Lung Malignancy and PTH Production
Lung malignancies, particularly squamous cell carcinomas, rarely produce true intact parathyroid hormone (PTH), and when they do, PTH levels are typically suppressed or inappropriately normal despite hypercalcemia—the hypercalcemia is almost always caused by PTH-related protein (PTHrP), not PTH itself. 1, 2
Mechanism of Hypercalcemia in Lung Cancer
The dominant mechanism is PTHrP-mediated hypercalcemia, not ectopic PTH production:
- Hypercalcemia occurs in 10-25% of lung cancer patients, most commonly with squamous cell carcinoma 1, 3
- PTHrP-mediated hypercalcemia accounts for the vast majority of malignancy-associated hypercalcemia cases 2
- In typical PTHrP-mediated hypercalcemia, intact PTH is suppressed (below normal range), not elevated 2
True Ectopic PTH Production: Extremely Rare
Authentic ectopic PTH production by lung cancer is extraordinarily rare, with only isolated case reports in the literature:
- One documented case showed a squamous cell lung carcinoma producing intact PTH with immunocytochemical confirmation in tumor tissue and cultured cells 4
- Another case report described concurrent elevation of both PTH and PTHrP in lung cancer with liver metastasis, confirmed by immunohistochemistry 5
- These represent exceptional cases, not the typical presentation 4, 5
Expected PTH Range in Lung Cancer with Hypercalcemia
The diagnostic pattern you should expect:
- PTH: Suppressed (typically <10-20 pg/mL, below the normal reference range of approximately 10-65 pg/mL) 2
- PTHrP: Elevated (ranging from 99 to 890 pmol/L in documented cases, with normal range 21-50.7 pmol/L) 6
- Calcium: Elevated (>11 mg/dL by definition) 6
- 1,25-dihydroxyvitamin D: Low or normal 2
In the exceedingly rare true ectopic PTH-producing tumors:
- PTH levels were inappropriately normal or elevated despite hypercalcemia 4, 5
- One case showed calcium-sensitive PTH production (122 pg/μg DNA at low calcium vs. 26 pg/μg DNA at high calcium) 4
- These tumors demonstrated PTH immunostaining on histopathology 4, 5
Clinical Implications and Diagnostic Approach
When evaluating hypercalcemia in lung cancer patients:
- Measure intact PTH first to distinguish PTH-dependent from PTH-independent causes 2
- If PTH is suppressed (expected finding), measure PTHrP as the next logical step 2
- The pattern of suppressed PTH with elevated PTHrP confirms the diagnosis in >95% of cases 2, 6
- Do not delay treatment while awaiting PTHrP results if hypercalcemia is severe or symptomatic 2
Prognostic Significance
Hypercalcemia in lung cancer carries an ominous prognosis:
- Median survival after diagnosis of hypercalcemia is approximately 27-30 days 2, 6
- All patients with tumor-induced hypercalcemia had advanced stage disease (Stage III or IV) 6
- This represents a medical emergency requiring immediate intervention 2
Critical Pitfall to Avoid
Do not assume elevated PTH means primary hyperparathyroidism in a lung cancer patient with hypercalcemia. If PTH is not suppressed as expected, consider:
- Laboratory error or assay interference
- Concurrent primary hyperparathyroidism (coincidental)
- The exceptionally rare ectopic PTH production (requires tissue confirmation) 4, 5
The key diagnostic error is failing to recognize that suppressed PTH is the expected finding in malignancy-associated hypercalcemia, not elevated PTH. 2