Why does squamous cell carcinoma release parathyroid hormone-related protein (PTHrP)?

Mechanism of PTHrP Production in Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) releases parathyroid hormone-related protein (PTHrP) as part of a paraneoplastic process that enables tumor growth and survival, which commonly leads to hypercalcemia of malignancy.

Pathophysiology of PTHrP Production in SCC

PTHrP is structurally similar to parathyroid hormone (PTH) but is produced by different cells and tissues. In squamous cell carcinoma:

• PTHrP is expressed in normal squamous epithelium of the skin, particularly in the prickle cell layer 1
• When squamous cells undergo malignant transformation, they often retain and amplify this ability to produce PTHrP
• This is particularly common in squamous cell carcinomas of the lung, head and neck, and esophagus 2, 3

Mechanism of Action

PTHrP mimics the action of PTH through:

1. Binding to PTH receptors (PTH1R) in bone and kidney
2. Increasing bone resorption by activating osteoclasts
3. Enhancing renal calcium reabsorption
4. Decreasing phosphate reabsorption in the kidney

Unlike normal PTH regulation which responds to serum calcium levels through negative feedback, tumor-produced PTHrP operates independently of calcium levels, leading to uncontrolled hypercalcemia.

Clinical Significance

• Hypercalcemia occurs in 10-25% of patients with lung cancer, most commonly in squamous cell histology 2
• PTHrP-mediated hypercalcemia is characterized by:
  • Suppressed intact parathyroid hormone (iPTH) levels
  • Low or normal calcitriol (1,25-dihydroxyvitamin D) levels
  • Elevated serum calcium
  • Elevated PTHrP levels 2
• The median survival after discovery of hypercalcemia of malignancy in lung cancer patients is approximately 1 month 2

Diagnostic Features

Laboratory findings in PTHrP-mediated hypercalcemia include:

• Elevated serum calcium
• Suppressed intact PTH levels
• Elevated PTHrP levels
• Normal or low 1,25-dihydroxyvitamin D levels
• Normal or high urinary calcium excretion

Tissue-Specific Considerations

Different SCC types may have varying propensities for PTHrP production:

• Lung SCC: High frequency of PTHrP production 4
• Head and neck SCC: Variable expression, not consistently detected in all patients 5
• Esophageal SCC: PTHrP production may be more prominent in metastases than in primary tumors 3
• Small cell carcinoma of the ovary, hypercalcemic type: Approximately 60% are associated with hypercalcemia due to PTHrP production 2

Treatment Implications

The presence of PTHrP-induced hypercalcemia does not necessarily indicate untreatable disease:

• Definitive treatment of the underlying SCC can normalize calcium levels 6
• Management of hypercalcemia includes:
  • IV fluid rehydration
  • Loop diuretics after volume restoration
  • Bisphosphonates (clodronate, pamidronate, zoledronic acid)
  • Calcitonin for acute management
  • Denosumab in refractory cases

Clinical Pitfalls and Caveats

1. Not all SCCs produce PTHrP: Testing should be guided by clinical suspicion and presence of hypercalcemia
2. Metastatic disease may produce more PTHrP: As seen in esophageal SCC, metastases may express higher levels than primary tumors 3
3. Poor prognostic indicator: While associated with poor prognosis, PTHrP-induced hypercalcemia should not automatically preclude curative treatment approaches 6
4. Differential diagnosis: Must distinguish from primary hyperparathyroidism, which presents with elevated iPTH and calcitriol levels 2

Understanding the mechanism of PTHrP production in SCC is crucial for proper diagnosis and management of these patients, particularly when hypercalcemia develops.