Parathyroid Carcinoma

Background

Parathyroid carcinoma (PC) is a rare but ominous cause of primary hyperparathyroidism (HPT). It accounts for less than 1% of the cases of primary HPT. In a retrospective study of two European cohorts of primary HPT from 2005 to 2014, the incidence of PC in patients with HPT was 0.3% and 2.1%, respectively. This difference was perhaps related to selection and referral biases. In a systematic review of 22,225 cases of primary HPT reported from 1995 to 2003, PC accounted for 0.74%. Interestingly, the reported incidence appears to be higher in some countries, like Japan and Italy (around 5%). In Europe, the incidence was reported to be 1.25 to 2.0 cases per 10,000,000 persons. In the Surveillance, Epidemiology, and End Results (SEER) cancer registry data from 2000 to 2012, the incidence rate was 0.41. Due to its rarity and the paucity of large-scale published patient series, there is still a lack of understanding of the natural course and prognostic implications of this disease. In addition, there is still no clear consensus on its management and follow-up (see Chapter 65 Surgical Pathology of the Parathyroid Glands).

Although primary HPT is more commonly associated with females (4:1), there is no gender difference in PCs. Males may have a slightly worse prognosis. It is usually diagnosed after age 30, and the mean age of diagnosis is 50 years old, which is 10 years earlier than benign parathyroid adenomas.

Risk Factors and Etiology

The etiology of PC remains largely unknown. A few risk factors have been identified based on epidemiology studies; however, mechanisms and causal relationships still remain poorly understood. Recently, some advances in molecular biology have shed light on the plausible pathogenesis of PC. Clinical risk factors are reviewed here.

Clinical Presentation

Most PCs are functional and hypersecrete parathyroid hormone (PTH). Patients with a PC typically present with severe hypercalcemia with overt dehydration. Renal (32% to 70%) and bone disease (34% to 73%), gastrointestinal complications including ulcers and pancreatitis (15%), and even parathyroid crisis (12%) are relatively common. Concomitant renal and bone complications can be found in 50% of patients with PC at diagnosis. The serum calcium level is usually above 14 mg/dL (3.5 mmol/L), and serum PTH concentration can be 5- to 10-fold higher than the upper normal limit ( Table 64.2 ).

A palpable neck mass is present in approximately 50% of PCs, which is not found in benign parathyroid adenomas or hyperplasia unless there is a concomitant thyroid nodule. Invasion to surrounding structures is not uncommon (34% to 75%). Strap muscles and the surrounding soft tissues are most often involved by the tumor bulk. Invasion to the recurrent laryngeal nerve (RLN) is seen in approximately 7% to 13% of patients with a PC. Tracheal involvement occurs in 11% of the patients and esophageal or carotid sheath involvement occurs in 2% of patients. Distant metastases at presentation are uncommon. Ultimately, lymph node (LN) metastasis (< 5%) and distant metastasis (< 2%), usually involving liver, lung, and bone, may occur. Inferiorly located parathyroid glands are much more commonly affected than superiorly located glands. Multiglandular carcinoma is extremely rare with only a few case reports.

Occasionally, PC can be nonfunctional (2% to 7%). To date, only 32 cases of nonfunctional PC have been reported in the literature. An older age for presentation in 60 to 70 year olds is observed, and half of these patients are presented with a neck mass between 5 and 11 cm in size. Understandably, they are diagnosed at a more advanced stage, with more locally aggressive tumor and more distant metastasis to lungs, cervical LN, liver, and bone. Diagnosis of these patients is based entirely on histologic findings, as they are normocalcemic with normal levels of PTH. In contrast to the more typical functional PC, these patents usually die of mass effect and tumor burden rather than hypercalcemia.