22 Parathyroid Carcinoma
22.1 Introduction
Hypercalcemia in the presence of high parathyroid hormone (PTH) levels usually signifies the presence of hyperparathyroidism. When these calcium levels are extreme in nature, it may raise the concern for parathyroid carcinoma. This is a rare disease that can lead to death by hypercalcemia if not treated. Regardless of the rarity of disease, providers treating hyperparathyroidism should be aware of the unique features that are suggestive of a malignant process of the parathyroid glands. This disease may be difficult to distinguish from a parathyroid adenoma, but malignant parathyroid neoplasms can often be predicted by the pattern of presentation along with intraoperative findings. These indolent tumors behave differently than many head and neck malignancies, and the cause of death is most often related to the degree of hypercalcemia. Although the primary treatment goal should consist of complete surgical excision, residual tumor can persist for long periods of time. Even when surgical cure is no longer possible, managing the patient’s hypercalcemia is important. This may require resection of local, regional, or distant metastatic disease. When surgical resection is not possible, medical management of the hypercalcemia is necessary. This chapter discusses the presentation of parathyroid carcinoma as well as current concepts on its management.
22.2 Epidemiology
Parathyroid carcinoma was first described by DeQuervain in 1904. 1 It is interesting that this was a nonfunctioning tumor, whereas the vast majority of parathyroid carcinomas are functioning tumors producing significant levels of parathyroid hormone. 2 , 3 , 4 It wasn’t until 1933 that Sainton and Millot described the first functioning parathyroid carcinoma. 5 Though most parathyroid carcinomas are functioning tumors with severely elevated calcium levels, which aids the diagnosis, nonfunctioning tumors may not be diagnosed until they are more advanced. Without the extreme elevation of serum calcium assisting with the detection of the parathyroid malignancy, these may not be recognized until there is a palpable neck mass or it has invaded structures of the neck that affect voice or swallowing.
Parathyroid carcinoma affects approximately 0.005% of individuals per year according to a review of the 286 cases in the National Cancer Database by Hundahl and colleagues. 6 In a separate study, Lee and colleagues evaluated the Surveillance, Epidemiology, and End Results (SEER) cancer registry from 1998 to 2003. 7 They noted that the incidence of parathyroid carcinoma had increased by 60% in the latter half of the study. This increase in incidence may be related to improved rates of diagnosis, but the exact reason is unknown. This incidence also varies geographically per country. In locations such as Japan and Italy, the incidence has been reported as high as 5% of all cases of hyperparathyroidism. 8 , 9 However, the incidence in the United States is < 1% of all hyperparathyroidism cases. 10 There are many possible explanations for the geographic differences, including genetic differences, referral patterns, and diagnostic criteria, among others. Although this is a low percentage of patients, the diagnosis must be kept in mind when evaluating a patient with hyperparathyroidism, and understanding the presenting signs and symptoms is helpful in this process. In contrast to primary hyperparathyroidism, which has a 3 to 4:1 female to male distribution, parathyroid carcinoma affects males and females equally. 6 Most affected individuals are middle-aged, though cases have been reported from 12 to 90 years of age. 7 , 11 , 12 , 13 We outline epidemiological differences between individuals with primary hyperparathyroidism versus those with parathyroid carcinoma. The following conditions are associated with parathyroid carcinoma:
Neck irradiation
Hyperparathyroidism—jaw tumor syndrome
Familial isolated hyperparathyroidism
Multiple endocrine neoplasia type 1
Although parathyroid carcinoma is rare, it must be considered in all individuals with primary hyperparathyroidism. Certain warning signs on presentation make the diagnosis more likely. These findings will be presented later in this chapter.
22.3 Tumor Pathogenesis
Parathyroid carcinoma may develop spontaneously or occur as part of a familial syndrome. Several conditions have been associated with spontaneous development of parathyroid carcinoma as already mentioned. Neck irradiation affects parathyroid glands and increases the likelihood of parathyroid disease, 14 , 15 and it has been associated with many cases of parathyroid carcinoma. 16 , 17 Koea and Shaw found that 1.9% of parathyroid carcinomas were associated with previous radiation. 18 This pathway of parathyroid carcinogenesis has also been suggested in at least one animal study where parathyroid carcinoma was seen in mice after exposure to neck irradiation. 19 This is not surprising because radiation is known to have carcinogenic effects years after exposure. Parathyroid carcinoma has also been associated with primary hyperparathyroidism, 4 , 6 , 20 secondary hyperparathyroidism, 21 and end-stage renal disease. 22 However, the rarity of disease makes strong correlations difficult.
Familial conditions associated with parathyroid carcinoma include familial isolated hyperparathyroidism, multiple endocrine neoplasia type 1 (MEN1), and hyperparathyroidism–jaw tumor (HPT-JT) syndrome. Familial isolated hyperparathyroidism is an autosomal-dominant disease that is distinct from MEN syndromes. 23 It can have pronounced elevations of calcium and parathyroid hormone levels, and it is associated with an increased risk of developing parathyroid cancer. MEN1 is another hereditary syndrome that has an association with parathyroid carcinoma. 24 , 25 , 26 Some studies have suggested that the genetic mutations associated with MEN1 are responsible for the increased risk, but the definitive evidence for this causality is lacking at the present. 27
HPT-JT syndrome is another autosomal-dominant syndrome that has ossifying jaw tumors, renal neoplasms, uterine tumors, and hyperparathyroidism. The genetic defect associated with this disease is a mutation in the HRPT2 gene that codes for parafibromin. 28 This protein is considered to be a tumor suppressor because it can induce apoptosis. This incidence of parathyroid carcinoma has been reported to be as high as 15% in this condition. 2 , 29
Sporadic cases of parathyroid carcinoma are also frequently associated with HRPT2 gene mutations. Multiple studies have found a high rate of HRPT2 gene mutations independent of HPT-JT syndrome. 30 , 31 Because parafibromin inactivation is linked to a large portion of parathyroid carcinomas, this mutation is considered a marker for parathyroid carcinoma. This gene may be involved in the majority of cases of sporadic parathyroid carcinoma.
22.4 Clinical Presentation
22.4.1 History
Parathyroid carcinomas are rare, typically slow-growing tumors with a tendency to recur locally and metastasize late. As previously stated, parathyroid cancer is equally distributed between men and women, whereas parathyroid adenomas and hyperplasia are three times more common in women. 32 Some studies suggest these tumors may present earlier in life compared with benign hyperparathyroidism. The average age at presentation is between 40 and 60, though it has been reported across a wide age range. 7 , 33
Nearly all tumors are functional (95%) and result in severe primary hyperparathyroidism. Typically, serum calcium and PTH levels are significantly elevated, with 70% having serum calcium concentrations > 14 mg/dL, and patients are very often symptomatic from their hypercalcemia. 12 , 34 Frequently, patients will present with both bone and kidney disease. In addition, patients can present with voice complaints and recurrent laryngeal nerve dysfunction, which, when coupled with primary hyperparathyroidism, should raise concern for parathyroid cancer. However, some parathyroid cancers may not be functional and present only with symptoms related to local tumor invasion.
Symptoms of hypercalcemia are not unique to parathyroid carcinoma. In fact, < 1% of patients with hypercalcemia and only 0.5 to 2% of patients with hyperparathyroidism will have cancer of the parathyroid gland. 35 However, patients with cancer typically have severe symptoms. Hypercalcemia can cause renal, bone, neuromuscular, rheumatologic, gastrointestinal, and cardiovascular symptoms, as well as form calcium deposits in the skin, cornea, and lungs (Table 22.1). 36 Although these symptoms may raise the level of suspicion for cancer, the degree of hypercalcemia should be the clinician’s best warning sign.
22.4.2 Physical Findings
Approximately 40% of patients with parathyroid cancer will present with a neck mass. 37 This occurs in the typical location for parathyroid glands: just off midline, on either side, and low in the neck. A neck mass in this location can be confused with level IV cervical lymphadenopathy or a thyroid nodule. Nonfunctional parathyroid carcinomas also most commonly present with a neck mass. These patients remain normocalcemic and usually have more advanced-stage disease at presentation, and their tumors are more aggressive. In contrast to patients with functional parathyroid cancers, patients with nonfunctional tumors die from mass effect and tumor burden, rather than from hypercalcemia. 34
Approximately 10% of patient will present with recurrent laryngeal nerve dysfunction. 12 Vocal fold paresis and paralysis symptoms include dysphonia, a hoarse or breathy voice, shortness of breath, and/or aspiration. The diagnosis is made by direct or indirect laryngoscopy demonstrating unilateral decreased or absent movement of the vocal fold.
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