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 the increased incidence of parathyroid cancer in studies such as this from Japanese centers.

Parathyroid cancer is biochemically functional in 96% of cases. For this reason, patients typically present with signs and symptoms of the metabolic disturbance of HPT and hypercalcemia rather than with those caused by local tumor growth or metastatic disease. Renal calculi occur in 30% to 64% of patients, and renal insufficiency is seen in up to 84% of patients because of the increased renal clearance of calcium.6 Other symptoms include polydipsia, polyuria, dehydration, fatigue, and weakness. Abdominal complications of hypercalcemia, including peptic ulcer disease (10% to 18% of cases) and acute pancreatitis (10% of cases), may also occur.6 Patients with parathyroid cancer may present emergently with a hypercalcemic crisis, characterized by severe dehydration, renal insufficiency, and reduced level of consciousness, in 8% to 17% of cases.3,12

Skeletal complications of HPT occur frequently in patients with parathyroid cancer. Radiographic changes consistent with osteitis fibrosa cystica, such as bone cysts and brown tumors of bone, are seen in 46% to 91% of patients as a result of the increased resorption of skeletal calcium, and symptoms of bone pain, deformity, or pathologic fracture may also occur.3,6 This is in sharp contrast to benign causes of HPT, in which such clinically significant bone disease occurs in only 5% of patients in North America. Parathyroid cancer should be suspected in all patients with a rapid onset of symptoms of HPT, severe hypercalcemia (>3.5 mmol/L or >14 mg/dL), or end-organ complications of HPT. Symptoms of local tumor growth, such as hoarseness of the voice from recurrent laryngeal nerve (RLN) involvement, are present in only 1.6% of patients.12

Unlike benign PHPT, parathyroid cancer may form a mass large enough to be palpable on physical examination in 21% to 45% of cases.6,12,13 In most patients with HPT in whom a neck mass is palpable, it is because of a thyroid nodule or other cause unrelated to parathyroid cancer; however, a high index of suspicion for this malignancy should be maintained in this setting. Clinical features that are suspicious for parathyroid cancer and that should alert the treating physician to this possible diagnosis are shown in Table 11-1.

There is no generally accepted staging system for parathyroid cancer. Local invasion into surrounding structures is seen in 34% to 70% of patients at the time of operation with the adjacent lobe of the thyroid, overlying strap muscles, and adjacent soft tissues involved most commonly.3,10,14 Invasion into the esophagus occurs in 2% to 14%, the trachea in 11%, the RLN in 7% to 13%, and carotid sheath structures in 2% of patients.3,6,10 Regional nodal metastases from parathyroid cancer are uncommon, with clinical involvement of regional nodes present in only 3% to 8% of cases.2,3,10,13 When involved, spread to both the central and lateral compartments of the neck may occur.6,10 Distal metastatic disease was documented in 4.5% of cases in the SEER database and has been reported in 5% to 11% of cases in smaller series.2,3 In a study of 27 patients with parathyroid cancer, distant metastases were present in 3.7% of patients at presentation but developed in 22% during long-term follow-up.10 The lungs, bones, and liver are the most frequent sites of distant metastatic disease. Rare sites of metastatic disease include the pleura, pericardium, and pancreas.

Parathyroid cancer arising primarily from a gland in a mediastinal location has been reported rarely, accounting for 2.3% of cases.6 Parathyroid cancer is nonfunctional in only 4% of patients.5 In this rare clinical scenario, parathyroid hormone (PTH) and calcium levels are not elevated, and the tumor presents as a locally invasive neck mass or with complications of metastatic disease.

The evaluation of patients with suspected parathyroid cancer involves biochemical and imaging investigations (Figure 11-1). The biochemical features of parathyroid cancer are those associated with HPT. Although parathyroid cancer cannot be differentiated from benign causes of HPT on biochemical criteria alone, parathyroid cancer is associated with elevation of serum calcium and PTH to levels greater than those normally associated with benign disease. Serum calcium is elevated in all cases of functional tumors, with mean levels of 3.4 to 3.65 mmol/L (13.5 to 14.6 mg/dL). Serum calcium is highly elevated, with values exceeding 3.5 mmol/L (14 mg/dL) in 39% of cases. Serum phosphate is reduced in 71% of cases. Intact PTH is elevated to levels three to 10 times greater than the normal range in patients with functional tumors. Elevation of PTH differentiates parathyroid cancer from other causes of hypercalcemia (e.g., disseminated malignancy or PTH-related peptide secreting tumors) in which PTH levels should be suppressed. Alkaline phosphatase levels may be elevated because of the presence of PHPT-related bone disease, and serum creatinine may be elevated because of complications of renal insufficiency.