Primary hyperparathyroidism and malignancy: Forgotten friends or new aquaintances.

Sir,

The article reporting primary hyperparathyroidism in a case of chronic myelogenous leukemia has raised an oft-neglected facet of primary hyperparathyroidism.[1] The association between primary hyperparathyroidism and malignancy has been noticed as far back as 1964. Dent and Watson describes a patient with squamous cell carcinoma of cervix along with primary hyperparathyroidism due to a parathyroid adenoma.[2] The metabolic abnormalities in this patient resolved after parathyroid surgery. Subsequent prospective studies have shown an increased risk of breast, kidney, gastrointestinal, endocrine, pancreatic cancers.[34] Cases of hematological malignancies like chronic lymphocytic leukemia and lymphoma have also been reported.[5] The risk of future malignancies was found to be unchanged even after 15 years of parathyroidectomy in one prospective study.[4] Thus, it is unlikely that the biochemical and metabolic abnormalities associated with primary hyperparathyroidism are responsible for the increased risk of malignancy.

Disordered regulation of Vitamin D metabolism may be an essential link between primary hyperparathyroidism and risk of malignancies. It has been well documented that Vitamin D receptors (VDR) are expressed not only in the intestine, bone, kidney, and parathyroid glands but also in most immune cell types, breast, colonic, and skin cancer cell lines.[6] Defects in the VDR gene alleles can thus cause both an abnormal parathyroid gland development as well as impaired apoptosis in other cell lines expressing VDR.

The clinical implications of the above observations can be seen from two perspectives. Firstly, patients with primary hyperparathyroidism asymptomatic or otherwise have a small but definite risk of malignancies. This risk has not been addressed in the clinical practice guidelines. There may be a case for adopting screening guidelines for certain malignancies after surgery for primary hyperparathyroidism, especially in patients with additional risk factors who are outside the purview of current screening guidelines. Patients with asymptomatic primary hyperparathyroidism on medical management may also benefit for education about their cancer risk during their follow-up. Secondly, not all cases of hypercalcemia in patients with malignancy will be due to PTHrP. Thankfully, we have come a long way from the days of Messers Dent and Watson when this differentiation was based on clinical assessment alone. Assay of PTH and PTHrP can now lead us to the correct diagnosis in such cases. If primary hyperparathyroidism is discovered in patients with malignancies early, parathyroidectomy might possibly improve the overall prognosis.