At a Glance

There are two main mechanisms by which cancer can lead to hypercalcemia. The first and most common is local action on bone as may be seen in multiple myeloma or carcinomas (e.g., breast or prostate) that metastasize to bone. The second mechanism is by tumors that secrete humoral factors that stimulate bone resorption. Squamous carcinomas are the most common malignancies that cause humoral-mediated hypercalcemia of malignancy. The major humoral factor is parathyroid hormone-related peptide (PTHrP), a protein that has similar action to parathyroid hormone (PTH) but a completely different structure.

The clinical features of hypercalcemia of malignancy resemble primary hyperparathyroidism. Patients may present either with vague, nonspecific symptoms (fatigue, muscle weakness, mental disturbances) or with symptoms more obviously related to hypercalcemia, such as kidney stones. In some patients, hypercalcemia of malignancy progresses quickly and is a grave prognostic sign.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The initial biochemical work-up of hypercalcemia consists of serum calcium, PTH, albumin, thyroid function tests (e.g., TSH, free thyroxine), and measures of kidney function (e.g., blood urea nitrogen, creatinine). A combination of hypercalcemia with low PTH should prompt a follow-up test of PTHrP. Keep in mind that standard PTH assays will not detect PTHrP. An elevated PTHrP is consistent with humor-mediated hypercalcemia of malignancy (e.g., squamous cell carcinoma). A normal or low PTHrP requires further work-up as clinically appropriate, such as imaging for presence of neoplasms.

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Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Low serum albumin can complicate interpretation of serum calcium. In patients with hypoalbuminemia, corrected calcium should be calculated or, alternatively, an ionized calcium should be measured. Renal failure can produce moderately elevated PTHrP concentrations.

What Lab Results Are Absolutely Confirmatory?

A markedly elevated PTHrP serum concentration provides strong evidence of humoral-mediated hypercalcemia of malignancy. There is no confirmatory test for hypercalcemia related to local actions of malignancies on bone. That diagnosis depends on combination of history, physical examination, imaging, and pathologic analysis of tumor.

Additional Factors of Clinical Importance

Hypercalcemia of malignancy can be life-threatening and may require aggressive maneuvers to lower calcium.

Errors in Test Selection and Interpretation

A need to understand difference between PTH and PTHrP exists. PTHrP is not detected by standard PTH assays and requires specialized testing, usually performed at reference laboratories.

Hypercalcemia of malignancy is a heterogeneous entity. Humoral-mediated hypercalcemia of malignancy is more readily diagnosed by laboratory testing but is less common than malignant neoplasms causing hypercalcemia by local resorption of bone. In the latter condition, there are no definitive laboratory tests and diagnosis depends on combination of history, physical examination, and imaging/pathological analysis.