What are the effects and management of hypercalcemia on the buccal mucosa?

Hypercalcemia in Buccal Mucosa Cancer: Causes and Management

Primary Causes of Hypercalcemia in Buccal Mucosa Cancer

Hypercalcemia in buccal mucosa (oral cavity) cancer occurs primarily through parathyroid hormone-related protein (PTHrP) secretion by the tumor, which stimulates excessive bone resorption by osteoclasts. 1

Pathophysiologic Mechanisms

• PTHrP-mediated hypercalcemia is the dominant mechanism in squamous cell carcinomas of the head and neck, including buccal mucosa cancer 1, 2
• The tumor secretes PTHrP systemically, activating osteoclasts and causing increased bone resorption even without skeletal metastases 1
• This results in excessive calcium release into the bloodstream, leading to polyuria, dehydration, and progressive renal impairment that further worsens hypercalcemia 2
• Hypercalcemia occurs in 10-25% of cancer patients, with squamous cell carcinomas being particularly high-risk 1

Clinical Presentation by Severity

• Mild hypercalcemia (calcium <12 mg/dL): Often asymptomatic but may cause fatigue and constipation in 20% of patients 3
• Moderate hypercalcemia (calcium 12-14 mg/dL): Polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain 1
• Severe hypercalcemia (calcium ≥14 mg/dL): Altered mental status, bradycardia, hypotension, somnolence, coma 1, 3

Diagnostic Workup

Measure serum intact PTH (iPTH) first to distinguish PTH-dependent from PTH-independent causes. 1, 3

Essential Laboratory Tests

• PTHrP levels: Elevated in tumor-mediated hypercalcemia with suppressed iPTH 1
• Serum calcium, albumin, magnesium, phosphorus: Correct calcium for albumin levels 1, 2
• iPTH: Suppressed (<20 pg/mL) in malignancy-associated hypercalcemia 3
• 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D: To exclude vitamin D-mediated causes 1

Key Diagnostic Pattern

• PTHrP-mediated hypercalcemia shows suppressed iPTH with low or normal calcitriol levels 1
• This distinguishes malignancy from primary hyperparathyroidism (where iPTH would be elevated) 3

Treatment Algorithm

Step 1: Immediate Rehydration (First-Line)

Administer intravenous normal saline immediately to correct hypovolemia and promote calciuresis. 1, 4, 3

• IV crystalloid fluids without calcium restore intravascular volume and enhance renal calcium excretion 1
• Maintain urine output ≥100 mL/hour (or 3 mL/kg/hour in children <10 kg) 4
• Loop diuretics (furosemide) should only be given after volume repletion, not before, to prevent worsening dehydration 1, 4

Step 2: Bisphosphonate Therapy (Definitive Treatment)

Zoledronic acid 4 mg IV infused over 15 minutes is the preferred bisphosphonate for malignancy-associated hypercalcemia. 1, 4, 2

• Zoledronic acid normalizes calcium in approximately 50% of patients by day 4 1
• Superior efficacy compared to pamidronate (which normalizes calcium in only 33% by day 4) 1
• Alternative: Pamidronate 90 mg IV over 2 hours if zoledronic acid unavailable 1
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia 4
• Reserve 8 mg dose for recurrent or refractory cases 1

Step 3: Bridging Therapy for Rapid Effect

Calcitonin 4 IU/kg subcutaneously or intramuscularly every 12 hours provides rapid calcium reduction within hours while awaiting bisphosphonate effect. 1, 4, 5

• Onset of action within hours but limited efficacy and duration 4, 3
• Dose may be increased to 8 IU/kg every 12 hours if inadequate response after 1-2 days 5
• Maximum dose: 8 IU/kg every 6 hours 5
• Use as bridge until bisphosphonates take effect (3-4 days) 4

Step 4: Refractory Cases

For hypercalcemia refractory to bisphosphonates or in patients with renal insufficiency, use denosumab. 1, 4

• Denosumab reduces serum calcium in 64% of bisphosphonate-refractory cases 1
• Preferred over bisphosphonates in renal disease 1
• Monitor calcium levels closely post-treatment due to high risk of hypocalcemia 1, 4

Step 5: Severe Hypercalcemia with Renal Failure

Hemodialysis with calcium-free or low-calcium dialysate is reserved for severe hypercalcemia complicated by renal insufficiency. 4, 6

• Effectively removes calcium through diffusive therapy 4
• Generally reserved for patients unresponsive to medical management 6

Special Considerations and Pitfalls

Critical Pitfalls to Avoid

• Never use loop diuretics before volume repletion—this worsens dehydration and hypercalcemia 1, 4
• Avoid NSAIDs and IV contrast in patients with renal impairment—these worsen kidney function 4
• Do not use chronic vaseline/petrolatum on lips—promotes mucosal dehydration and infection risk 7

Oral Care During Cancer Treatment

Implement rigorous oral hygiene to prevent mucosal injury and infection in patients with buccal mucosa cancer. 7

• Brush teeth 4 times daily with soft toothbrush and fluoride-containing, non-foaming toothpaste 7
• Rinse with alcohol-free mouthwash at least 4 times daily 7
• Avoid smoking, alcohol, citrus fruits, hot/spicy foods 7
• Daily oral mucosa inspection for early detection of complications 7

Monitoring and Prevention

• Monitor serum creatinine before each zoledronic acid dose—withhold if renal deterioration occurs 4
• Baseline dental examination required—monitor for jaw osteonecrosis with bisphosphonate use 1
• Correct hypocalcemia before initiating bisphosphonates 4
• Supplement with oral calcium 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment 4

Prognosis

Median survival after discovery of malignant hypercalcemia in head and neck cancer is approximately 1 month, reflecting advanced disease. 1

• Hypercalcemia of malignancy is associated with poor survival overall 3
• Treatment reduces serum calcium and improves symptoms transiently, but underlying malignancy determines outcome 3
• Aggressive supportive care and definitive cancer treatment are essential 1