Parathyroid carcinoma is a rare malignant neoplasm of the parathyroid gland that is affecting approximately 1% of all patients with primary hyperparathyroidism (PHPT). It was first described by De Quervain in 1904 and continues to defy diagnosis and treatment because of its rarity, overlapping features with benign parathyroid disease, and lack of distinct characteristics. It may occur sporadically or as a part of a genetic syndrome. Parathyroid carcinoma commonly has an indolent growth with a tendency for local invasion, and it occurs with equal frequency in men and women. In many cases, because of the rarity of the disease and clinical features mimicking benign parathyroid pathology, preoperative diagnosis of parathyroid carcinoma is difficult. In addition, the pathologic diagnosis of malignancy is challenging; however, severe hypercalcemia combined with high parathyroid hormone levels and gross operative findings should arouse suspicion of parathyroid carcinoma.
The etiology of parathyroid carcinoma is poorly understood. There is a well-described genetic predisposition. Parathyroid cancer has been associated with a rare autosomal dominant inherited disorder known as hyperparathyroidism–jaw tumor syndrome. In this condition, affected persons develop primary hyperparathyroidism and ossifying fibromas of the mandible and maxilla and, less commonly, renal lesions such as cysts, hamartomas, or Wilms tumors. Approximately 10% to 15% of affected persons develop parathyroid cancers. Hyperparathyroidism–jaw tumor syndrome is resulted from germline mutations in the tumor suppressor gene CDC73 (formerly HRPT2), located on chromosome 1. Parathyroid cancer has been rarely reported in familial isolated hyperparathyroidism and multiple endocrine neoplasia type 1 and type 2A syndromes.
More than 90% of parathyroid carcinomas are hormonally functional and hypersecrete parathyroid hormone (PTH). The majority of patients exhibit strong symptomatology of hypercalcemia at presentation. As opposed to benign primary hyperparathyroidism, patients with parathyroid carcinoma are severely symptomatic at presentation from severe hypercalcemia. These include severe nephrolithiasis, nephrocalcinosis, and impaired renal function in up to 80% of affected persons and severe bone involvement in up to 90%, recurrent severe pancreatitis and peptic ulcer disease. Bone disease includes osteitis fibrosa cystica, diffuse osteopenia, or pathologic fractures from extreme osteoporosis. Other symptoms include fatigue, loss of concentration, malaise, bone pain, polydipsia, polyuria, and depression. A palpable neck mass can be present in 30% to 75% of patients with parathyroid carcinoma, a finding that is quite rare in benign disease. Hoarseness may develops as a result of recurrent laryngeal nerve palsy. Enlarged, palpable lymph nodes can also be a result of metastatic disease. When patients develop marked hyperparathyroidism, they may progress to hypercalcemic crisis, also known as parathyrotoxicosis. This condition presents with anorexia, nausea, vomiting, constipation, acute pancreatitis, shortened QT interval, apathy, drowsiness, and coma, and, if left untreated, it can lead to death.
Diagnosis of parathyroid carcinoma is difficult to establish preoperatively because of its rarity, lack of definitive diagnostic markers and overlapping clinical features of benign primary hyperparathyroidism. As a result initial surgical treatment is inadequate essentially leading to disease recurrence where complete cure is unlikely. Parathyroid carcinoma should be suspected in the presence of markedly elevated parathyroid hormone levels (>5 times the upper limit of normal) and serum calcium concentrations (usually more than 14 to 15 mg/dL). Imaging techniques such as neck ultrasound and 99mTc sestamibi scan can help localize disease, but they are not specific for the cancer and not useful in the assessment of malignancy. PET CT has been shown to be usefull for the detection of metastatic parathyroid cancers. Fine needle aspiration (FNA) biopsy of the parathyroid gland prior to initial operation is not recommended due to technical difficulty in differentiating benign and malignant disease on cytology specimens and the possible associated risk of tumor seeding from the needle track.
Complete, En bloc surgical resection of the tumor with clear margins remains the best chance of cure. Although prolonged survival is possible with recurrent or metastatic disease, cure is rarely achievable. Persistent or recurrent disease occurs as high as in 50% to 80% of patients with parathyroid carcinoma. Surgical resection is also the primary mode of therapy for recurrence since it can offer significant palliation for the metabolic derangement caused by hyperparathyroidism and allows hypercalcemia to become more medically manageable, but reoperation is rarely curative and eventual relapse is likely. Efficacy of adjuvant therapies, such as radiotherapy and chemotherapy, in management of persistent, recurrent, or metastatic disease has been disappointing. Chemotherapy and external beam radiation treatments have been generally ineffective in the treatment of parathyroid carcinoma. Typically, these patients require repeated operations that predispose them to accumulated surgical risks with each intervention. In inoperable cases, few palliative treatment options exist, although treatment with calcimimetics can effectively control hypercalcemia in some patients. Most patients ultimately succumb to complications of hypercalcemia rather than from tumor burden or infiltration.
The reported survival rate is less than 50% to 85% at 10 years. Local recurrence, after surgery with en bloc resection, occurs at regional lymph nodes in 30% (between 22% and 60%) of cases, while distant metastases most frequently involve the lungs, liver, and bone. Despite recurrences, prolonged survival is possible with aggressive resection and medical management. Adverse prognostic factors for survival are initial management with simple parathyroidectomy alone, the presence of nodal or distant metastatic disease at presentation, nonfunctioning parathyroid carcinoma, lymph node or distant metastases, number of recurrences, higher calcium level at recurrence, and a high number of calcium-lowering medications. Although prolonged survival is possible in patients with recurrent disease, cure is unlikely. A comprehensive multidisciplinary approach with appropriate initial surgery, selective use of radiation therapy, and medical treatment for hypercalcemia offers patients with parathyroid carcinoma the best chance of cure.
Hyperparathyroidism-jaw tumor syndrome
Hyperparathyroidism-jaw tumor syndrome is a rare, autosomal-dominant, disorder characterized by the development of primary hyperparathyroidism secondary to parathyroid tumors in approximately 90% of patients, and 35% of patients may also develop ossifying fibromas of the mandible and/or maxilla. Less commonly patients may developed renal lesions (Wilms tumors, polycystic disease, hamartomas, and adenocarcinomas) and uterine tumors. Disease develops secondary to germline-inactivating mutations of the tumor suppressor gene HRPT2/CDC73. The youngest reported case of PHPT in a family diagnosed with hyperparathyroidism-jaw tumor syndrome is in a 7-year-old child.
Primary hyperparathyroidism in patients with this syndrome is more aggressive disease compare to sporadic primary hyperparathyroidism, with frequent multiglandular involvement, increased risk of persistent/recurrent disease, and a higher frequency of parathyroid carcinoma and metastasis. However, more recent studies identified multiglandular involvement in 13.2% of patients, biochemical recurrence in 17.6–22.3%, longer disease-free intervals (mean, 13.7 years), and fewer cases of parathyroid carcinoma (4.4–24.3%).
Given their high susceptibility to parathyroid cancer, there is long-term follow-up in patients with hyperparathyroidism-jaw tumor syndrome is essential. Frequent monitoring to detect the potential development of parathyroid carcinoma is important part of follow up process. Family members of affected patients should be offered genetic counseling and testing for a CDC73 germline mutation. Recommendation for genetic screening within affected families should be started at 5 years of age. Given the genetic predisposition and high cancer risk, bilateral neck exploration to assess all 4 parathyroid glands with en bloc resection of enlarged glands suspicious for cancer would serve these patients best.
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