Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages

Nearly one-half of all hypercalcemic patients with lymphoma present with inappropriately elevated circulating concentrations of the active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25(OH)(2)D-3). However, the cellular source of the vitamin D hormone in lymphomas remains unclear. To address this, we report the case of a 75-year-old man with hypercalcemia associated with raised circulating concentrations of 1,25(OH)(2)D-3 and suppressed parathyroid hormone (PTH) levels. Positron emission tomographic (PET) and computed tomographic (CT) imaging revealed the presence of a large lymphoma that was confined to the spleen; subsequent pathological analysis showed that this was an intermediate grade B-cell lymphoma. After surgical removal of the spleen, serum calcium and 1,25(OH)(2)D-3 levels became normalized within 24 h. Immunolocalization of the vitamin D-activating enzyme 25-hydroxyvitamin D-3-1alpha-hydroxylase (1alpha-hydroxylase) in sections of resected spleen showed that staining was negative in the lymphoma cells but positive in neighboring macrophages. This case study indicates that the hypercalcemia associated with lymphomas may be due, in some instances, to excessive extrarenal production of 1,25(OH)(2)D-3. Furthermore, by using immunohistochemistry to assess the distribution of 1alpha-hydroxylase, we have been able to show for the first time that tissue macrophages, rather than actual tumor cells, are the most likely ectopic source of this enzyme. Based on this case study, we propose that the abnormal synthesis of 1,25(OH)(2)D-3 associated with some lymphomas is because of paracrine regulation of tumor-associated macrophages.