Parathyroid carcinoma is a rare cause of hypercalcemia, accounting for more than 2% of cases with primary hyperparathyroidism.
The disease presents in midlife and occurs with similar frequency in both sexes. The etiology of parathyroid carcinoma is obscure; an association with prior neck irradiation is not apparent. Parathyroid carcinoma can be associated with the hereditary hyperparathyroidism–jaw tumor syndrome, which is due to an inactivating mutation of the HRPT2 gene that encodes the parafibromin protein. In addition, somatic mutations of the HRPT2 gene have been demonstrated in sporadic parathyroid carcinomas (66% to 100%) but have not been seen with sporadic adenomas.
Most patients with parathyroid cancer have symptomatic moderate to severe hypercalcemia (mean serum calcium level, 15 mg/dL) and high parathyroid hormone levels. They often present with a palpable neck mass. Unlike benign hyperparathyroidism, renal and bone abnormalities are more common in patients with parathyroid cancer.
Rarely, nonfunctioning tumors may present as neck masses; their clinical course is similar to that of functioning tumors. Clinical concern about parathyroid cancer should be raised in the presence of a palpable neck mass and severe hypercalcemia, recurrent hyperparathyroidism, or associated vocal cord paralysis.
The principal features of parathyroid cancer include a trabecular pattern, mitotic figures, thick fibrous bands, and capsular or vascular invasion of disease. Other important features include lymphatic or hematogenous metastases and histologic evidence of tumor infiltration into the surrounding tissues (including macroscopic adherence or vocal cord paralysis).
Although cytologic evidence of mitoses is necessary to establish the diagnosis of carcinoma, mitotic activity alone is an unreliable indicator of malignancy. The only reliable microscopic finding of malignancy is invasion of surrounding structures or metastasis to lymph nodes or other organs.
Surgical treatment of primary hyperparathyroidism
The diagnosis of parathyroid carcinoma is sometimes made during surgical exploration for primary hyperparathyroidism. Most surgeons advocate identification of all four parathyroid glands. In most cases, the upper glands can be found on the posterior aspect of the upper third of the thyroid lobe, just cephalad to the inferior thyroid artery and adjacent to the recurrent laryngeal nerve as it enters the larynx.
The inferior parathyroid glands are more variable in location. Most are found on the posterior or lateral aspect of the lower pole of the thyroid gland, but the inferior parathyroid glands may be ectopically placed in the superior or true mediastinum, often within the thymus.
The inferior and, less commonly, superior glands can be found in an ectopic location in the upper or lateral neck, adjacent to the esophagus, or within the carotid sheath.
Surgical exploration for primary hyperparathyroidism. Most cases of primary hyperparathyroidism are caused by a single hyperfunctioning parathyroid adenoma. If the surgeon finds one (or occasionally two) enlarged abnormal gland(s) and the remaining glands are normal, the enlarged gland should be removed.
If four enlarged glands are found, indicating the rare case of primary parathyroid hyperplasia, subtotal parathyroidectomy including 3.5 glands should be performed. Consideration should be given to transplanting the remaining gland remnant to an ectopic location that would be easily accessible to the surgeon if hyperparathyroidism recurs.
If only normal glands are found at exploration, a missed adenoma in an ectopic location should be suspected. Thorough intraoperative neck and superior mediastinal exploration should be performed, and if the missing gland cannot be found, thymectomy and hemithyroidectomy should be performed to exclude an intrathymic or intrathyroidal adenoma. Localization studies, including CT/MRI or radionuclide imaging, should precede reexploration for a missed adenoma.
Intraoperative parathyroid hormone (ioPTH) levels are increasingly used to guide surgery for primary hyperparathyroidism. A 50% or greater decrease in the ioPTH level from the preexcision value to the 10-minute postexcision value is used as a predictor of successful surgery. The advent of ioPTH monitoring, coupled with preoperative localization studies (sestamibi scanning), has facilitated less invasive surgical techniques, such as minimally invasive parathyroidectomy. This has resulted in shorter average hospitalization stays and reduced postoperative recovery times. Loss of parafibromin and Rb expression and overexpression of galectin-3 can be distinguishing features of parathyroid carcinoma vs other parathyroid tumors.
The use of ioPTH with parathyroid hyperplasia requires more strict evaluation of ioPTH levels. Siperstein et al performed a prospective evaluation of ioPTH and bilateral neck exploration and found that up to 15% of cases will have additional "abnormal" glands that were not predicted by ioPTH or preoperative imaging. This study demonstrates the need for long-term follow-up of patients undergoing focused parathyroid surgery.
If parathyroid carcinoma is suspected, based on the severity of hyperparathyroidism or invasion of surrounding tissues by a firm parathyroid tumor, aggressive wide excision is indicated. This procedure should include ipsilateral thyroidectomy and en bloc excision of surrounding tissues as necessary.
Patterns of recurrence of cancer. The average time from initial surgery to the first recurrence of cancer is approximately 3 years but may be as long as 10 years. The thyroid gland is the usual site of involvement, with disease "seeding" in the neck a common pattern. Other sites of involvement include the recurrent nerve, strap muscles, esophagus, and trachea.
Distant metastases can be present at the time of initial surgery, or local spread to contiguous structures in the neck may be followed subsequently by distant metastases to the lungs, bone, and liver.
In a recent analysis, 85% of patients with parathyroid carcinoma were alive 5 years after diagnosis; death usually results from complications of the hypercalcemia rather than from the tumor burden.
Treatment of isolated metastases. Isolated metastases should be aggressively resected to enhance survival and control hypercalcemia. Liver-directed therapies can be considered to reduce tumor/hormonal burden.
Morbidity and mortality are generally caused by the effects of unremitting hypercalcemia rather than tumor growth. Medical treatment provides temporary palliation of hypercalcemia. Drugs used include bisphosphonates, such as pamidronate(Drug information on pamidronate) (60 to 80 mg every 4 to 6 days) or zoledronic acid(Drug information on zoledronic acid) (Zometa); calcitonin, at 4 to 8 IU/kg every 6 to 12 hours; mithramycin (plicamycin [Mithracin]), at 25 μg/kg every 4 to 6 days; and gallium nitrate (Ganite), at 100 to 200 mg/m²/d IV for 5 days. Cinacalcet (Sensipar), a calcimimetic that targets the calcium-sensing receptor on parathyroid cells and reduces parathyroid hormone secretion, is an FDA-approved oral treatment of hypercalcemia associated with parathyroid carcinoma (up to 90 mg bid) in patients who do not respond to surgery or other medical treatments.
Sidebar: A proof-of-concept study using denosumab (Xgeva) to treat hypercalcemia of malignancy is ongoing and may provide potential therapeutic options for hypercalcemia in patients with parathyroid carcinoma that do not respond to standard therapy (Hu et al: ASCO 2011; available at www.asco.org in the trials in progress section).
There is little evidence for an effect of adjuvant radiation therapy in achieving locoregional control. Some institutions have used surgical margin status to determine whether patients receive adjuvant radiation therapy including elective nodal irradiation.