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Carcinoma of the parathyroid gland is a rare endocrine malignancy, accounting for only 0.005% of all cancer registrations in the US National Cancer Database (NCDB).1 Using information from the Surveillance, Epidemiology and End Results (SEER) database, the incidence in the United States is estimated to be 5.73 per 10 million population, increasing by 60% from 1988 to 2003.2 Parathyroid cancer accounts for 0.5% to 1% of cases of primary hyperparathyroidism (PHPT) in series from Western nations and 2.8 to 5% of cases in Japan.3–6 It affects males and females equally and is evenly distributed within different socioeconomic and racial groups in the NCBD.1 The mean age of diagnosis of parathyroid cancer is 47 to 56 years, and 73% of cases occur in patients older than age 45 years.1,2

Few risk factors have been identified for parathyroid cancer. Hyperparathyroidism–jaw tumor (HPT-JT) syndrome is a familial condition with an autosomal dominant pattern of inheritance caused by an inactivating mutation of the tumor suppressor gene HRPT2. The HRPT2 gene is located on chromosome 1q, codes for the nuclear protein parafibromin, and is thought to be involved in cell growth cycle regulation.7,8 Affected HPT-JT family members develop PHPT secondary to parathyroid adenomas, fibro-osseous tumors of the mandible and maxilla, renal hamartomas, renal stromal cell tumors, and cystic disease of the kidneys.8 Patients with HPT-JT have a markedly increased risk of parathyroid cancer, which is seen in 10% to 17% of patients.7,8 The HRPT2 gene is also involved in the pathogenesis of sporadically occurring cases of parathyroid cancer, with somatic mutation of this gene identified in 67% of parathyroid cancers and germline mutations identified in 20% of patients with parathyroid cancer without a family history of HPT-JT.9

Although parathyroid cancer has been reported in patients with other familial forms of hyperparathyroidism (HPT), namely multiple endocrine neoplasia syndrome types 1 and 2A and familial isolated hyperparathyroidism, there is no evidence to associate these conditions with an increased risk of this malignancy. A family history of HPT is present in only 4.7% of individuals with parathyroid cancer.6 A history of previous head and neck irradiation is present in up to 7.4% of patients with parathyroid cancer, and this has also been suggested as a risk factor for this malignancy.10

Parathyroid cancer has been reported in patients with chronic renal failure receiving hemodialysis.11 It has been suggested that patients with end-stage renal disease (ESRD) are at increased risk for this malignancy occurring within hyperplastic or adenomatous parathyroid glands because of chronic overstimulation. Such an association has not been proven, and if ESRD was a strong risk factor for parathyroid carcinoma, then the incidence of this malignancy would be expected to be much higher in North America than is presently seen. It is conceivable that differing pathologic criteria for the diagnosis between Japan and North America may account for ...

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