Hypercalcemia of malignancy
1. What are the two major categories of hypercalcemia of malignancy?
2. What types of cancers are associated with HHM?
Carcinoma of the lung, particularly squamous cell carcinoma, is the most common. Other tumors associated with this disorder are squamous cell carcinomas of the head, neck, and esophagus and adenocarcinomas of the breast, kidney, bladder, pancreas, and ovary.
HHM results when solid malignancies, both solitary and metastatic, secrete into the circulation one or more substances that cause hypercalcemia. The humoral mediator identified in more than 90% of cases is parathyroid hormone–related peptide (PTHrp). Other humoral substances that are occasionally secreted and contribute to the development of hypercalcemia include transforming growth factor-alpha (TGF-α), tumor necrosis factor (TNF), and various interleukins and cytokines.
PTHrp is a protein that has sequence homology with the first 13 amino acids of parathyroid hormone (PTH). Both PTH and PTHrp bind to a common receptor (PTH/PTHrp receptor), resulting in stimulation of bone resorption and inhibition of renal calcium excretion. PTHrp is found in high concentrations in breast milk and amniotic fluid, but it can be detected in almost every tissue in the body; its level is increased in the circulation during pregnancy. The physiologic endocrine function of PTHrp may be to govern the transfer of calcium from the maternal skeleton and bloodstream into the developing fetus and into breast milk. As a generalized paracrine factor, it also regulates growth and development of many tissues, most prominently the skeleton and breast.
5. How does PTHrp cause hypercalcemia in patients with cancer?
Elevated circulating concentrations of PTHrp stimulate generalized bone resorption, flooding the bloodstream with excessive calcium; PTHrp also acts on the kidneys, preventing excretion of the greater calcium load. This combination produces an increase in the serum calcium concentration. Hypercalcemia induces polyuria, which leads to dehydration with impaired renal function, further reducing calcium excretion and leading to a cycle of progressive and eventually life-threatening hypercalcemia.
6. How do you make a diagnosis of HHM?
Hypercalcemia in any patient with a known malignancy should make one suspect this diagnosis. Occasionally, however, a raised serum calcium level is the first clue to an underlying cancer. The key to the diagnosis is a suppressed serum intact PTH level; this finding reliably excludes hyperparathyroidism, the other leading cause of hypercalcemia. Serum PTHrp levels are nearly always high, but the measurement of PTHrp, which is an expensive test, is not necessary for diagnosis in most instances. If a patient meeting these diagnostic criteria does not have a known tumor, a careful search for an occult malignancy should be undertaken.
7. What types of cancer are associated with LOH?
Breast cancer with skeletal metastases, multiple myeloma, and lymphoma are the major cancers associated with LOH.
KEY POINTS 1: HYPERCALCEMIA OF MALIGNANCY
1. Hypercalcemia of malignancy is most often due to tumor production of parathyroid hormone–related peptide (PTHrp), which binds to parathyroid hormone (PTH) and PTH/PTHrp receptors to stimulate bone resorption.
2. The key diagnostic test in hypercalcemic patients is measurement of serum PTH, which is elevated or high normal in primary hyperparathyroidism but low or undetectable in hypercalcemia of malignancy and most other hypercalcemic disorders.
3. The development of hypercalcemia of malignancy portends a poor prognosis in most patients with cancer, because it tends to occur with advanced tumor stages.
4. Serum calcium levels can be lowered effectively in patients with hypercalcemia of malignancy by the intravenous administration of saline, bisphosphonates and denosumab.
LOH generally occurs when cancer cells are present in multiple sites throughout the skeleton. The pathogenesis involves the elaboration by malignant cells of osteoclast-stimulating factors directly onto the surface of bone. Such factors include PTHrp, the protein DKK1, lymphotoxin, interleukins, transforming growth factors, prostaglandins, and procathepsin D.
9. How do you make a diagnosis of LOH?
The diagnosis is fairly straightforward when hypercalcemia develops in a patient with one of the previously noted malignancies. Again, the key is demonstration of a suppressed serum intact PTH level, indicating that hyperparathyroidism is not the culprit. Patients without a known malignancy should undergo a complete blood count, serum and urine protein electrophoresis, and bone scan; if these studies are not informative, a bone marrow biopsy should be performed.
10. Can lymphomas cause hypercalcemia by other mechanisms?
Some lymphomas express 1α-hydroxylase activity. This enzyme converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which then stimulates increased intestinal calcium absorption and bone resorption. This process may eventually lead to hypercalcemia, particularly in patients who have reduced renal calcium excretion due to dehydration or intrinsic renal disease.
11. What is the prognosis for patients with hypercalcemia of malignancy?
Because hypercalcemia generally correlates with far-advanced disease, the overall prognosis is quite poor. In one study, the median survival of patients in whom hypercalcemia developed was only 30 days. Effective treatments are available to reduce the serum calcium levels, however.
12. How do you treat hypercalcemia of malignancy?
Treatment of the underlying malignancy is the most effective measure. For symptomatic patients, rapid reduction of serum calcium is also indicated. An intravenous saline infusion (200-500 mL/h, if tolerated) to enhance renal calcium excretion should be the initial measure in most patients. Furosemide 20 to 40 mg intravenous (IV) can be added after adequate hydration is achieved. Antiresorptive medications should be given concomitantly. The most effective of these are the intravenous bisphosphonates and denosumab. Suggested treatment regimens are shown in Table 15-1.
TABLE 15-1.
TREATMENT REGIMENS FOR HYPERCALCEMIA OF MALIGNANCY
| MEDICATION | DOSAGE |
| Zoledronic acid (Zometa) | 4 mg in 50 mL normal saline IV over 15 min |
| Pamidronate (Aredia) | 60–90 mg in 250–500 mL NS IV over 2–4 h |
| Denosumab (Xgeva) | 120 mg SC every 4 weeks |
| Plicamycin | 25 mg/kg IV over 4–6 h |
| Calcitonin | 4–8 IU/kg SC or intramuscular twice daily |
| Gallium nitrate | 100–200 mg/m2/24 h for 5 days |
| Prednisone | 60 mg daily for 10 days |
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