Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas.

DISTINCT SYNDROME of calcitriol (1,25-dihyA droxyvitamin D,)-mediated hypercalcemia is seen in patients with Hodgkin's disease and non-Hodgkin's lymphomas (NHL). In addition to hypercalcemia, this syndrome is characterized by intestinal hyperabsorption of calcium, normal serum phosphate levels, the absence of renal phosphate wasting, and increased renal excretion of calcium. Other characteristic features include normal or suppressed serum parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) concentrations and normal nephrogenous cyclic adenosine monophosphate production. Dysregulated extra-renal production of calcitriol, the active metabolite of vitamin D, appears to be the underlying defect, although it is unclear whether the lymphoma cells or infiltrating host monocytes and macrophages are the primary source. Applying the pathophysiology of hypercalcemia in sarcoidosis as a model, interferon-y production by lymphocytes stimulating monocyte and macrophage 1 a-hydroxylase activity and enhancing vitamin D activation may be an early initiating event. There is also evidence that other osteolytic factors such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) may act in concert with calcitriol to exacerbate the hypercalcemia. In isolated cases of human T-cell lymphotrophic virus type1 (HTLV1 )-related adult T-cell leukemia/lymphoma, where elevated calcitriol levels have been reported, the underlying mechanism is probably stimulation of renal vitamin D activation by PTHrP acting on renal PTH receptors. Calcitnol ( 1,25-dihydroxyvitamin D,)-mediated hypercalcemia is a distinct pathophysiologic entity within the broad field of malignancy-associated hypercalcemia. At our current level of understanding, it is useful to divide malignancy-associated hypercalcemia into three major categories: humoral hypercalcemia of malignancy usually mediated by PTHrP, local osteolytic hypercalcemia, and hypercalcemia caused by the dysregulated production of calcitriol, the active metabolite of vitamin D (Table 1). In each category, the underlying pathophysiologic mechanism results in a characteristic clinical picture, although it is possible for more than one mechanism to contribute to the pathogenesis of hypercalcemia in an individual patient. The most common form of hypercalcemia associated with solid tumors is humoral hypercalcemia of malignancy, mediated by PTHrP,' which acts systemically to causegeneralized increased osteoclastic bone resorption, increased renal resorption of calcium, and renal phosphate wasting (Table 2). These features are often present even in patients with osseous meta~tases.~,, Although PTHrP has been implicated in the hypercalcemia of human T-cell-lymphotrophic virus type1 (HTLV1)-related adult T-cell leukemia/ lymphoma (ATLLr and isolated cases of NHL,5,6 most patients with hematologic malignancies complicated by hypercalcemia do not have elevated systemic levels of PTHrP.7-9 Conversely, dysregulated calcitnol production is a very rare occurrence in patients with hypercalcemia associated with solid t ~ m o r s , ' ~ ' ~ where suppressed serum concentrations of calcitriol are characteristic. The second major category of malignancy-associated hypercalcemia is local osteolytic hypercalcemia. The predominant cause of the hypercalcemia in these cases is localized bone resoption by activated osteoclasts in the vicinity of tumor cells metastatic to bone. Although not well characterized, a variety of cytokines and local regulatory factors have been implicated in this type of hypercalcemia (Table 1). The third major category of hypercalcemia is calcitriolmediated hypercalcemia. This is the most frequent cause of hypercalcemia seen in patients with Hodgkin's disease and NHL,l4,I5 where hypercalcemia has been reported to occur in 5% and 15% of patients, respectively.16 There are no data specifically examining the clinical impact of hypercalcemia in these disorders. However, patients with malignancy-associated hypercalcemia are usually symptomatic, and hypercalcemia adds significantly to their morbidity and mortality.17 Further, hypercalcemia is a poor prognostic feature in a number of hematologic and therapies specifically directed toward preventing osteolysis have shown improved outcomes for patients with both metastatic breast cance?1s22 and multiple myeloma.23s24 Finally,