Parathyroid carcinoma is a rare malignant neoplasm of the parathyroid causing parathyroid hormone (PTH)–dependent hypercalcemia. Diagnosis is difficult so a high level of suspicion must be maintained, particularly in patients with markedly elevated serum calcium levels, local symptoms, and elevated PTH levels. Presence of these or clinical suspicion at surgery should allow consideration for a more aggressive surgical resection at the initial surgery. In this chapter we review current information on genetics and features of parathyroid carcinoma, and treatment options in the perioperative period.

Parathyroid carcinoma arises from parenchymal cells of the parathyroid. It is a rare neoplasm with an incidence of 5.73 per 10 million, that is, <1% of the population.^1–3 It accounted for 0.005% of all cancers in the National Cancer Database from 1985 to 1995.⁴ A review of the Surveillance, Epidemiology, and End Results (SEER) cancer registry identifying patients with parathyroid carcinoma from 1988 to 2003 in the United States demonstrated a 60% rise in incidence of parathyroid carcinoma from 3.58 to 5.73 per 10 million.² A review of the European Cancer registry from 1995 to 2002 demonstrated an incidence of 0.02% per 10 million among 27 European countries, emphasizing the rarity of this cancer.⁵ Approximately 1% of hyperparathyroidism is attributed to parathyroid carcinoma, and retrospective studies have demonstrated an even distribution between men and women.⁴ Benign parathyroid disease has a female predominance (3–4:1), occurring a decade later than parathyroid carcinoma which usually manifests at an average age of 48 years.^1,3,6 Parathyroid carcinoma rarely occurs in children.^7,8

Risk factors associated with the occurrence of parathyroid carcinoma include membership in kindred of familial parathyroid carcinoma or hyperparathyroidism-jaw tumor (HPT-JT) syndrome.¹ HPT-JT syndrome is an autosomal dominant disorder due to HRPT2 gene mutation, with predisposition for multiglandular parathyroid neoplasms coupled with the presence of fibro-osseous lesions of the mandible and maxilla and renal lesions. Fifteen percent of HPT-JT syndrome patients develop parathyroid carcinoma.^1,9

Parathyroid carcinoma has been seen in several patients exposed to chronic parathyroid stimulation in secondary hyperparathyroidism, especially from chronic renal failure, suggesting that this persistent stimulation results in malignant transformation of hyperplastic parathyroid cells and the development of parathyroid carcinoma.^1,10–13

In a review by Koea and Shaw,¹⁴ a history of neck radiation was found in 1.4% of their parathyroid carcinoma cases. This review also demonstrated a possible geographic distribution with an incidence of 1% in the United States and 5% in Japan and Italy of all patients with hyperparathyroidism;¹⁵ however, it is unclear if the higher incidence in Japan and Italy is due to differentiation of disease susceptibility or due to a different diagnosing criteria.⁴

Parathyroid carcinoma arises usually from normal parenchymal cells of the parathyroid gland. It usually arises in a single gland, but can infiltrate locally or metastasize to other organs, especially thyroid and lungs, and can be more widespread to the liver, bones, adrenal glands, and pancreas.¹ The average age of occurrence is 48 years with many patients incurring an indolent course with recurrences 15 to 20 years after initial diagnosis. However median survival from first recurrence is 28 months.¹⁶ The lethality of the disease is more likely due to hypercalcemia rather than from the tumor itself, with morbidity and mortality due to metabolic complications of the hypercalcemia including uremia, arrhythmias, pancreatitis, and wasting.^1,17,28

As with benign parathyroid tumors, the pathogenesis of parathyroid carcinoma remains incompletely elucidated. Normal parathyroid cells have a low rate of turnover. One study demonstrated an increase in proliferation in cancer cells as compared to benign tumors. A study by Fernandez-Ranvier et al¹⁸ demonstrated a high Ki-67 proliferative index that was found exclusively in parathyroid carcinoma samples as compared to its benign counterparts. High Ki-67 proliferative index was also a marker for metastasis. Aneuploidy was associated with a poorer prognosis compared with diploid tumors.^1,19,20

Cryns et al²¹ showed that parathyroid carcinoma displayed somatic loss of DNA at the Retinoblastoma (Rb) locus with associated decreased immunohistochemical staining of retinoblastoma protein.¹ Allelic loss of p53 and abnormal p53 protein expression was also described by Cryns et al²² in a small number of parathyroid carcinoma cases. Although parathyroid carcinoma is not a feature of multiple endocrine neoplasia type I, Haven et al²³ identified a missense and two frameshift menin mutations in 3 of 23 sporadic parathyroid carcinoma cases, suggesting that menin may be involved in the development or progression of parathyroid carcinoma.

Cyclin D1, a cell cycle regulator, is also overexpressed in parathyroid carcinoma. This could be due to rearrangement of the parathyroid regulatory region and PRAD1 gene on chromosome 11 encoding cyclin D1. Cyclin D1 overexpression may also be due to loss of parafibromin, which has been shown to negatively regulate cyclin D expression.^1,24,25 Parafibromin (cdc73) is a tumor suppressor protein encoded by the HRPT2 gene on chromosome 1q25, and is a part of the RNA polymerase transcription regulatory PAF1 complex involved in inhibiting c-myc proto-oncogene. Mutation in HRPT2 is found in more than half of HPT-JT and sporadic parathyroid carcinoma cases. The exact mechanism by which loss of parafibromin leads to parathyroid carcinoma remains unknown.^1,24–28 Due to the high percentage of sporadic carcinoma patients with a mutation in HRPT2, it may suggest an incomplete expression of hyperparathyroid jaw syndrome and therefore a potential benefit for screening of first-degree relatives.^29,30 Thus patients with sporadic parathyroid carcinoma should be screened for CDC73/HRPT2. ³¹ A study evaluating a French national cohort of patients with parathyroid carcinoma identified 13 different mutations of the HRPT2 gene, while 35% patients were noted to have gross deletion of the gene.³²

A microarray analysis of parathyroid carcinoma and normal tissue demonstrated elevated PTH expression in parathyroid carcinoma, but less than its paired normal tissue. Calcium sensing receptor, cyclin D1, and ubiquitin carboxyl terminal esterase L1 (UCHL1) were also found to be upregulated in carcinoma, while a separate study also saw increased levels of amyloid β precursor protein and E-cadherin.^1,33 The up-regulation of UCHL1 in parathyroid carcinoma causes an increase in protein PGP9.5, with a resulting loss of nuclear parafibromin expression.^1,34 Table 39-1 shows various levels of expression of specific genes in parathyroid carcinoma versus normal parathyroid. However, larger studies are still required for full genetic profiling.

Most parathyroid carcinomas present with typical symptoms of primary hyperparathyroidism making it hard to differentiate from benign disease on a clinical basis. Common manifestations are skeletal (presenting as depression, muscle weakness, fatigue, and pathological fractures), and renal sequel (polydipsia, polyuria, nephrolithiasis, and renal insufficiency). Patients also present with gastrointestinal symptoms ranging from nausea, anorexia, constipation, or vague abdominal pain. The one notable difference between primary hyperparathyroidism and parathyroid carcinoma is that the latter often display severely elevated average calcium levels as well as more elevated PTH levels. Serum calcium levels are often greater than 14 mg/dL with accompanying PTH levels several fold higher than the normal range; because of this patients will often present with symptomatic hypercalcemia, with up to 15% presenting with dehydration and/or altered mental status. Another commonly seen presentation is a palpable neck mass, reported in 34% of patients in one series of 163 patients. Nonfunctional parathyroid carcinomas are rare, with a reported 19 cases over 80 years. Unilateral vocal paralysis with hypercalcemia in a patient without previous neck operation should be highly suspicious for cancer.^1,28,35–41

No histopathological markers have yet been identified for parathyroid carcinoma, with the primary presenting biochemical marker being severe hypercalcemia. In a review of 133 patients, 65% had serum calcium of >14 mg/dL, while ranging between 10 and 24 mg/dL. Other significant findings are elevated PTH, commonly 3 to 10 times the normal limit, with normal renal function, high alkaline phosphatase, hypophosphatemia, and metabolic acidosis.^1,37,38

Preoperative imaging for parathyroid adenoma is usually the same as for patients with carcinoma. Technetium-99m-sestamibi scanning can aid in localizing the parathyroid gland and is similarly useful in detecting metastatic parathyroid carcinoma but cannot alone differentiate cancer from benign adenomas.^1,42,43 Ultrasonography is also utilized commonly in these patients, and in a study of 16 patients with parathyroid carcinoma and 61 patients with adenoma Hara et al⁴⁴ found that large size, irregular borders, and inhomogeneous features on ultrasound were features consistent with parathyroid carcinoma. This report also found that 94% of the 16 patients with carcinoma had a depth-width ratio (DW) of >1 compared to 5% of the 61 patients with adenoma. Therefore, large tumors with irregular margins, inhomogeneous, and DW ratio of >1 should arise suspicion for parathyroid carcinoma.¹ A retrospective review from 2004 to 2009 of 69 patients revealed benign tumors to have a median size of 23 mm (ranging from 15 to 53 mm) and malignant tumors with median size of 38 mm (ranging from 20 to 75 mm).^38,45

Computed tomography (CT) of chest and abdomen can help distinguish recurrence or metastases. Parathyroid scintography identified 67% of recurrences, whereas CT identified only 53% in a series of eight patients with recurrent parathyroid carcinoma. Incongruent data were noted in 78% of the cases, and therefore the use of both scans is recommended in preoperative planning for recurrent parathyroid carcinoma.^1,46

Upon suspicion of a diagnosis of parathyroid carcinoma through biochemistry and radiographic imaging, biopsy is not advised for resectable cases to avoid disrupting tumor capsule leading to tumor implantation. However, biopsy can be used in recurrent or metastatic disease to establish scar from recurrence as the disease is presumed to have already spread.³⁸