Parathyroid adenomas represent a common endocrine problem, whereas parathyroid carcinomas are very rare tumors. With an estimated incidence of 0.015 per 100,000 population and an estimated prevalence of 0.005% in the United States, parathyroid cancer is one of the rarest of all human cancers.[1,2] In Europe, the United States, and Japan, parathyroid carcinoma has been estimated to cause hyperparathyroidism (HPT) in 0.017% to 5.2% of cases; however, many series report this entity to account for less than 1% of patients with primary HPT.[1,3-5] The median age in most series is between 45 and 51 years.[1] The ratio of affected women to men is 1:1 in contrast to primary HPT in which there is a significant female predominance (ratio of 3–4:1).[5]
Operatively, parathyroid cancers may be distinguished from adenomas by their firm, stony-hard consistency and lobulation; adenomas tend to be soft, round, or oval in shape, and of a reddish-brown color.[5] In most series, the median maximal diameter of parathyroid carcinoma is between 3.0 cm and 3.5 cm compared with approximately 1.5 cm for benign adenomas.[1] In approximately 50% of patients, the malignant tumor is surrounded by a dense, fibrous, grayish-white capsule that infiltrates adjacent tissues.[5]
Histopathologically, as with other endocrine neoplasms, it is difficult to make the distinction between benign and malignant parathyroid tumors.[1,5,6] The extent to which capsular and vascular invasion appears to be unequivocally correlated with tumor recurrences and metastases makes a strong case for these findings to be considered the sole pathognomonic markers of malignancy.[6,7]
The etiology of parathyroid carcinoma is unknown. However, an increased risk of parathyroid cancer has been associated with multiple endocrine neoplasia type 1 and with autosomal dominant familial isolated hyperparathyroidism.[8-10] Parathyroid cancer has also been associated with external radiation exposure; however, most reports describe an association between radiation and the more common parathyroid adenoma.[1,5]
Parathyroid cancer typically runs an indolent, albeit tenacious, course because the tumor has a rather low malignant potential. At initial presentation, few patients with parathyroid carcinoma have metastases either to regional lymph nodes (<5%) or distant sites (<2%).[1] In a National Cancer Database series of 286 patients, only 16 (5.6%) had lymph node metastases noted at the time of initial surgery.[2] A higher proportion of parathyroid cancers locally invade the thyroid gland, overlying strap muscles, recurrent laryngeal nerve, trachea, or esophagus. Some patients are not identified preoperatively or intraoperatively as having parathyroid carcinoma and undergo parathyroid procedures devised to treat parathyroid adenoma. Only after review of the postsurgical pathology, or when these patients experience local or distant recurrence, is a correct diagnosis of parathyroid carcinoma made.[1] Parathyroid carcinoma tends to be localized in the inferior parathyroid glands. One series reported that a primary tumor originating in the inferior parathyroid glands was found in 15 of 19 cases involving local invasion.[11,12]
Parathyroid cancers are hyperfunctional unlike other endocrine tumors that become less hormonally active when malignant.[1] The clinical features of parathyroid carcinoma are caused primarily by the effects of excessive secretion of parathormone (PTH) by the tumor rather than by the infiltration of vital organs by tumor cells. Serum PTH levels may be three to ten times above the upper limit of normal for the assay employed. This marked elevation is uncommon in primary HPT where serum PTH concentrations are typically less than twice that of normal.[5] Accordingly, signs and symptoms of hypercalcemia typically dominate the clinical picture and may include typical hyperparathyroid bone disease and features of renal involvement, such as nephrolithiasis or nephrocalcinosis.[1] Renal colic is a frequent presenting complaint of patients with parathyroid carcinoma.[5] In a study involving 43 cases, the prevalence of nephrolithiasis was reported to be 56%, and the prevalence of renal insufficiency was reported to be 84%.[13]
The prevalence of bone disease is much greater in patients with parathyroid carcinoma than it is in patients with parathyroid adenoma, with 70% or fewer patients manifesting symptoms related to calcium absorption with osteoporosis and bone pain.[14,15] In benign parathyroid disease, it is unusual to have both renal and bone symptomatology documented at the time of diagnosis.[16] These symptoms are present simultaneously at diagnosis in 50% or fewer patients with parathyroid cancer.[1] In contrast, simultaneous renal and overt skeletal involvement is distinctly unusual in primary HPT.[5] For more information about bone pain, see Cancer Pain.
The following signs and symptoms of the hyperparathyroid state associated with parathyroid cancer may be found at diagnosis:[1,5]
For more information about some of these symptoms, see Cancer Pain, Nutrition in Cancer Care (for weight loss information), and Nausea and Vomiting Related to Cancer Treatment.
Certain clinical features may help distinguish parathyroid carcinoma from parathyroid adenoma.
Parathyroid carcinoma should be suspected clinically if the patient presents with the following diagnostic features:[1,5,17,18]
The medical management of hypercalcemia, particularly in patients with unresectable disease or without measurable disease, is critical and must be the initial treatment goal in all patients with HPT. Conventional treatment with intravenous fluids, diuretics, and antiresorptive agents such as bisphosphonates, gallium, or mithramycin may help control the hypercalcemia.[12] Calcimimetic agents that directly block secretion of the parathyroid hormone from the glands may offer an important approach to medical therapy of primary HPT associated with parathyroid cancer.[19,20]
Surgery is the only effective therapy for parathyroid carcinoma.[1,5,6] Preoperative suspicion and intraoperative recognition of parathyroid carcinoma is critical to achieve a favorable outcome, which involves en bloc resection of the tumor with all potential areas of invasion at the initial operation.[12,21,22]
One analysis of the literature indicated a local recurrence rate of 8% after an en bloc resection and 51% after a standard parathyroidectomy.[23] En bloc excision during the initial procedure for parathyroid cancer may involve resection of the recurrent laryngeal nerve because the nerve is at risk for invasion by any residual tumor and subsequent loss of function. The increased potential for long-term local control achieved by en bloc excision outweighs the complication of postoperative vocal cord paralysis, which can be improved with techniques such as Teflon injection into the paralyzed cord. Cervical lymph node dissection should be performed only for enlarged or firm nodes, particularly those found in the level VI paratracheal nodes and levels III and IV internal jugular nodes.[1]
Because of the fairly indolent biology of this cancer, the management of recurrent or metastatic disease is primarily surgical. Significant palliation may result from the resection of even very small tumor deposits in the neck, lymph nodes, lungs, or liver.[2,13,16,24,25] Accessible distant metastases should be resected when possible.[5] Localization studies performed before the first operation or reoperation may include technetium Tc 99m-sestamibi (MIBI) scan, single photon emission computed tomography, computed tomography (CT)-MIBI image fusion, ultrasound, CT, selective angiogram, and selective venous sampling for PTH.[3] CT and magnetic resonance imaging are useful imaging adjuncts for the localization of distant metastases.[5,26]
Nonsurgical forms of therapy for parathyroid carcinoma generally have poor results.[1,5,6,11] Some investigators have advocated the use of adjuvant radiation therapy to decrease the local recurrence rate.[27,28] Patients with this disease should be monitored for life because they may be at a relatively high risk of multiple relapses over prolonged periods of time.[11] Patients rarely die of the tumor itself; rather, they die of the metabolic complications of uncontrolled HPT.
Approximately 40% to 60% of patients experience a postsurgical recurrence, typically within 2 to 5 years after the initial resection.[17,21] In most cases, hypercalcemia precedes physical evidence of recurrent disease. The location of recurrence is typically regional, either in the tissues of the neck or in cervical lymph nodes, and accounts for approximately two-thirds of recurrent cases.[18] Often, local recurrences in the neck are difficult to identify because they may be small and multifocal, and they may involve scar tissue from a previous surgical procedure. Use of ultrasonography, sestamibi-thallium scanning, and positron emission tomography may help to identify difficult-to-detect recurrent disease.[29-31]
In older studies, distant metastases were reported in 25% of patients, primarily in the lungs but also in the bone and liver.[18,32] Other series indicate that the incidence of recurrence may be higher, possibly because of more accurate pathological diagnoses that exclude patients with atypical adenomas.[1] Because of its low malignant potential, the morbidity and mortality associated with parathyroid cancer primarily result from the metabolic consequences of the disease and not directly from malignant growth.[11,32] In a National Cancer Database series of 286 patients, the 10-year survival rate was approximately 49%.[2] A smaller series reported a 10-year survival rate of 77%, which might be related to improvements in supportive medical care and in the prevention of fatal hypercalcemia.[11]
The histological distinction between benign and malignant parathyroid tumors is difficult to make.[1] Although cell type is not known to be of prognostic significance, histological cell types include chief cell, transitional clear cell, and mixed cell types. Standard criteria of malignancy often cannot be confirmed in retrospective reviews of patients with carcinoma. Macroscopic and microscopic infiltrations often do not correlate, and adhesion to surrounding structures does not necessarily imply malignancy. Features such as dense fibrous trabeculae, trabecular growth patterns, mitoses, and capsular invasions, which have been classically associated with carcinomas, have also been found in parathyroid adenomas.[2-4] Capsular and vascular invasion appears to correlate best with tumor recurrence.[3,5] In a study of 286 patients, pathologists described well-differentiated carcinomas in approximately 80% of the patients.[6]
An aneuploid DNA pattern is more common, and mean nuclear DNA content is greater in carcinomas than in adenomas. When present in a carcinoma, aneuploidy appears to be associated with a poorer prognosis.[7-9] Aneuploidy occurs too frequently in parathyroid adenomas to be significant in differentiating benign from malignant parathyroid lesions.[9-11] In general, the clinical course and the gross pathology observed at surgery are as important as the histology to define a lesion as a parathyroid carcinoma.[12]
Because of the low incidence of parathyroid carcinoma, an American Joint Committee on Cancer staging system has not yet been formulated and, thus, is not applicable to this malignancy. In addition, neither tumor size nor lymph node status appear to be important prognostic markers for this malignancy.[1]
Patients are considered to have either localized or metastatic disease.[2,3]
Localized Parathyroid Cancer
Localized parathyroid cancer is disease that involves the parathyroid gland with or without invasion of adjacent tissues.
Metastatic Parathyroid Cancer
Metastatic parathyroid cancer is disease that spreads beyond the tissues adjacent to the involved parathyroid gland(s). Parathyroid carcinoma most frequently metastasizes to regional lymph nodes and lungs, and it may involve other distant sites, such as liver, bone, pleura, pericardium, and pancreas.[4]
The rarity of this tumor does not allow for large published series of treatment experience or permit the systematic evaluation of combination therapies.[1,2] The relatively slow cell-doubling time for this tumor makes radical surgery a therapeutic option even for patients with metastatic disease. Treatment and control of secondary hypercalcemia must be the initial treatment goal in all patients with hyperparathyroidism.
Treatment options for localized parathyroid cancer include the following:[1-4]
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Metastatic disease can appear shortly after the initial diagnosis and operation or for up to 20 years later.[1] Because of the difficulty in making a histological diagnosis, the appearance of recurrent or metastatic disease in a patient previously operated on for hypercalcemia can be the first indicator that the tumor was malignant.[2] Approximately 50% of patients who experience recurrence will have distant metastases.[3] The most common site of distant metastasis is the lung.[4,5] Some patients experience years of survival even after the diagnosis of distant metastases.[5] Aggressive surgical resection has been associated with a 30% long-term survival rate in retrospective series.[3,6]
Treatment options for metastatic parathyroid cancer include the following:[1,3-10]
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Approximately 40% to 60% of patients experience a postsurgical recurrence, typically between 2 to 5 years after the initial resection.[1,2] Because it is difficult to establish a histological diagnosis of parathyroid cancer at the time of initial surgery, the appearance of recurrent or metastatic tumor can be the first sign of malignancy.[3]
Because these tumors are slow-growing, repeated resection of local recurrences and/or distant metastases can result in significant palliation.[4-8] Pulmonary metastases and bone metastases should be resected, if possible, to decrease the magnitude of the hypercalcemia.[7,9] Occasionally, long-term salvage is achieved in this group of patients with aggressive surgical treatment.[10] The major morbidity of recurrent or metastatic parathyroid cancer results from severe hypercalcemia, which can be difficult to control. For patients not fit for surgery, treatment with bisphosphonates, plicamycin, calcitonin, and gallium pamidronate may control hypercalcemia.[11] Control of malignant hypercalcemia with these medical measures is often only temporary.
Treatment options for recurrent parathyroid cancer include the following:[4-10]
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of parathyroid cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Parathyroid Cancer Treatment is:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Parathyroid Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/parathyroid/hp/parathyroid-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389236]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.