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 .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 .017% to 5.2% of the 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]

The etiology of parathyroid carcinoma is unknown; however, an increased risk of parathyroid cancer has been associated with multiple endocrine neoplasia 1 and with autosomal dominant familial isolated hyperparathyroidism.[6-8] 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, very few patients with parathyroid carcinoma have metastases either to regional lymph nodes (<5%) or distant sites (<2%).[1] In the 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 the primary tumor originating in the inferior parathyroid glands was found in 15 of 19 cases involving local invasion.[9,10]

Approximately 40% to 60% of patients experience a postsurgical recurrence, typically in the range of 2 to 5 years after the initial resection.[11,12] In most cases, hypercalcemia precedes physical evidence of recurrent disease. (Refer to the PDQ summary on Hypercalcemia for more information.) 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.[13] 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.[14-16] In older studies, distant metastases were reported to occur in 25% of patients, primarily in the lungs but also in the bone and liver.[13,17] More recent series indicate that the incidence of recurrence may be higher, possibly because of more accurate pathologic 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.[9,17] In the National Cancer Database series of 286 patients, the 10-year survival rate was reported to be approximately 49%.[2] A smaller series has 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.[9]

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 the patients, the malignant tumor is surrounded by a dense, fibrous, grayish-white capsule that infiltrates adjacent tissues.[5] Histopathologically, as with other endocrine neoplasms, the distinction between benign and malignant parathyroid tumors is difficult to make.[1,5,18] 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.[18,19]

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 3 to 10 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] (Refer to the PDQ summary on Hypercalcemia for more information.) Renal colic is a frequent presenting complaint of patients with parathyroid carcinoma.[5] In a study involving 43 cases, the prevalence of nephrolithiasis and the prevalence of renal insufficiency were reported to be 56% and 84%, respectively.[20]

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.[21,22] (Refer to the PDQ summary on Pain for more information.) In benign parathyroid disease, it is unusual to have both renal and bone symptomatology documented at the time of diagnosis.[23] 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]

Signs and symptoms of the hyperparathyroid state associated with parathyroid cancer that may be found at diagnosis include: [1,5]

• Subcortical bone resorption.
• Bone pain.
• Pathological fractures.
• Palpable neck mass.
• Renal calculi.
• Renal disease.
• Renal colic.
• Peptic ulcer.
• Recurrent pancreatitis.
• Fatigue.
• Muscle weakness.
• Weight loss.
• Anorexia.
• Polyuria.
• Polydipsia.
• Dehydration.
• Nausea and vomiting.

(For information on some of the above symptoms, refer to the PDQ summaries on Pain, Fatigue, Nutrition in Cancer Care [for weight loss information], and Nausea and Vomiting.)

Certain clinical features may help to distinguish parathyroid carcinoma from parathyroid adenoma.

Parathyroid carcinoma should be suspected clinically if: [1,5,11,13]

• Hypercalcemia is greater than 14 milligrams per deciliter. (Refer to the PDQ summary on Hypercalcemia for more information.)
• Serum PTH levels are greater than twice that of normal.
• A cervical mass is palpated in a hypercalcemic patient.
• Hypercalcemia is associated with unilateral vocal cord paralysis.
• Concomitant renal and skeletal disease are observed in a patient with a markedly elevated serum PTH.

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 biphosphonates, gallium, or mithramycin may help control the hypercalcemia.[10] Calcimimetic agents that directly block secretion of the parathyroid hormone from the glands may offer an important new approach to medical therapy of primary HPT associated with parathyroid cancer.[24,25] (Refer to the PDQ summary on Hypercalcemia for more information.)

Surgery is the only effective therapy for parathyroid carcinoma.[1,5,18] 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.[10,12,26] One analysis of the literature indicated an overall 8% evidence of local recurrence after an en bloc resection compared with a 51% incidence after a standard parathyroidectomy.[27] 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.[2,20,23,28,29] Accessible distant metastases should be resected when possible.[5] Localization studies performed before the first operation or reoperation may include technetium Tc 99m sestamibi scan, single photon emission computed tomography, CT-MIBI image fusion, ultrasound, computed tomography (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.[5,30]

Nonsurgical forms of therapy for parathyroid carcinoma generally have poor results.[1,5,9,18] Some investigators have advocated the use of adjuvant radiation therapy to decrease the local recurrence rate.[31,32] 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.[9] As stated previously, patients rarely die from the tumor itself; rather, they die from the metabolic complications of uncontrolled HPT.

References

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2. Hundahl SA, Fleming ID, Fremgen AM, et al.: Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985-1995: a National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 86 (3): 538-44, 1999.  [PUBMED Abstract]
   
   
3. Fraker DL: Update on the management of parathyroid tumors. Curr Opin Oncol 12 (1): 41-8, 2000.  [PUBMED Abstract]
   
   
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