryngeal nerve, esophagus and trachea.⁶ Lymph node metastases is present at the initial operation in 3–19%,^3,6,8,9,72 and distant metastases are present in 3–4%.^6,8,71

Frozen section is not helpful to distinguish benign from malignant disease, and excisional biopsy is not recommended due to the risk of intraoperative seeding of tissue leading to parathyromatosis.³ In some cases, carcinoma may be difficult to differentiate from adenoma,⁸⁶ which is usually of soft consistency, round or oval and reddish brown in color.⁷⁰ Surgeons do not recognize the presence of cancer in some 25% of cases.⁸⁴ Although exceedingly rare, carcinoma of multiple glands has been documented in 3 cases in the literature, emphasizing the importance of four-gland exploration at the initial operation to avoid a reoperation for missed disease.^87–89

Diagnosis

In the absence of obvious metastatic disease the distinction between parathyroid carcinoma and adenoma is difficult utilizing microscopic histopathologic criteria. The principal histologic features that distinguish parathyroid carcinoma from adenoma, identified by Schantz and Castleman based on their examination of 70 parathyroid cancers, were the presence of parenchymal mitoses, trabeculated parenchyma including often thick fibrous bands, and capsular or vascular invasion.⁹⁰ Because any of these individual features can also be found in atypical parathyroid adenomas, capsular or lymphovascular invasion remains the most specific histopathologic feature of primary parathyroid cancer (Fig. 3).

Figure 3.

Hematoxylin and eosin histologic section of parathyroid carcinoma invading adjacent soft tissue and muscle (4X magnification).

Because of the difficulty of distinguishing benign from malignant parathyroid tumor based on morphological criteria alone, considerable effort has been directed at identifying immunohistochemical tumor markers useful to this end. Given the strong evidence linking HRPT2/CDC73 inactivation with parathyroid malignancy, the most promising marker to date has been parafibromin, either used alone or in conjunction with other markers. The original report found that loss of nuclear expression of parafibromin could identify definite parathyroid malignancies with 96% sensitivity and 99% specificity and noted that absent nuclear staining also characterized HPT-JT associated adenomas.⁹¹ Subsequent investigators have also found loss of parafibromin expression to be a highly useful marker of parathyroid malignancy, although with generally lower specificity and sensitivity.^52,92,93 Clark and co-workers found that the combination of markers that includes loss of parafibromin and RB1 expression and overexpression of galectin-3 was most specific for parathyroid cancers.⁶² Strong staining for protein gene product 9.5 was found to be at least as sensitive and specific for parathyroid malignancy as complete loss of parafibromin nuclear expression and was additionally positive in an HPT-JT-associated parathyroid tumor expressing a missense mutant of parafibromin.⁹⁴

The cell proliferative marker Ki-67 (target of the MIB-1 monoclonal antibody), often in conjunction with other antigens, has proven useful in some laboratories to identify a subset of parathyroid cancers. Several investigators noted a uniquely high proliferative rate and Ki-67 labeling index in parathyroid malignancies and proposed a cutoff point that helps to distinguish parathyroid cancers,^61,95 although others challenge the diagnostic utility of the Ki-67 labeling index as a sole criterion because of significant overlap with adenomas.⁶⁰ The combination of other markers with the Ki-67 labeling index, including underexpression of p27Kip1⁹⁶ or CaSR,⁹⁷ or galectin-3 overexpression⁹⁸ may improve its predictive value. The Ki-67 index may also be useful as a prognostic factor for parathyroid cancer recurrence.⁹⁹

Recently loss of the Wnt pathway components adenomatous polyposis coli (APC) and glycogen synthase kinase 3-β were found to be specific markers of parathyroid malignancy, with lost APC immunoreactivity reported to be 100% specific and 75% sensitive for the detection of parathyroid cancer.¹⁰⁰

Non-functional parathyroid carcinoma

Non-functional parathyroid carcinoma is extremely rare. Fewer than 20 cases have been reported in the literature since 1929,¹⁰¹ including a case in the context of FIHP with germline mutation of HRPT2/CDC73.³¹ Patients are normocalcemic at diagnosis and, in all those in whom it was measured, PTH is within the normal range. About 80% present with a neck mass, and other common findings at presentation include dysphagia, hoarseness or vocal cord paralysis, and dyspnea.^101,102 Grossly, tumors are usually described as similar in appearance to functional parathyroid carcinoma, and they also appear similar histologically.¹⁰² Tumor immunohistochemistry demonstrating the presence of PTH, and absence of thyroglobulin, thyroid transcription factor 1 and calcitonin may help ascertain the diagnosis.^74,103,104

Treatment of parathyroid cancer: surgical

Most authors recommend en bloc resection at the initial surgery to offer the best chance for cure. This approach requires recognition of the possibility of malignancy during exploration. Adequate surgical excision requires removal of the ipsilateral thyroid lobe and isthmus, skeletonization of the trachea, and excision of any skeletal muscle intimately related to the tumor. The surgeon must be careful not to rupture the capsule of the tumor to avoid seeding of the surgical field.¹ If the recurrent laryngeal nerve is involved and not functioning, it should be resected. Central neck and ipsilateral modified functional radical neck resection are usually performed only if enlarged or abnormal appearing lymph nodes are found to be involved on frozen section analysis.^3,84

Because of the rarity of the disease and the infrequency of pre-operative diagnosis, no prospective data exists regarding the initial surgical approach. Although en bloc resection is recommended, in practice it is the first surgical procedure performed in only about 12% of cases.⁸ While some retrospective case series and reviews support the contention that en bloc surgical resection at the initial operation decreases recurrence,^{3,4,6,7,76,105} this finding has not been corroborated by others.^8,71 Up to 86% of patients may have inadequate surgical resection at the initial operation.⁹

With persistent and recurrent disease, it is important to exclude metastases to the lung or bone before proceeding to repeat neck exploration. Prior to neck exploration, at least two non-invasive localizing studies should be performed. If non-invasive studies are negative or equivocal, selective venous catheterization with PTH sampling should be pursued to confirm the finding of a non-invasive study.⁸⁴ Patients should also have a direct laryngoscopy to evaluate their vocal cord function before reoperation for persistent and recurrent disease.

Following preoperative localization, treatment of locally recurrent disease, although not expected to be curative, is successful in improving symptoms and lowering serum calcium levels in 68–86%.^4,76,99 Subsequent re-operations generally have lower success rates, but may result in successful palliation of selected patients. Because of the rarity of the disease and its indolent nature, survival benefit has not been definitively demonstrated with re-operation. Complications of both initial and repeat neck operations include recurrent laryngeal nerve injury, transient and permanent hypoparathyroidism, esophageal or tracheal injury and neck hematoma.⁸⁴

Multiple authors have reported palliative effects of resection of distant metastases, particularly in the lung^1,106 and bone.¹⁰⁷ If metastatic disease is localized, resection reduces tumor burden, improves symptoms and may lower or even normalize serum calcium and PTH.^108,109 With widely metastatic parathyroid carcinoma, reoperation is not likely to improve symptoms or reduce the serum calcium.⁸⁴

Treatment of parathyroid cancer: radiotherapy

Parathyroid carcinoma is generally not believed to be radiosensitive, and radiation treatment as primary therapy has not been demonstrated to have a significant effect in either the neck or at sites of distant metastases. Several case reports, however, have suggested that adjuvant radiation treatment after surgical treatment may reduce the chance of local recurrence.^4,71 It is difficult to know, however, the efficacy of adjuvant radiotherapy as some patients with parathyroid cancer may have long disease-free intervals after parathyroidectomy alone.

Treatment of parathyroid cancer: other modalities

Unresectable disease due to diffuse metastases in the lung has been treated with multiple sessions of radiofrequency ablation (RFA) in a patient with parathyroid carcinoma.¹¹⁰ A combination of RFA and transcatheter arterial embolization has been used similarly to treat multiple metastatic lesions in the liver in a single patient.¹¹¹ Improvement in both serum calcium and PTH levels were demonstrated following treatment in both reports. Recurrent disease in the neck has been treated with ultrasound-guided percutaneous alcohol injection and short-term improvements in calcium and PTH levels were achieved.¹¹²

In general, chemotherapy has not been demonstrated to be beneficial in parathyroid carcinoma. Short-term responses have been demonstrated with single-agent dacarbazine¹¹³ and combination chemotherapy regimens of fluorouracil, cyclophosphamide, and dacarbazine¹¹⁴ in patients with metastatic disease, but a survival benefit was not demonstrated.

Because the major morbidity and ultimate cause of death in most patients with parathyroid carcinoma is severe hypercalcemia, medical management has focused on controlling calcium levels in patients with persistent disease. Acute hypercalcemia is treated with standard therapies such as intravenous hydration, furosemide, calcitonin, glucocorticoids, mithramycin, and hemodialysis, but these treatments are ineffective for long-term management, with effects lasting days to several months at best. Short-term decreases in serum calcium have been demonstrated with the intravenous bisphosphonates pamidronate¹¹⁵ and zoledronate.¹¹⁶ Initial treatment appears to be clinically significant in some patients, but the effect generally diminishes with subsequent infusions. Oral bisphosphonates have not been reported to be effective in the management of hypercalcemia related to parathyroid carcinoma.

Calcimimetics have emerged as a more effective solution to mitigate the hypercalcemia of parathyroid cancer. After promising results with a first-generation calcimimetic,¹¹⁷ a second-generation calcimimetic, cinacalcet, was shown to decrease serum calcium by 1 mg/dL in 62% of patients enrolled in an open-label, single-arm trial. Patients tolerated total daily doses up to 360 mg. In responders, the magnitude of decrease in calcium levels was greatest in those with the highest baseline calcium levels. Interestingly, decreases in serum calcium were achieved despite no significant decrease in serum PTH.¹¹⁸

Immunization with synthetic human and bovine PTH peptides resulted in production of anti-PTH antibodies and decrease in the serum calcium of more than 1 mmol/L in a patient with parathyroid cancer and unresectable metastases.¹¹⁹ Tumor shrinkage, in addition to an improvement in serum calcium and PTH, has been demonstrated in another patient.¹²⁰

It is likely that denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor kappa-b ligand with potent anti-resorptive actions in bone, will be tested for efficacy in controlling the hypercalcemia of parathyroid cancer.¹²¹

Natural history of parathyroid cancer

Following initial surgery, anywhere from 25–80% of patients with parathyroid cancer develop local recurrence. Recurrence is detected on average 2–4 years after the initial operation, and these patients have a median survival on the order of 5–6 years after the initial diagnosis.^{2–4,6,71,76,122} Approximately 25% of patients develop distant metastases at some point during the disease. Rarely, they are present at the time of diagnosis. At the other extreme, metastases have been documented as long as 20 years after the original diagnosis following a period of quiescence.¹²³ Five year survival rates from case series and registry data of the last 20 years are fairly consistent at 76–85%, and 10 year survival rates range anywhere from 49–77%.^8,9,71,76 The most compelling data regarding treatment comes from reports of complete surgical (en bloc) resection at the initial operation. Anywhere from 28–50% of these patients remain alive with no recurrent disease at follow-up.^3,4,6,105 Although modalities such as surgery, adjuvant radiation, RFA, and calcimimetics have demonstrated responses in clinical parameters, insufficient information is available to determine the effects of these therapies on survival. The prognosis appears to be worse in patients with non-functional parathyroid carcinoma since local invasion and distant metastases appear to be more likely at the time of diagnosis.^101,102

Conclusions

Parathyroid carcinoma is a rare endocrine malignancy whose recognition requires a high index of suspicion based on clinical features, such as a palpable neck mass and severe primary HPT. Histologic features can be non-specific. Diagnosis is definitive when local invasion, lymph node or distant metastases are demonstrated. Somatic mutation of HRPT2/CDC73 is a common finding in sporadic parathyroid carcinomas, and because some 25% of apparently sporadic cases harbor germline HRPT2/CDC73 mutation, DNA analysis should be offered to all patients. Pre-operative suspicion is crucial since parathyroid carcinoma may be difficult to distinguish from benign adenoma intraoperatively and en bloc resection is potentially curative. Adjuvant radiation therapy following surgical resection is an area of ongoing investigation. Local recurrence is common with possible late occurrence of distant metastases, especially to lung and bone. Surgical resection, arterial embolization, or radiofrequency ablation of persistent or recurrent disease is rarely curative, but may reduce serum calcium. Cinacalcet and intravenous bisphosphonates are the most effective medical treatments currently available for the hypercalcemia of recurrent or persistent parathyroid cancer.