Chapter 22-4: Humoral Hypercalcemia of Malignancy

TEXTBOOK PRESENTATION

Hypercalcemia of malignancy is most commonly detected in patients with previously diagnosed cancers. It is uncommon for symptomatic hypercalcemia to be the presenting symptom of a malignancy. Hypercalcemia of malignancy carries a horrendous prognosis with a 50% 30-day mortality.

DISEASE HIGHLIGHTS

1. Hypercalcemia of malignancy is a heterogeneous process.

   1. The most common pathophysiology behind hypercalcemia of malignancy is the elaboration of PTHrP by tumor cells. This is referred to as humoral hypercalcemia of malignancy (HHM).

   2. Tumors metastatic to bone may also cause hypercalcemia through local osteolytic effects on the bones, sometimes via local elaboration of PTHrP. This syndrome is discussed below.

   3. It is likely there is a great deal of overlap between these first 2 causes.

   4. Rarely, tumors can cause hypercalcemia by elaborating vitamin D (seen most commonly with lymphoma).

2. The malignancies that commonly cause hypercalcemia are (in approximate order of frequency):

   1. Lung

   2. Breast

   3. Plasma cell myeloma

   4. Lymphoma

   5. Head and neck

   6. Renal

   7. Prostate

3. PTHrP is a normal, physiologic, protein that is produced by many nonneoplastic tissues.

   1. The protein shares considerable sequence homology to PTH and binds to the same receptor.

   2. PTH and PTHrP affect the bones and kidneys in the same way.

   3. Certain malignancies elaborate the protein in relatively large amounts.

      1. PTHrP is detectable in 80% of patients with hypercalcemia and malignancy.

      2. The most common tumors that produce PTHrP are squamous cell carcinomas and adenocarcinomas of the lung, pancreas, and kidney.

   4. In hypercalcemia of malignancy secondary to PTHrP, hypercalcemia commonly precedes bony metastasis.

EVIDENCE-BASED DIAGNOSIS

1. Similar to primary hyperparathyroidism, hypercalcemia of malignancy seldom presents significant diagnostic confusion.

2. In patients with a known malignancy, the diagnosis is made by detecting high PTHrP and low PTH levels.

TREATMENT

1. The ultimate treatment for hypercalcemia of malignancy is the treatment of the underlying disease.

2. Beyond treatment of the malignancy, treatment aimed directly at hypercalcemia depends on its severity.

3. The mainstays of treatment for moderate and severe elevations of calcium are the bisphosphonates.

   1. Bisphosphonates work by inhibiting osteoclast activity.

   2. Pamidronate and zoledronic acid are both approved for the treatment of hypercalcemia of malignancy in the United States.

4. For patients with severe, symptomatic hypercalcemia, therapy must be more rapidly effective than treatment of the underlying disease or bisphosphonate therapy (which takes about 48 hours to reach full effectiveness).

   1. Saline hydration treats the hypovolemia that frequently accompanies hypercalcemia and decreases reabsorption of calcium in the proximal tubule of hypovolemic, hypercalcemic patients.

   2. Once hydration is attained, a loop diuretic can further assist in achieving calciuresis.

   3. Calcitonin

      1. Calcitonin rapidly decreases calcium levels by increasing renal calcium excretion and decreasing bone resorption.

      2. Calcitonin’s effect is short-lived as tachyphylaxis develops after about 48 hours.

5. In all patients being treated for hypercalcemia of malignancy, care should be taken to institute other measures known to decrease serum calcium. Calcium supplements should be stopped, drugs that lead to hypercalcemia (lithium, thiazides) ...