Can cancer first manifest as hypercalcemia?

Cancer Can First Manifest as Hypercalcemia

Yes, cancer can first manifest as hypercalcemia before any other symptoms of the underlying malignancy are apparent. This presentation is known as hypercalcemia of malignancy and can be the initial clinical finding that leads to the diagnosis of cancer.

Mechanisms of Cancer-Related Hypercalcemia

Hypercalcemia occurs in 10-25% of patients with cancer during the course of their disease 1. Several mechanisms can lead to hypercalcemia in cancer patients:

1. Parathyroid hormone-related protein (PTHrP) production - The most common mechanism where tumors secrete PTHrP, causing humoral hypercalcemia of malignancy
2. Increased active vitamin D (calcitriol) - Some tumors produce excessive amounts of 1,25-dihydroxyvitamin D
3. Localized osteolytic hypercalcemia - Direct bone invasion by tumor cells causing increased bone resorption
4. Rarely, ectopic parathyroid hormone production by tumors

Clinical Presentation of Hypercalcemia as Initial Cancer Manifestation

When hypercalcemia is the first sign of cancer, patients typically present with:

• Neurological symptoms: Confusion, altered mental status, lethargy
• Gastrointestinal symptoms: Nausea, vomiting, constipation, anorexia
• Renal symptoms: Polyuria, polydipsia, dehydration, renal failure
• Cardiovascular symptoms: Bradycardia, hypertension, shortened QT interval
• Musculoskeletal symptoms: Weakness, myalgia, bone pain

The severity of symptoms correlates with both the calcium level and the rapidity of onset 1.

Cancer Types Most Commonly Presenting with Hypercalcemia

Certain cancers are more likely to present initially with hypercalcemia:

• Lung cancer (particularly squamous cell carcinoma) 1
• Breast cancer
• Multiple myeloma
• Renal cell carcinoma
• Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) 1

Diagnostic Approach When Hypercalcemia Is the Initial Presentation

When a patient presents with hypercalcemia without known cancer, the diagnostic evaluation should include:

1. Laboratory testing:

   • Serum calcium (ionized and total)
   • Intact parathyroid hormone (iPTH) - typically suppressed in malignancy
   • PTHrP - often elevated in humoral hypercalcemia of malignancy
   • 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D levels
   • Albumin, magnesium, and phosphorus

2. Imaging studies to search for occult malignancy:

   • Chest X-ray or CT scan
   • Abdominal/pelvic CT
   • Mammography (in women)
   • Bone scan if bone pain is present

Prognostic Implications

Hypercalcemia as the initial manifestation of cancer often indicates poor prognosis. The median survival after discovery of hypercalcemia of malignancy in patients with lung cancer is approximately 1 month 1.

Management of Cancer-Related Hypercalcemia

Management involves treating both the hypercalcemia and the underlying malignancy:

1. Immediate management of hypercalcemia:

   • Hydration: IV crystalloid fluids without calcium
   • Bisphosphonates: First-line pharmacologic therapy (pamidronate or zoledronic acid) 1
   • Denosumab: For cases refractory to bisphosphonates 1
   • Calcitonin: For rapid but short-term calcium reduction
   • Glucocorticoids: Particularly useful in lymphomas and vitamin D-mediated hypercalcemia 2
   • Loop diuretics: After adequate hydration

2. Treatment of the underlying malignancy once identified

Key Pitfalls to Avoid

1. Misattribution to primary hyperparathyroidism: While primary hyperparathyroidism is the most common cause of hypercalcemia in the general population, in hospitalized patients and those with severe symptoms, malignancy should be strongly considered.

2. Inadequate hydration: Patients with hypercalcemia are often severely dehydrated, and aggressive IV fluid resuscitation is critical before administering loop diuretics.

3. Delayed cancer workup: When hypercalcemia is identified without an obvious cause, prompt investigation for malignancy is essential.

4. Overlooking the possibility of SCCOHT in young women: This rare but aggressive ovarian cancer affects females under 40 years of age and approximately 60% of cases are associated with hypercalcemia 1.