In confirmed hypercalcemia, differential diagnosis is usually among PHPT, malignancy (metastatic to bone or the ectopic PTH syndrome), and all other etiologies. In most cases the differential eventually resolves into PHPT versus hypercalcemia of malignancy (HCM). There is no single laboratory test that can distinguish between PHPT and HCM every time with certainty. As noted previously, the better midmolecule PTH assays usually can differentiate normal from either PHPT or HCM and frequently can differentiate PHPT from HCM. If PHPT and HCM are not clearly separated, intact PTH assay might be obtained since it is generally better at separating PHPT and HCM. In any case a nomogram containing a scattergram of known cases is necessary. If the different PTH assays are not available, some other tests might indirectly provide evidence one way or the other. Hand x-rays are helpful if typical changes of PHPT are found (but this occurs in only a small percentage of cases). Renal stones are common in PHPT and uncommon in tumor. The quickest and easiest screening test for myeloma is serum protein electrophoresis, although serum and urine immunoelectrophoresis is more sensitive. A serum chloride value at the upper limit of the reference range or above is evidence against metastatic tumor. A bone scan and x-ray skeletal survey are useful to detect metastatic tumor. Some investigators advocate the assay of calcitonin, which is elevated with varying frequency in tumors associated with hypercalcemia and is usually not elevated in PHPT (some investigators report mild elevation in some patients). Unfortunately, regardless of the test results, PHPT may be present concurrently with malignancy in about 5% of patients with cancer.

Serum calcitonin assay. Calcitonin (thyrocalcitonin, TCT) is secreted by nonfollicular C cells of the thyroid. An increased serum calcium level induces thyroid C cells to produce more calcitonin as part of hypercalcemia compensatory mechanisms. A major exception is PHPT, where the TCT level is usually normal or low, for poorly understood reasons (one report indicates an elevation in 10% of cases). The TCT level may be elevated in a considerable percentage of certain tumors known to metastasize to bone, such as lung carcinoma (about 30%-50% of cases; literature range 21%-62%) and breast carcinoma (about 50%; range, 38%-75%). Medullary thyroid carcinoma (MTC) produces elevated basal TCT in about 75% of cases (range, 33%-100%). Total serum calcium in MTC is usually normal. MTC or C-cell hyperplasia is found in >95% of patients with multiple endocrine neoplasia (MEN) syndromes type 2A and 2B. Type 2A also includes pheochromocytoma (about 50% cases) and PHPT (10%-25% cases). PHPT also is part of MEN type 1, which does not include MTC. The TCT level may be increased in the Zollinger-Ellison syndrome, as well as in certain nonneoplastic conditions such as chronic renal failure or pernicious anemia, and values may overlap with MCT. In summary, an elevated TCT level in a patient with possible PHPT raises the question of medullary carcinoma of the thyroid or some other malignancy, if the patient is not in renal failure.

Ectopic parathyroid hormone syndrome.

Nonparathyroid tumors that secrete PTH or PTH-like hormones (ectopic PTH syndrome) can produce considerable diagnostic problems. In one study, 19% of patients with tumor-associated hypercalcemia had no evidence of bone metastases. On the average, PTH assay values in ectopic PTH syndrome are lower than PTH values in PHPT. Although there is some overlap, the degree of overlap depends on the individual antiserum. There is disagreement regarding the nature of the ectopically produced hormone; that is, whether it is true PTH or a nonidentical molecule with a similar structure and PTH-like action that cross-reacts with most current PTH antisera. To further confuse matters, it is estimated that 5%-10% of patients with malignancy and hypercalcemia also will have a coexisting parathyroid adenoma with PHPT. It has also been stated that 15% of patients with PHPT have some coexisting disorder that could produce hypercalcemia.