Differential Diagnosis

The most important consideration in the differential diagnosis of hypercalcemia in a patient with a malignant neoplasm is intercurrent primary hyperparathyroidism. One clue to this possibility is the presence of chronic hypercalcemia, especially hypercalcemia that predates discovery of the malignant tumor. It is important to measure the PTH level in all patients with cancer and hypercalcemia, using a two-site assay for intact PTH (immunoradiometric or immunochemoluminescent). In such assays, the level of PTH is consistently suppressed below 20 ng/L (2 nmol/L) in patients with malignancy-associated hypercalcemia.1 ''50 (Older midregion and aminoter-minal assays were not able to detect suppression of PTH in patients with nonparathyroid hypercalcemia and should not be used in this setting.) The finding of a high-normal or increased level of intact PTH suggests the presence of primary hyperparathyroidism. In a 1994 study of 123 consecutive hyper-calcemic patients, 6 (5%) had biochemical evidence of primary hyperparathyroidism together with a malignant neoplasm.51 As mentioned, true ectopic secretion of PTH is rare, which should be considered in patients with inappropriately increased PTH levels in the presence of a malignant neoplasm in whom a thorough exploration of the parathyroid glands was negative.

It is probably unnecessary to measure PTHrP or 1,25-(OH)2-D in all patients with malignancy-associated hypercalcemia. In the typical patient with a diffusely metastatic solid tumor and a suppressed level of PTH, determination of PTHrP is unlikely to change either the diagnosis or the management. Some studies have suggested that high PTHrP levels predict a poor response to antiresorptive therapy of hypercalcemia, but as discussed later (under "Treatment of Hypercalcemia"), it is not clear whether this effect is robust enough to mandate additional laboratory testing. However, in lymphoma patients, a determination of l,25-(OH)2-D may guide the subsequent treatment of hypercalcemia with corticosteroids. Assays of PTHrP and l,25-(OH)2-D are also indicated in hypercalcemic patients with suppressed PTH levels but without an obvious malignancy.

The serum or plasma level of PTHrP can be determined in aminoterminal,1113 midregion,15 or carboxyterminal radioimmunoassays (RIAs) or in two-site immunoradiometric assays (IRMAs).5253 Both aminoterminal RIAs and IRMA assays for PTHrP are currently available commercially in the United States. Although the absolute level of PTHrP is considerably higher in midregion RIAs than in aminoterminal assays or IRMAs, all classes of assays perform similarly in the setting of malignancy-associated hypercalcemia (see Fig. 61-2). IRMA assays for PTHrP are highly sensitive and specific. However, they require collection of blood in special tubes containing protease inhibitors because proteases present in serum are capable of cleaving the PTHrP molecule at a site that disrupts the two-site assay.

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