Parathyroid carcinoma is a rare condition, accounting for 0.005% of all cancers in the United States and less than 1% of patients with primary hyperparathyroidism (HPT). The incidence of parathyroid carcinoma, however, appears to be increasing. The Surveillance, Epidemiology, and End Results Cancer Registry showed a 60% increase in incidence from 1988 to 2003.
Robert A. Wermers, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic in Minnesota, says, "Parathyroid carcinoma should be suspected in patients with primary HPT who have severe hypercalcemia (serum calcium concentrations that are 3 to 4 mg/dL above the upper limit of the reference range) and markedly increased blood concentrations of parathyroid hormone (PTH) (concentrations that are 3- to 10-fold greater than the upper limit of the reference range).Complications related to primary HPT, such as nephrolithiasis, renal insufficiency, and metabolic bone manifestations are more likely to be present in patients with parathyroid carcinoma."
Additional clinical clues that a patient with primary HPT may have parathyroid carcinoma include a palpable neck mass, recurrent laryngeal nerve paralysis, and recurrent primary HPT in a patient with severe primary HPT.
Parathyroid carcinoma has been identified in patients with familial primary HPT due to mutations in HRPT2 — the gene associated with hyperparathyroidism — jaw tumor syndrome (HPT-JT). An estimated 15% to 20% of primary HPT cases in families with HPT-JT are due to parathyroid carcinoma. Some patients with sporadic parathyroid carcinomas have also been shown to have somatic or germline mutations in HRPT2.
The natural history of parathyroid carcinoma can be variable. Some individuals experience a long, indolent course. Geoffrey B. Thompson, M.D., of the Department of Surgery at Mayo Clinic in Minnesota, explains, "Complete surgical resection of the tumor is the mainstay of treatment of parathyroid carcinoma. En bloc tumor resection is the procedure of choice." A review from Mayo Clinic in Minnesota that spans 70 years shows that disease recurrence is frequent, with 26 of 43 patients (60%) requiring a second operation."
When locally invasive disease or metastases are present, chemotherapy and radiation therapy have been used with varying degrees of success. Robert L. Foote, M.D., of the Department of Radiation Oncology at Mayo Clinic in Minnesota, comments, "In general, radiation therapy for inoperable parathyroid carcinoma has been found to be ineffective. Case reports of adjuvant radiation therapy for parathyroid carcinoma, however, have shown promise."
"We recently reviewed our experience with five patients with parathyroid carcinoma who received adjuvant radiation therapy because of the concern of possible residual microscopic disease after surgery," says Dr. Foote. The median radiation dose was 70 Gy (range, 60-70 Gy), administered in 35 fractions (range, 30-35 fractions) over 50 days (range, 42-63 days).
At the time of last follow-up, with a median follow-up period of 101 months (range, 77-115 months):
"Although the data are limited by the small number of patients, it appears that parathyroid carcinoma may be a radiosensitive tumor. Furthermore, some patients with parathyroid carcinoma appear to benefit from adjuvant radiation therapy. It is unclear which patients may benefit the most from adjuvant radiotherapy, however, given the often unpredictable nature of this malignancy," notes Dr. Foote.
Dr. Thompson explains, "Aggressive resection of recurrent disease can offer considerable clinical benefit in patients with metastatic parathyroid carcinoma. The lung is the most common site of distant metastases in patients with parathyroid carcinoma. Long-term remission has been described in patients undergoing removal of lung metastases."
Dr. Wermers adds, "When parathyroid carcinoma is widely metastatic and surgical resection is no longer an option, treatment of the hypercalcemia becomes the primary clinical focus, since it is the main cause of death."
Saline infusions and potent, intravenously administered bisphosphonates may control hypercalcemia transiently. Cinacalcet hydrochloride is a calcimimetic agent that is approved by the U.S. Food and Drug Administration for the treatment of refractory hypercalcemia due to parathyroid carcinoma. It directly reduces PTH secretion by binding to the calcium-sensing receptor on parathyroid cells, thereby increasing their sensitivity to extracellular calcium. The use of cinacalcet, however, is limited by its high cost and adverse effects, the most severe of which is nausea.
Anti-PTH immunotherapy has also shown promise, with biochemical improvement and tumor shrinkage in a small number of patients with refractory parathyroid carcinoma.