Parathyroid Carcinoma

Parathyroid carcinoma is a rare malignant tumour of the parathyroid glands, responsible for under 1% of primary hyperparathyroidism. The incidence is about 1 in 3 to 6 million each year, with equal frequency in men and women.

Most cases are sporadic. Germline variants of CDC73 (HRPT2) are found in about 15 to 30% of patients, including those with hyperparathyroidism jaw tumour syndrome and familial isolated hyperparathyroidism. Rare cases occur in MEN1 and MEN2A.

It presents with severe hypercalcaemia (often over 3.5 mmol/L) and a high parathyroid hormone. Recurrence after resection is frequent (about 50% over 5 years) and death usually arises from the metabolic effects of hypercalcaemia, not tumour bulk.

Pathophysiology.

Inactivation of the tumour suppressor parafibromin (CDC73) and other genomic changes drive uncontrolled growth and hormone production. Tumours invade the thyroid and surrounding tissue and spread to lymph nodes, lung, liver and bone.

Severe hypercalcaemia causes dehydration, kidney injury, pancreatitis and arrhythmia.

• Severe hypercalcaemia: polyuria, thirst, nausea, vomiting, constipation, weakness, confusion and drowsiness.
• Skeletal disease (bone pain, fractures, brown tumours), kidney stones and kidney impairment, and pancreatitis.
• A palpable neck mass (30 to 50%) and hoarseness from recurrent laryngeal nerve involvement.

Red flags.

• Calcium over 3.5 mmol/L with confusion or kidney injury (hypercalcaemic crisis).
• Neck mass with voice change.

• Albumin adjusted calcium raised (often over 3.5 mmol/L) with parathyroid hormone markedly raised (often over 5 times the upper limit), alkaline phosphatase raised and phosphate low.
• Neck ultrasound, technetium sestamibi, and CT or MRI of the neck and chest. Fluorodeoxyglucose PET-CT in suspected metastatic disease.
• Suspect carcinoma before surgery when calcium and parathyroid hormone are very high, a neck mass is palpable or the patient is young. Avoid fine needle aspiration because of the risk of tumour seeding.
• Histology: invasion of capsule, vessels or adjacent tissue, mitoses and fibrous bands. Parafibromin staining supports the diagnosis.
• CDC73 testing for all patients, with family testing if a variant is found. Exclude MEN1 and MEN2A.

Differential diagnosis.

• Parathyroid adenoma, atypical adenoma and parathyroid hyperplasia.
• Severe primary hyperparathyroidism of other causes, malignancy associated hypercalcaemia (low parathyroid hormone) and vitamin D toxicity.
• Familial hypocalciuric hypercalcaemia (low calcium to creatinine clearance ratio, under 0.01).

• Surgery is the only cure: en bloc resection of the tumour with the ipsilateral thyroid lobe and involved structures, with lymph node dissection if involved. Avoid capsule rupture.
• Preoperative control of hypercalcaemia: intravenous 0.9% sodium chloride 1000 mL over the first hour then 200 to 300 mL/h, zoledronic acid 4 mg intravenously over 15 minutes, and calcitonin 4 units/kg every 12 hours for rapid effect. Add denosumab 120 mg subcutaneously for resistant disease.
• Cinacalcet 30 mg twice daily, increased every 2 to 4 weeks up to 90 mg four times daily, controls calcium if surgery is not possible or disease recurs.
• Recurrence: re-operate when possible, including lung and liver metastasectomy. Radiotherapy and chemotherapy have limited benefit.
• Monitor for hungry bone syndrome after surgery: calcium carbonate 1 to 2 g elemental calcium daily in divided doses with calcitriol 0.5 to 1 microgram daily, and intravenous calcium gluconate for tetany.
• Genetic counselling for CDC73 carriers (50% risk for children).

Special groups. Pregnancy: surgery in the second trimester with medical control of calcium. Children and young adults: examine for CDC73-related disease.

Monitoring. Calcium and parathyroid hormone at 24 hours, 1 week and 6 weeks after surgery, every 3 months for 2 years, then every 6 months for life, and imaging if levels rise.

Referral and escalation. Endocrine surgery with endocrinology and oncology; urgent admission for hypercalcaemic crisis.