- Malignancy-Associated Hypercalcemia (MAH) – Epidemiology
- Occurs in 20% to 30% of patients with cancer during their disease course
- Accounts for roughly 90% of hypercalcemia cases in hospitalized patients
- Most common cause of hypercalcemia in hospitalized patients:
- Whereas primary hyperparathyroidism is most common in the outpatient setting
- Most common cancers Table 1
- Overall prognosis:
- Median survival after diagnosis of MAH – 3 to 4 months
- Indicates advanced malignancy
- Median survival after diagnosis of MAH – 3 to 4 months
- Mechanisms of Hypercalcemia in Malignancy:
- Humoral Hypercalcemia of Malignancy (HHM):
- Accounts for ~ 80% of cases
- Pathophysiology:
- Tumor secretes PTH-related peptide (PTHrP)
- PTHrP mimics PTH actions:
- ↑ osteoclastic bone resorption
- ↑ renal calcium reabsorption
- ↓ phosphate
- Laboratory profile Table 2
- Common cancers:
- Squamous cell lung carcinoma
- Head and neck squamous cell carcinoma
- Renal cell carcinoma
- Bladder cancer
- Ovarian cancer
- Clinical features:
- Rapid onset
- Often severe hypercalcemia
- Advanced malignancy
- Osteolytic Metastases:
- ~ 20% of cases
- Pathophysiology:
- Direct tumor invasion of bone:
- Stimulate osteoclast activity via the release of:
- IL-1
- IL-6
- TNF
- RANKL
- These cytokines stimulate osteoclasts → localized bone destruction → calcium release
- Stimulate osteoclast activity via the release of:
- Direct bone destruction → calcium release
- Direct tumor invasion of bone:
- Typical malignancies:
- Breast cancer
- Multiple myeloma:
- Myeloma cells activate osteoclasts
- Suppress osteoblast activity
- Produce osteolytic lesions
- Lymphoma
- Metastatic prostate (less common cause of hypercalcemia)
- Laboratory profile Table 3
- Vitamin D–Mediated Hypercalcemia:
- Rare (less than 1% to 2% of the cases)
- Pathophysiology:
- Tumor produces 1-alpha hydroxylase
- ↑ conversion of 25-OH vitamin D → 1,25-OH vitamin D
- Seen in:
- Hodgkin lymphoma
- Non-Hodgkin lymphoma
- Some granulomatous tumors
- Laboratory profile Table 4
- Ectopic PTH Production:
- Extremely rare (< 1%of the cases)
- True PTH secretion by tumor
- Seen in:
- Small cell lung cancer
- Ovarian carcinoma
- Humoral Hypercalcemia of Malignancy (HHM):
- Clinical Manifestations:
- Symptoms depend on rate of rise and level of calcium
- Neurologic:
- Confusion
- Lethargy
- Coma
- Gastrointestinal:
- Nausea
- Constipation
- Pancreatitis
- Renal:
- Polyuria
- Dehydration
- Acute kidney injury
- Cardiac:
- Shortened QT interval
- Arrhythmias
- Neurologic:
- Symptoms depend on rate of rise and level of calcium
- Laboratory Clues Distinguishing MAH from PHPT Table 5
- Treatment:
- Immediate Management:
- Aggressive IV hydration (normal saline)
- Calcitonin:
- Rapid onset (4 to 6 hours):
- Temporary effect
- Rapid onset (4 to 6 hours):
- IV bisphosphonates:
- Zoledronic acid
- Pamidronate
- Onset:
- 24 to 48 hours
- Onset:
- Refractory Hypercalcemia:
- Denosumab
- Glucocorticoids (vitamin D–mediated cases)
- Dialysis (severe renal failure)
- Immediate Management:
- Key Teaching Points for Residents:
- Malignancy = most common cause of hypercalcemia in hospitalized patients
- PTH is suppressed
- PTHrP accounts for ~ 80% of cases
- Severe calcium (>14 mg/dL) should raise suspicion for malignancy
- Median survival ~ 3 to 4 months → poor prognostic marker
- Key References:
- Stewart AF. Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373–379.’
- Clines GA. Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes.2011;18:339–346.
- Goldner W. Cancer-related hypercalcemia. J Oncol Pract. 2016;12:426–432.
- Mirrakhimov AE. Hypercalcemia of malignancy: pathogenesis and treatment. North Am J Med Sci.2015;7:483–493.
| Cancer Type | Frequency of MAH |
|---|---|
| Lung cancer (especially squamous cell) | ~25–30% |
| Breast cancer | ~20–25% |
| Multiple myeloma | ~15–20% |
| Renal cell carcinoma | ~5–10% |
| Head and neck squamous cell carcinoma | ~5–10% |
| Others (ovarian, lymphoma, bladder) | <5% |
| Test | Result |
|---|---|
| Calcium | ↑ |
| PTH | Suppressed |
| PTHrP | Elevated |
| Phosphate | Low |
| 1,25-vitamin D | Low/normal |
| Test | Result |
|---|---|
| Calcium | ↑ |
| PTH | Suppressed |
| PTHrP | Normal |
| Vitamin D | Normal |
| Test | Result |
|---|---|
| Calcium | ↑ |
| PTH | Suppressed |
| 1,25-OH vitamin D | Elevated |
| Feature | Primary Hyperparathyroidism | Malignancy Hypercalcemia |
|---|---|---|
| PTH | High or inappropriately normal | Suppressed |
| Calcium level | Mild–moderate (10.5–12 mg/dL) | Often >13–14 mg/dL |
| Symptom onset | Chronic | Acute / severe |
| PTHrP | Normal | Elevated (HHM) |
| Vitamin D | Normal | May be elevated in lymphoma |
Rodrigo Arrangoiz MS, MD, FACS, FSSO 