Ectopic PTH Production by Cancers: An Extremely Rare Phenomenon
True ectopic production of intact parathyroid hormone (PTH) by malignant tumors is exceedingly rare, with only isolated case reports documented in the literature, whereas PTH-related protein (PTHrP) is the overwhelmingly common cause of malignancy-associated hypercalcemia. 1, 2, 3
The Dominant Mechanism: PTHrP, Not PTH
The critical distinction in cancer-related hypercalcemia is that PTHrP—not intact PTH—is responsible for the vast majority of cases:
In nearly all hypercalcemic patients with solid tumors (27/29 in one series), PTHrP levels were elevated while PTH levels were suppressed, confirming that PTHrP is the primary mediator of humoral hypercalcemia of malignancy (HHM). 4
PTH levels are characteristically suppressed in malignancy-associated hypercalcemia due to the negative feedback from elevated calcium, making true ectopic PTH production highly unusual. 4
The correlation between corrected serum calcium and PTHrP levels is strong (r = 0.75, p < 0.001), further establishing PTHrP as the dominant mechanism. 4
Documented Cases of True Ectopic PTH Production
While extraordinarily rare, authentic ectopic PTH secretion has been confirmed in specific tumor types:
Squamous Cell Lung Carcinoma
The first definitively proven case involved a 71-year-old man with squamous cell lung carcinoma where immunocytochemical analysis and cultured tumor cells demonstrated PTH production (122 ± 16 pg/μg DNA at low calcium vs. 26 ± 2 pg/μg DNA at high calcium). 1
A second case documented concurrent elevation of both PTH and PTHrP in lung cancer with liver metastasis, with histopathologic examination revealing PTH immunostaining in tumor tissue and no parathyroid gland abnormalities on autopsy. 3
Gynecologic Malignancies
- Dedifferentiated endometrial carcinoma has been reported to produce ectopic PTH, with molecular analysis confirming PTH gene and protein expression within the tumor, and normalization of PTH levels post-resection followed by re-elevation with metastases. 2
Rhabdomyosarcoma
- Metastatic nasopharyngeal rhabdomyosarcoma demonstrated PTH mRNA in tumor cells via RT-PCR and sequence analysis, with elevated serum PTH (62.22 pmol/L) and pleural fluid PTH (47.28 pmol/L). 5
Tumor Types Associated with Ectopic ACTH (Not PTH)
The provided guidelines extensively discuss ectopic ACTH production rather than PTH, which occurs in:
Neuroendocrine tumors in the lung, thyroid, pancreas, or bowel are the probable sources of ectopic ACTH when Cushing syndrome presents with elevated ACTH levels. 6
Small cell lung cancer frequently presents with paraneoplastic syndromes including ectopic ACTH secretion causing Cushing's syndrome (with high serum cortisol and ACTH, hypernatremia, hypokalemia, alkalosis). 6
Clinical Diagnostic Approach
When evaluating hypercalcemia in a cancer patient:
Measure intact PTH and PTHrP simultaneously: Suppressed PTH with elevated PTHrP indicates typical HHM; elevated PTH suggests either primary hyperparathyroidism or the exceptionally rare ectopic PTH production. 4
Exclude primary hyperparathyroidism first: Perform parathyroid imaging and assess for parathyroid adenoma, as this is far more common than ectopic PTH production. 7, 8
If PTH is elevated with confirmed malignancy and no parathyroid pathology: Consider immunohistochemical staining of tumor tissue for PTH and molecular analysis (RT-PCR for PTH mRNA) to confirm ectopic production. 1, 2, 5
Assess tumor calcium sensitivity: Cultured tumor cells from true ectopic PTH-producing tumors demonstrate calcium-sensitive PTH secretion, similar to normal parathyroid tissue. 1
Critical Clinical Pitfall
Do not assume ectopic PTH production when PTH is elevated in a cancer patient—primary hyperparathyroidism coexisting with malignancy is substantially more common than true ectopic PTH secretion. 4 The diagnosis of ectopic PTH production requires definitive molecular or immunohistochemical confirmation of PTH production by tumor cells, not merely elevated serum PTH levels. 1, 2, 5