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Parathyroid carcinoma

Parathyroid carcinoma
Authors:
Ghada El-Hajj Fuleihan, MD, MPH
Andrew Arnold, MD
Section Editor:
Marc K Drezner, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jun 2022. | This topic last updated: Oct 11, 2021.

INTRODUCTION — Parathyroid carcinoma is a rare cause of primary hyperparathyroidism, which is usually caused by a parathyroid adenoma and occasionally by primary parathyroid hyperplasia. Other rare causes are parathyroid cyst and ectopic secretion of parathyroid hormone (PTH) from a nonparathyroid tumor. Compared with patients with parathyroid adenomas, patients with parathyroid carcinomas are more likely to have symptoms, a neck mass, bone and kidney disease, marked hypercalcemia, and very high serum parathyroid hormone concentrations. This topic will provide an overview of parathyroid carcinoma. Other aspects of primary hyperparathyroidism are discussed elsewhere.

(See "Primary hyperparathyroidism: Clinical manifestations".)

(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

(See "Primary hyperparathyroidism: Management".)

(See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

(See "Parathyroid cysts".)

(See "Parathyroid exploration for primary hyperparathyroidism".)

(See "Pathogenesis and etiology of primary hyperparathyroidism".)

INCIDENCE — Parathyroid carcinoma is a rare cause of hyperparathyroidism [1]. In a systematic review of 22,225 cases of primary hyperparathyroidism reported between 1995 and 2003, parathyroid carcinoma accounted for 0.74 percent of the cases [2]. In a retrospective study of two European cohorts of patients with primary hyperparathyroidism, the frequency of parathyroid carcinoma ranged from 0.3 to 2.1 percent [3].

From 1988 to 2003, 224 patients with parathyroid carcinoma were identified by the Surveillance, Epidemiology, and End Results (SEER) cancer registry data [4]. During this time period, the incidence of parathyroid carcinoma increased from 3.58 to 5.73 per 10 million population. The increase was accompanied by a significant decrease in the proportion of patients with large (≥4 cm) tumors and increase in proportion with negative lymph nodes, suggesting that earlier diagnosis may account for the increased incidence. From 2000 to 2012, the incidence rate for parathyroid carcinoma (SEER database) was 0.36, and there was a decrease in the incidence rate between 2000 to 2002 and 2010 to 2012 [5]. In a nation-wide cohort study from Korea (2002 to 2017), there was an increase in age-adjusted incidence rates, from 3.8 to 6.6 per 10 million person-years [6], mirroring earlier increments noted in Western populations.

The occurrence of parathyroid carcinoma in patients with multiple endocrine neoplasia type 1 (MEN1) is very rare; only one case was reported in a series of 348 cases of MEN1 (0.28 percent) from the Mayo Clinic from 1977 to 2013 [7]. Similarly, in a retrospective review of 291 cases of MEN1 at MD Anderson, 242 patients had hyperparathyroidism, and of those, two (0.8 percent) had parathyroid carcinoma [8]. Another retrospective study at a teaching hospital in Peking from 1999 to 2019 identified 153 cases of MEN1-associated primary hyperparathyroidism, of which only one (0.7 percent) was a parathyroid carcinoma [9]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

MOLECULAR PATHOGENESIS

HRPT2/CDC73 — Mutation of the HRPT2 (also called CDC73) tumor suppressor gene has been recognized to play a central role in the molecular pathogenesis of parathyroid carcinoma. HRPT2 is located on chromosome 1 and encodes parafibromin, a protein whose function remains under investigation but appears to involve regulation of gene expression and inhibition of cell proliferation. Studies have confirmed the presence of HRPT2 mutations in both the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and sporadic parathyroid carcinoma, as well as their rare presence in isolated familial hyperparathyroidism [10,11].

HPT-JT – Inactivating germline mutations in the HRPT2 gene are responsible for an autosomal dominant type of familial hyperparathyroidism, HPT-JT [12]. Patients with HPT-JT are predisposed to ossifying fibromas of the jaw, cystic and neoplastic renal lesions, uterine tumors, and parathyroid neoplasia with an increased risk of parathyroid cancer. Parathyroid carcinoma was reported to occur in approximately 15 percent of patients with HPT-JT [13]. In HPT-JT, all parathyroid glands are at risk for tumor development, but the tumors can occur asynchronously over many years.

Sporadic parathyroid carcinoma – Sporadic (nonfamilial) parathyroid carcinomas frequently bear HRPT2 mutations [11,14,15]. One of two original studies reported HRPT2 mutations in 10 of 15 sporadic parathyroid cancers [14], and the other identified such mutations in four of four carcinomas [15]. Most mutations were somatic and clonal [14], implying a selective advantage (attesting to their pathogenetic importance).

Unsuspected germline mutations were also discovered in a substantial minority of patients who presented clinically with sporadic parathyroid carcinoma, suggesting that some of these individuals may have HPT-JT or a phenotypic variant [14]. This recognition that family members of some patients with apparently sporadic parathyroid cancer are also at risk for this malignancy created a new indication for genetic testing. (See 'Genetic testing' below.)

Although a wide range of mutation frequencies (13 to 100 percent) have been reported across studies, likely related to sample size issues and/or inconsistencies in inclusion criteria, HRPT2 mutations have generally been detectable in a majority of clearly malignant sporadic parathyroid carcinomas [16]. Conversely, intragenic inactivating mutations of HRPT2 in otherwise unselected, typical sporadic parathyroid adenomas are extremely rare [17]. Somatic HRPT2 intragenic mutations tend to be found only rarely in non-HPT-JT-related atypical parathyroid neoplasms that lack the classical invasive or metastatic features of carcinomas [18], but higher frequencies have also been reported [19]. The clinical utility of immunohistochemical detection of the parafibromin protein in distinguishing parathyroid carcinoma from atypical parathyroid adenomas is uncertain [20-22].

Other genes — Application of whole exome sequencing and other next-generation sequencing (NGS) methods have importantly expanded the landscape of genomic alterations in parathyroid carcinoma [23-28].

Germline variants – Certain germline missense variants of the parathyroid transcription factor gene GCM2 have been proposed to cause familial isolated hyperparathyroidism (FIHP) and have also been associated with sporadic primary hyperparathyroidism [29]. The penetrance and clinical significance of detecting these variants (in FIHP kindreds or in the general population) require further study, especially because some variants have relatively high population allele frequencies compared with CDC73 or MEN1 mutations [29,30]. However, as these variants may contribute to an increased risk of accentuated or aggressive primary hyperparathyroidism phenotypes, including multigland disease or even parathyroid carcinoma [31,32], it seems prudent to bear this potential risk in mind for known GCM2 variant-carriers while further investigation proceeds and more definitive information is acquired.

Somatic mutations – Recurrent somatic driver mutations were found in several established cancer genes not previously implicated in this disease; notably, these include PI3K/AKT/MTOR pathway alterations in more than 20 percent of cases [23,24,28] and cyclin D1 amplification in almost 30 percent, the latter reinforced by candidate gene analysis [33].

These discoveries may prove to be important clinically in that some metastatic/surgically incurable parathyroid cancers can carry tumor-specific mutations against which new targeted therapeutic agents may already exist. For example, the presence of a PIK3CA or MTOR mutation, or of CCND1 amplification, raises the possibility that treatment with new drugs, initially designed to target such mutations in other tumor types, could be effective in these selected parathyroid carcinomas [23]. In some cases, a high tumor mutation burden could suggest a vulnerability to immune checkpoint inhibitors [27]. (See 'Novel precision/molecularly targeted cancer therapy' below.)

A major caveat in interpreting some of the NGS studies is that diagnostic inclusion criteria for carcinoma were not always clear or consistent, and some differed from other studies in not requiring local invasion or metastases. Other concerns requiring cautious interpretation in specific instances include use of formalin-fixed paraffin-embedded (FFPE) material known to cause sequence artifacts; lack of matched normal control samples, potentially obfuscating somatic versus rare germline mutations; and technical issues of data acquisition, variant calling, and annotation. Ultimately, clinical trials will be needed to validate the actionability of reported molecular targets in parathyroid carcinoma [34].

CLINICAL PRESENTATION — The major clinical manifestations of parathyroid carcinoma can be summarized from several small studies [21,35-39]:

Mean age – 44 to 54 years (equivalent incidence in males and females)

Mean serum calcium concentration – 14.6 to 15.9 mg/dL (3.7 to 4.0 mmol/L)

Serum calcium concentration above 14 mg/dL (3.5 mmol/L) – 65 to 75 percent

Mean serum parathyroid hormone (PTH) concentrations 5- to 10-fold higher than the upper limit of normal

Parathyroid crisis – 12 percent

Neck mass – 34 to 52 percent

Bone disease – 34 to 73 percent

Renal disease – 32 to 70 percent

Pancreatitis – 0 to 15 percent

No symptoms – 2 to 7 percent

Predilection for a single inferior gland has been noted in case series [40,41]. Multiglandular parathyroid carcinoma is extremely rare [42].

Up to one-third of subjects have lymph node metastases at initial presentation, and one-third have distant metastases, usually to liver and bone [41].

Comparison with clinical manifestations of benign parathyroid disease – Although there is overlap in the clinical and biochemical presentation of benign parathyroid disease and parathyroid carcinoma, there are some features that increase the likelihood of parathyroid cancer [43]. Whereas benign hyperparathyroidism is more common in females (3:1), the incidence of parathyroid cancer is equal between the two sexes. Compared with patients with parathyroid adenomas, patients with parathyroid carcinomas are more likely to have symptoms, larger tumor size, bone and kidney disease, marked hypercalcemia, and very high serum PTH concentrations (5- to 10-fold higher than the upper limit of normal) [21,35-38].

A retrospective study of 311 cases of primary hyperparathyroidism, of which nine were parathyroid carcinomas, demonstrated that PTH levels less than four times the upper limit of normal and a tumor weight <1.9 g made the likelihood of parathyroid carcinoma essentially zero [44]. (See "Primary hyperparathyroidism: Clinical manifestations".)

Atypical presentations – Although most patients with parathyroid carcinoma have hypercalcemia, some patients remain normocalcemic; these patients often present with a neck mass. Nonfunctioning parathyroid carcinomas are rare, with 32 cases reported [45,46]. In a review of 17 such cases, patients were reported to be diagnosed at a more advanced stage of disease, and their tumors may be more aggressive [47]. Frequent locations for metastases include the lungs, cervical lymph nodes, liver, and bone [48]. In contrast to patients with functional parathyroid cancers, patients with nonfunctional tumors die from mass effect and tumor burden rather than from hypercalcemia [49].

DIAGNOSIS — Parathyroid carcinoma should be suspected in a patient with primary hyperparathyroidism who presents with parathyroid crisis (or marked hypercalcemia and very high parathyroid hormone [PTH] concentrations) or a neck mass. The diagnosis of parathyroid carcinoma is typically made at the time of surgery to correct severe hyperparathyroidism.

Although the classic pathologic features of a trabecular pattern, mitotic figures, thick fibrous bands, and capsular and vascular invasion, when present, are highly suggestive of parathyroid carcinoma [50,51], the two criteria upon which a more definitive diagnosis of parathyroid cancer can be made are:

Local invasion of contiguous structures

or

Lymph node or distant metastases

Gross invasion beyond the capsule and including extracapsular vascular invasion appear to correlate best with cancer diagnosis [21]. The use of an immunohistochemical panel that includes parafibromin, galactin-3, PGP9.5, and Ki67 has been suggested from a small series to aid in diagnosis of parathyroid carcinoma, with a sensitivity of 80 percent and specificity of 100 percent [22].

Although preoperative localization studies help plan the operative approach in patients who have a biochemically confirmed diagnosis of hyperparathyroidism, they do not reliably distinguish parathyroid carcinoma from adenoma. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism", section on 'Imaging modalities'.)

In some cases, it may not be possible to differentiate parathyroid adenoma or carcinoma at the time of initial surgery. There may be pathological features suggestive of, but insufficient for, diagnosing carcinoma. These tumors are called atypical parathyroid adenomas [52]. Local recurrence or the occurrence of distant metastases at subsequent follow-up ultimately determines the correct diagnosis.

GENETIC TESTING — A subset of patients with sporadic parathyroid cancer has clinically unsuspected germline HRPT2/CDC73 mutations [14], and such mutations carry important implications for management of the patient and/or for early detection or prevention of parathyroid malignancy in family members [14]. The following are general principles and management guidelines only and are not intended to supplant the need for endocrine and medical genetic evaluation of specific individuals and their families who are ascertained in this way. Genetic counseling is strongly recommended.

Indications — Genetic testing for germline HRPT2 mutation is clinically appropriate in most patients with sporadic parathyroid carcinoma, particularly if there are family members who could benefit from the genetic diagnosis. Genetic HRPT2 testing is also indicated when parathyroid carcinoma occurs in a setting of known familial hyperparathyroidism [10], or when features suggestive of hyperparathyroidism-jaw tumor syndrome (HPT-JT) are present in the index patient.

It is not known whether germline HRPT2 testing may be indicated in patients with sporadic "atypical" parathyroid adenomas, which exhibit clinical or pathological features suggestive of, but insufficient for, diagnosing carcinoma. Such an indication has been suggested [18] and deserves further study. There is no role for HRPT2 germline testing in patients with typical sporadic parathyroid adenomas.

Genetic diagnosis of a germline HRPT2 inactivating mutation in a patient with sporadic parathyroid carcinoma indicates that such a patient may have classic HPT-JT, expressing its initial manifestation, or phenotypic variants, such as familial isolated hyperparathyroidism, or a form of HPT-JT with altered penetrance of the component features. Pending additional data on variant syndromes ascertained in this fashion, one must conservatively assume they carry a similarly amplified risk of parathyroid cancer (15 percent), as is found in classic HPT-JT.

HRPT2 mutation present

Index patient – For the proband (index patient) with apparently sporadic parathyroid cancer, management of the existing malignancy would typically not be altered by genetic diagnosis of HRPT2 mutation. However, this genetic diagnosis would mean that all parathyroid glands remain at increased risk for developing entirely new tumors, themselves potentially malignant. Thus, in several situations, such as recurrent hyperparathyroidism after seemingly successful surgery or worsened hypercalcemia in the face of apparently stable metastatic tumor burden, knowledge of an HPRT2 mutation would caution against the assumption that the original tumor is entirely responsible and could focus surgical attention on previously normal parathyroids in the neck or mediastinum.

Family members – If the index patient proves to have a detectable pathogenic germline mutation, then relatives at risk can be definitively tested (also less expensively) for the presence or absence of that specific mutation. One major benefit of testing is the reassurance provided to relatives who prove to have not inherited the mutation, diminishing anxiety as well as ongoing costs of disease surveillance.

For relatives who did inherit the mutation, their heightened risk of parathyroid malignancy mandates careful clinical attention, beginning with immediate biochemical testing for primary hyperparathyroidism followed by surgery for those whose biochemical screen is suggestive or diagnostic of primary hyperparathyroidism. (See 'Resectable disease' below.)

For individuals who carry the HRPT2 mutation but have no evidence of hyperparathyroidism, a program of prospective surveillance is recommended. The optimal way to conduct such surveillance remains uncertain and will be informed by ongoing clinical experience, emerging data on disease penetrance, and available therapies. For now, we think a reasonable approach would be measurement of serum calcium and parathyroid hormone (PTH) every six months, maintaining a high level of suspicion in interpreting results and a low threshold for proceeding to parathyroid surgery. The sensitivity of such screening may be enhanced by use of ionized calcium measurements, while specificity may be enhanced by maintenance of adequate vitamin D status.

HRPT2 mutation absent or unknown — This is a less helpful and less definitive result than a positive test would be because even among families with classic HPT-JT, up to 40 percent have no detectable mutation [10,12]. Such families may still have occult HRPT2 mutations that evade detection because only the coding region of the gene is generally sequenced, and inactivating mutations would be expected to occur in noncoding regions in some families.

Therefore, a negative test does not provide strong reassurance that the index patient with sporadic parathyroid carcinoma is HRPT2 mutation free. Under these circumstances, the likelihood of a familial syndrome might gain clinical support by jaw, kidney, and uterine imaging. Overall, however, this uninformative genetic test result means that the patient and family may still be at risk for harboring an occult mutation and should be treated and followed accordingly. Genetic counseling to assess the diminished, but not negligible, level of risk may be especially helpful in this setting.

How does one approach the patient with sporadic carcinoma for whom genetic testing will not or cannot be done, perhaps because of expense or personal choice? Jaw and kidney imaging of the patient and family may provide helpful information, but all family members who might have inherited the proband's potentially mutant HRPT2 allele would be considered to be at risk and in general be subjected to the surveillance as described above. Genetic counseling expertise is an essential component of the decision-making.

STAGING — Parathyroid carcinoma is included in the newest release (eighth edition, 2017) of the tumour, node, metastases (TNM) cancer manual from the combined American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) (table 1) [53]. However, they acknowledge that available data on tumor characteristics and prognosis are so limited that proposing a staging system at this time would be premature. They propose and define specific variables to be ascertained and recorded prospectively to facilitate development of a formal staging system in the future.

Three studies have shown that tumor size was a better predictor of prognosis than lymph node status [54-56]. In a retrospective review of patients with parathyroid carcinoma from the National Cancer Database from 1985 to 2006, the main prognostic factors in 733 identified cases (mean age 56 years) for 5 and 10 years overall survival were age at diagnosis, male sex, and tumor size, but not lymph node involvement, nor node dissection [54].

TREATMENT — The primary treatment of parathyroid carcinoma is surgery. When the tumor is no longer amenable to surgical intervention, treatment becomes focused on the control of hypercalcemia with medical therapy, which can include bisphosphonates, calcimimetic agents, or denosumab. Treatment with radiotherapy and chemotherapy has been disappointing.

Resectable disease — Surgery is the mainstay of therapy for both the initial treatment of parathyroid carcinoma and for the treatment of locally recurrent or metastatic disease.

Extent of resection

Preoperatively suspected parathyroid cancer – When the diagnosis of parathyroid cancer is suspected or known preoperatively, initial surgery should include parathyroidectomy or en-bloc resection of the parathyroid mass and any adjacent tissues that have been invaded by tumor [40]. In the Surveillance, Epidemiology, and End Results (SEER) registry, 78.6 percent of patients had a simple parathyroidectomy and 12.5 percent underwent en-bloc resection [4].

En-bloc resection could include the ipsilateral thyroid lobe, paratracheal alveolar and lymphatic tissue, the thymus or some of the neck muscles, and in some instances, the recurrent laryngeal nerve [35-38]. Some [57,58], but not all [38], centers recommend ipsilateral lymph node dissection. There is no consensus about the benefit of elective neck dissection of the central compartment [34,59]. It is important to avoid capsular violation or tumor spillage. (See "Parathyroid surgery for inherited syndromes", section on 'HPT-JT' and "Parathyroid surgery for inherited syndromes", section on 'Extent of resection'.)

Postoperatively diagnosed – In some cases, it is impossible to differentiate parathyroid adenoma from carcinoma at the time of diagnosis or initial surgery. If the diagnosis of parathyroid carcinoma is made postoperatively, reoperation with ipsilateral thyroidectomy is frequently performed [57,58,60]. If a parathyroid tumor appears to be well demarcated (not invading surrounding tissue) but is found on pathological examination to invade adjacent tissue, reoperation to remove all tumor tissue is recommended because there are no pathologic criteria that distinguish a carcinoma that will follow an indolent course from one with a more aggressive course.

Surgical approach for HRPT2 mutation carriers – Given the rarity of HRPT2-related disorders, the lack of controlled studies, and varying findings in different reports of surgical experience (each with small numbers of cases), there is no consensus on the optimal surgical approach for HRPT2 mutation carriers. The optimal approach to initial parathyroid surgery in hyperparathyroid patients with known HRPT2 mutation should take into account the substantial malignant potential, tempered by the expectation from classic HPT-JT that most tumors will still be benign, together with the increased risk of multiglandular disease, asynchrony in tumor development, and observations that tumors can occasionally be nonfunctional [47,49,61].

We generally advise that bilateral exploration be performed, identifying all parathyroid glands. This advice is strongly dependent on the availability of a highly experienced parathyroid surgeon. Grossly abnormal or suspicious-appearing glands should be resected, bearing in mind the risk of malignancy. Resection itself should be selective, and it seems reasonable for the surgeon to leave in situ any normal-appearing glands, marking their location to facilitate possible future operations.

An alternative, more limited surgical approach has also been advocated, more akin to the type of focused exploration commonly performed for typical parathyroid adenomas. This approach might be expected to carry a lower risk of surgical complications compared with bilateral exploration, and it can be successful in that HRPT2 mutation carriers may often have developed a tumor in only one gland at the time of initial parathyroidectomy. On the other hand, this latter approach runs the risk of missing tumors, including potentially aggressive lesions, in additional parathyroid glands that may have evaded detection with preoperative imaging and may also be nonfunctional or poorly functional [61,62]. (See "Parathyroid surgery for inherited syndromes", section on 'HPT-JT'.)

Total parathyroidectomy has been advocated by some clinicians for HRPT2 mutation carriers with hyperparathyroidism, given that all their parathyroid tissues have increased malignant potential. Currently, we do not favor this approach, because of the considerable morbidity associated with management of lifelong hypoparathyroidism, the significant but non-overwhelming penetrance of malignancy, and the expectation that prospective surveillance should identify tumors sufficiently early to prevent death from metastatic cancer. Prophylactic total parathyroidectomy could gain more support if/when treatment modalities for hypoparathyroidism improve (eg, with availability of inexpensive and easily administered PTH replacement therapy).

Metastatic disease – Because nonsurgical therapies for parathyroid carcinoma have had disappointing results, surgical resection of distant metastases (bone and lung) has been performed in some circumstances, primarily to debulk tumor as palliation of the effects of hypercalcemia [63,64].

Recurrent disease – Patients with recurrent parathyroid carcinoma can also be treated surgically. Most recurrences occur within the neck [65]. Resection of lesions in the neck (as well as lungs and liver) will often result in significant palliation of hypercalcemia. However, these reoperations are associated with substantial morbidity. As an example, in one series of 18 patients who underwent 28 reoperations, complications, most commonly recurrent laryngeal nerve palsies, occurred in 9 of the 28 procedures (32 percent) [66]. Preoperative localizing studies are recommended to minimize morbidity. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

Preoperative medical management — Prior to surgery, patients should receive medical therapy to lower elevated calcium levels and correct other metabolic disturbances [67]. Acute hypercalcemia due to parathyroid carcinoma is treated similarly to hypercalcemia due to any other cause. The treatment of hypercalcemia is reviewed in detail elsewhere. (See "Treatment of hypercalcemia", section on 'Severe hypercalcemia'.)

Postoperative management

Monitoring serum calcium — The postoperative management of patients with parathyroid carcinoma should include close monitoring of the patient's serum calcium concentration. Patients in whom the preoperative serum calcium is very high may develop the "hungry bone syndrome" after the tumor is completely removed and, therefore, need large doses of intravenous calcium and oral calcitriol (see "Hungry bone syndrome following parathyroidectomy in end-stage kidney disease patients"). As the bones heal, the requirements for calcium and calcitriol decrease.

Role of adjuvant radiation therapy — In the absence of definitive data, we do not routinely administer adjuvant radiation, particularly because it may be difficult to differentiate atypical parathyroid adenomas from carcinoma at the time of initial surgery (see 'Diagnosis' above). In addition, radiation may increase the difficulty of subsequent neck surgery, often necessary in patients with parathyroid carcinoma.

The experience with adjuvant radiation therapy is limited to small observational studies, which are often limited by selection bias [1,41,68-71]. As examples:

In one series of 26 patients with locally invasive disease followed for a mean of 7.9 years (range 2 to 21), only one of six patients who had adjuvant radiation therapy had a local relapse, compared with 10 of 20 who had not received radiation therapy [41].

In a series of 57 patients from the Mayo Clinic who had surgical resection, locoregional disease progression occurred in 25 patients (44 percent) at a median follow-up of 27 months. On univariate analysis, surgical margin status was a predictor of locoregional progression. Four patients who were treated with surgery and adjuvant radiation therapy with doses of 66 to 70 Gy had no recurrence at 60 months of follow-up [71]. The surgical margins were negative in three of these patients and within 2 mm in one patient. It is possible, therefore, that these patients were not at risk for locoregional disease progression.

In an analysis of the National Cancer Database for patients with parathyroid carcinoma who underwent surgery between 2004 and 2016, 126 (14 percent) received external beam radiotherapy (EBRT) [72]. EBRT was not associated with a difference in overall survival. In addition, the overall survival of the subset of patients with completely resected localized disease and who also received EBRT (49 of 517, 10.5 percent) was not improved.

Unresectable disease — When parathyroid carcinoma is widely disseminated and no longer amenable to surgical resection, the prognosis is generally poor. In this setting, major morbidity and mortality result from severe hypercalcemia. Adequately controlling hypercalcemia can prolong survival [68]. In addition, palliative radiation therapy for bone metastases or locoregional disease has been reported [71].

Controlling hypercalcemia — Hypercalcemia is the principal cause of morbidity and mortality from parathyroid carcinoma [35-37]. In patients with unresectable disease, palliative treatment to control severe hypercalcemia is indicated. The initial treatment of hypercalcemia in patients with parathyroid carcinoma is similar to management in patients with hypercalcemia due to other causes and includes hydration with infusion of saline to restore fluid volume and intravenous bisphosphonates. (See "Treatment of hypercalcemia" and 'Bisphosphonates' below.)

As the disease progresses, hypercalcemia typically becomes refractory to bisphosphonates. The addition or substitution of cinacalcet, which acts by a different mechanism of action than bisphosphonates, has been reported to successfully control hypercalcemia in some patients. The development of nausea and vomiting may limit dose escalation. (See 'Calcimimetics' below.)

Denosumab is an option for patients who have hypercalcemia refractory to both bisphosphonates and cinacalcet. (See 'Denosumab' below.)

Bisphosphonates — The initial treatment of hypercalcemia in patients with parathyroid carcinoma includes saline hydration and intravenous bisphosphonates. Among currently available bisphosphonates, intravenous zoledronic acid or pamidronate are the preferred agents for the treatment of hypercalcemia due to parathyroid carcinoma.

Pamidronate has been reported to improve hypercalcemia in individual cases of parathyroid carcinoma [73,74]. One would therefore predict that the bisphosphonate zoledronic acid, which is more potent than pamidronate in treating hypercalcemia of malignancy [75], would also be effective for hypercalcemia due to parathyroid carcinoma, although this effect has not yet been documented. The administration and dosing of bisphosphonates to treat hypercalcemia due to parathyroid carcinoma are the same as those to treat other causes of hypercalcemia. (See "Treatment of hypercalcemia", section on 'Bisphosphonates'.)

Calcimimetics — For patients with hypercalcemia that is refractory to bisphosphonates, the addition or substitution of a calcimimetic drug (eg, cinacalcet) may be beneficial. Calcimimetic drugs reduce parathyroid hormone (PTH) secretion by increasing the sensitivity of the calcium-sensing receptor [76,77]. Cinacalcet, a longer-acting calcimimetic drug, is approved by the US Food and Drug Administration (FDA) for the treatment of hypercalcemia in parathyroid cancer, secondary hyperparathyroidism associated with renal failure, and severe hypercalcemia in patients with primary hyperparathyroidism unable to undergo parathyroidectomy. (See "Primary hyperparathyroidism: Management", section on 'Calcimimetics' and "Management of secondary hyperparathyroidism in adult dialysis patients", section on 'Calcimimetics'.)

In a 16-week, open-label study of 29 patients with inoperable parathyroid carcinoma, cinacalcet (dose titrated to achieve calcium ≤10 mg/dL or up to 90 mg four times daily) successfully reduced serum calcium concentration by at least 1 mg/dL in 62 percent of patients [77]. Mean PTH levels decreased but not significantly. Adverse events (nausea, vomiting, headache, dehydration) were common and resulted in discontinuation in five patients.

The initial dose of cinacalcet is 30 mg twice daily. The dose can be increased sequentially every two to four weeks (60 mg twice daily, 90 mg twice daily, 90 mg three times or four times daily), depending upon the serum calcium level and tolerance of the drug. Nausea and vomiting often limit the ability to increase the dose of the drug. Serum calcium and phosphorous should be monitored within one week of dose initiation or adjustment. If a maintenance dose is achieved, serum calcium and phosphorous can be monitored every one to two months.

Denosumab — Denosumab is an option for patients with parathyroid cancer who have hypercalcemia refractory to bisphosphonates and cinacalcet. It is a potent inhibitor of bone resorption. In case reports, denosumab, typically used as monotherapy, effectively controlled refractory hypercalcemia in patients with parathyroid cancer previously treated with surgery, bisphosphonates, calcium receptor agonist, and dacarbazine [78-81]. In one patient, high-dose (120 mg) monthly denosumab was required to reduce severely elevated serum calcium levels [82]. Stabilization of serum calcium may last for a few weeks or as long as two years [81].

Novel precision/molecularly targeted cancer therapy — Some metastatic/surgically incurable parathyroid cancers can carry tumor-specific mutations (eg, PIK3CA or MTOR mutations) against which new targeted therapeutic agents may already exist. (See 'Other genes' above.)

For a tumor this rare, future case reports of such therapeutic interventions will be valuable, and most importantly, these prospective applications of "precision medicine" must be rigorously tested [34,59]. Inclusion of parathyroid carcinoma patients in "basket" clinical trials of new targeted agents, in which eligibility is based on the presence of a particular driver mutation without regard to the tissue/histologic origin of the tumor, should be seriously considered when clinically appropriate.

Chemotherapy — In general, attempts to reduce tumor burden with chemotherapy have been disappointing [68]. Given the rarity of parathyroid carcinoma, chemotherapy has been difficult to evaluate systematically, and there are no prospective randomized trials. Various agents, either alone or in combination, have resulted in rare responses. One patient with pulmonary metastases responded to treatment with dacarbazine, 5-fluorouracil, and cyclophosphamide with normalization of serum calcium for 13 months [68], while another with recurrent disease responded to dacarbazine alone with a two-month normalization of serum calcium [83].

Biotherapy — Biologic agents based on gene products such as parafibromin, an inhibitor of cell proliferation in parathyroid neoplasia, telomerase inhibitors such as azidothymidine, and immune therapy constitute novel emerging therapies with encouraging in vitro results and may prove useful clinically in the future [40].

COURSE AND OUTCOME — Hypercalcemia is the principal cause of morbidity and mortality from parathyroid carcinoma [35-37]. The carcinomas grow very slowly in most patients but can occasionally be aggressive [84]. It appears that the disease typically follows one of three courses: one-third of patients are cured at initial or follow-up surgery, one-third recur after a prolonged disease-free survival but may be cured with reoperation, and one-third of patients experience a short and aggressive course [60].

Patients should be followed for the possibility of recurrence with measurement of serum calcium and parathyroid hormone (PTH) levels initially every six months and then annually. If there is biochemical evidence of recurrence, other tests that may be indicated to identify the sites of disease include neck ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and fludeoxyglucose-positron emission tomography (FDG-PET). There is no role for imaging in patients in whom calcium and PTH levels are normal.

As noted, the recurrence rate is high, even after seemingly successful surgery. In one study, as an example, among 22 patients who had normal serum calcium concentrations after surgery, the recurrence rates at 1, 5, and 10 years were 27, 82, and 91 percent, respectively [37]. In this and several other older studies, the combined 5- and 10-year survival rates varied from 50 to 70 and 13 to 35 percent, respectively [35-37], with a mean survival time of six to seven years [35,36].

However, survival may be improving. The National Cancer Database survey (1985 to 1995) reported 5- and 10-year survival rates of 55.5 and 49 percent, respectively, in their series of 286 patients [85]. An updated report from 1985 to 2006 with a total of 733 evaluable patients revealed 5- and 10-year overall survival rates of 82.3 and 66 percent, respectively [54], results that are consistent with reports from the Surveillance, Epidemiology, and End Results (SEER) cancer registry (1988 to 2003 and 2000 to 2012) with 10-year survival rates of 64.8 and 65.4 percent, respectively [4,5]. Young age, female sex, recent year of diagnosis, smaller tumor size, and absence of distant metastases were associated with improved survival [54,85,86].

SUMMARY AND RECOMMENDATIONS

Clinical presentation – Parathyroid carcinoma is a rare cause of primary hyperparathyroidism, which is usually caused by a parathyroid adenoma and occasionally by primary parathyroid hyperplasia. Compared with patients with parathyroid adenomas, patients with parathyroid carcinomas are more likely to have symptoms, a neck mass, bone and kidney disease, marked hypercalcemia, and very high serum parathyroid hormone concentrations. (See 'Clinical presentation' above.)

Diagnosis – The diagnosis of parathyroid cancer is typically made at the time of surgery to correct severe hyperparathyroidism. The classic pathologic features of a trabecular pattern, mitotic figures, thick fibrous bands, and capsular and vascular invasion, when present, are highly suggestive of parathyroid carcinoma, but definitive diagnosis depends on the presence of invasion into surrounding tissues or distant metastasis. In some cases, it may not be possible to diagnose parathyroid carcinoma at the time of hyperparathyroidism presentation or initial surgery. Local recurrence or the occurrence of distal metastases at subsequent follow-up ultimately determines the correct diagnosis. (See 'Diagnosis' above.)

Genetic testing – Some patients with apparently sporadic parathyroid carcinoma have germline HRPT2/CDC73 mutations, and genetic evaluation can play an important role in management of such patients and family members. (See 'Genetic testing' above.)

Treatment

Resectable disease – Surgery is the mainstay of therapy for both the initial treatment of parathyroid carcinoma and for the treatment of locally recurrent or metastatic disease. Treatment with radiotherapy and chemotherapy has been disappointing. (See 'Resectable disease' above.)

Unresectable disease – When parathyroid carcinoma is widely disseminated and no longer amenable to surgical resection, the prognosis is generally poor. In this setting, major morbidity and mortality results from severe hypercalcemia. Adequately controlling hypercalcemia can prolong survival. (See 'Unresectable disease' above.)

Controlling hypercalcemia – The initial treatment of hypercalcemia in patients with parathyroid carcinoma is similar to management in patients with hypercalcemia due to other causes and includes hydration with infusion of saline to restore fluid volume and intravenous bisphosphonates. As the disease progresses, hypercalcemia typically becomes refractory to initial medical therapy. The addition or substitution of cinacalcet has been reported to successfully control hypercalcemia in some patients. Denosumab is an option for patients who have hypercalcemia refractory to both bisphosphonates and cinacalcet. (See 'Controlling hypercalcemia' above.)

Novel molecularly targeted therapy – Some patients with disseminated disease carry potentially actionable somatic mutations in their tumors, which could lead to their consideration for trials of specifically targeted therapeutic agents. (See 'Novel precision/molecularly targeted cancer therapy' above.)

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Topic 2042 Version 16.0

References