Elsevier

Seminars in Oncology

Volume 37, Issue 6, December 2010, Pages 580-590
Seminars in Oncology

Endocrine cancer
Parathyroid Cancer

https://doi.org/10.1053/j.seminoncol.2010.10.013Get rights and content

Parathyroid cancer is an uncommon malignancy and rare cause of primary hyperparathyroidism (HPT) with a high morbidity and patient death in advanced cases usually resulting from intractable hypercalcemia. Inactivation of the HRPT2/CDC73 gene, encoding the putative tumor-suppressor protein parafibromin and discovered in the context of the hyperparathyroidism–jaw tumor (HPT-JT) syndrome, is a common, somatic event in most parathyroid cancers. Approximately 25% of patients with apparently sporadic parathyroid cancer carry germline HRPT2/CDC73 mutation. Germline DNA analysis for HRPT2/CDC73 mutation is recommended in all patients with parathyroid cancer because of the potential benefit for first-degree relatives, who should nevertheless undergo serum calcium screening. The histopathologic diagnosis of parathyroid cancer is nonspecific unless vascular, lymphatic, capsular, or soft tissue invasion is seen, or metastases are clinically evident. Immunohistochemical analysis of parathyroid tumors for loss of parafibromin expression offers promise as a diagnostic tool. En bloc tumor resection offers the highest chance of cure in patients with suspected parathyroid carcinoma. No adjuvant chemotherapy regimen has yet proven effective, and the role of local adjuvant radiotherapy is being evaluated. Metastatic disease can be palliated with surgical debulking. Medical therapy with the calcimimetic cinacalcet and bisphosphonates can ameliorate hypercalcemia in patients with inoperable disease.

Section snippets

Epidemiology and Demographics

Parathyroid carcinoma is a rare cause of primary HPT. Early single-institution case series suggested that it was responsible for 2% to 5% of all cases,1, 2, 3 but these figures are likely overestimates resulting from referral and publication biases, and/or the use of variable diagnostic criteria. Data from the largest single-institution study, a comprehensive literature review, and recent tumor registries indicate that it accounts for less than 1% of all cases in most parts of the world.4, 5, 6

Etiology and Pathophysiology

The etiology of parathyroid cancer, like that of other malignancies, likely involves the interaction of multiple environmental and genetic factors. Exposure to radiation, especially during childhood, increases the risk of benign parathyroid disease,10, 11, 12 as well as concurrent thyroid and parathyroid neoplasia,13, 14, 15 but whether such exposure plays an etiologic factor in parathyroid carcinoma remains unclear. Case reports and retrospective identification of several cases of parathyroid

Clinical Presentation of Parathyroid Cancer

The clinical presentation of parathyroid carcinoma is usually related to symptoms caused by the effects of markedly elevated serum PTH and hypercalcemia, rather than mass effects due to local infiltration or distant metastases. Systemic symptoms of hypercalcemia include fatigue, weakness, weight loss, anorexia, nausea, vomiting, polyuria, polydipsia, and depression. Manifestations of hyperparathyroid bone disease include osteitis fibrosa cystica, subperiostial bone resorption, “salt and pepper”

Laboratory Testing and Imaging in Parathyroid Cancer

No single laboratory finding is diagnostic of parathyroid carcinoma, but certain findings may offer clues that it ought to be included in the differential diagnosis of a patient presenting with primary HPT. The typical serum calcium in parathyroid cancer patients at presentation reported in the last three decades is 14.6–15.0 mg/dL,3, 4, 72 and approximately 60% to 65% of patients present with a calcium level greater than 14 mg/dL.3, 4, 72 A subset of functional parathyroid cancers demonstrate

Surgical Findings

The diagnosis of parathyroid carcinoma is often suspected due to characteristic findings at the time of initial surgery. The tumor usually has a firm or hard consistency, is sometimes lobulated, and is usually surrounded by a dense fibrous capsule that gives it a white, grey-white, or grey-brown hue. Parathyroid carcinoma often adheres to and infiltrates adjacent structures.1, 84, 85 The most common sites of local invasion are the ipsilateral thyroid gland, strap muscles, ipsilateral recurrent

Diagnosis

In the absence of obvious metastatic disease the distinction between parathyroid carcinoma and adenoma is difficult using microscopic histopathologic criteria. The principal histologic features that distinguish parathyroid carcinoma from adenoma, identified by Schantz and Castleman based on their examination of 70 parathyroid cancers, were the presence of parenchymal mitoses, trabeculated parenchyma including often thick fibrous bands, and capsular or vascular invasion.90 Because any of these

Nonfunctional Parathyroid Carcinoma

Nonfunctional parathyroid carcinoma is extremely rare. Fewer than 20 cases have been reported in the literature since 1929,101 including a case in the context of FIHP with germline mutation of HRPT2/CDC73.31 Patients are normocalcemic at diagnosis and, in all those in whom it was measured, PTH is within the normal range. About 80% present with a neck mass, and other common findings at presentation include dysphagia, hoarseness or vocal cord paralysis, and dyspnea.101, 102 Grossly, tumors are

Surgical

Most investigators recommend en bloc resection at the initial surgery to offer the best chance for cure. This approach requires recognition of the possibility of malignancy during exploration. Adequate surgical excision requires removal of the ipsilateral thyroid lobe andisthmus, skeletonization of the trachea, and excision of any skeletal muscle intimately related to the tumor. The surgeon must be careful not to rupture the capsule of the tumor to avoid seeding of the surgical field.1 If the

Natural History of Parathyroid Cancer

Following initial surgery, anywhere from 25% to 80% of patients with parathyroid cancer develop local recurrence. Recurrence typically is detected 2 to 4 years after the initial operation, and these patients have a median survival on the order of 5 to 6 years after the initial diagnosis.2, 3, 4, 6, 71, 76, 122 Approximately 25% of patients develop distant metastases at some point during the disease. Rarely, they are present at the time of diagnosis. At the other extreme, metastases have been

Conclusions

Parathyroid carcinoma is a rare endocrine malignancy whose recognition requires a high index of suspicion based on clinical features, such as a palpable neck mass and severe primary HPT. Histologic features can be nonspecific. Diagnosis is definitive when local invasion or lymph node or distant metastases are demonstrated. Somatic mutation of HRPT2/CDC73 is a common finding in sporadic parathyroid carcinomas, and because some 25% of apparently sporadic cases harbor germline HRPT2/CDC73

Acknowledgments

The authors thank Dr Stephen J. Marx for his critical reading of the manuscript, and our colleagues Drs Lee S. Weinstein, Monica C. Skarulis, and Sunita K. Agarwal of the National Institute of Diabetes and Digestive and Kidney Diseases for their ongoing support and encouragement. The Intramural Research Program of the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases supported this research.

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    The Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute supported this research.

    Conflict of Interest Statement: The authors declare that they have no conflicts of interest, or competing financial or personal relationships that could inappropriately influence the content of this article.

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