Has paraneoplastic syndrome with secretion of intact Parathyroid Hormone (PTH) been reported in patients with breast adenocarcinoma?

Paraneoplastic Syndrome with Intact PTH Secretion in Breast Adenocarcinoma

True ectopic secretion of intact parathyroid hormone (PTH) by breast adenocarcinoma has not been documented in the medical literature; hypercalcemia in breast cancer is caused by either bone metastases or parathyroid hormone-related peptide (PTHrP) secretion, not intact PTH. 1

Mechanisms of Hypercalcemia in Breast Cancer

Breast cancer-associated hypercalcemia occurs through two well-established mechanisms:

• Osteolytic bone metastases: Direct tumor invasion of bone causing local calcium release 2
• Humoral hypercalcemia of malignancy (HHM): Systemic secretion of PTHrP by the tumor 3, 4

PTHrP is the paraneoplastic mediator in breast cancer, not intact PTH. PTHrP expression is detected in approximately 64% of breast carcinomas by immunohistochemistry, with strong expression in 32% of positive cases 5. This protein shares structural homology with PTH at the N-terminus but is a distinct molecule encoded by a different gene 4.

Evidence Against Intact PTH Secretion

The literature consistently demonstrates that:

• Intact PTH levels are suppressed in hypercalcemic cancer patients, including those with breast cancer 1
• In a study of 34 hypercalcemic cancer patients, all showed suppressed PTH levels, while 27 of 29 patients with solid tumors (including breast cancer) had elevated PTHrP 1
• True ectopic secretion of intact PTH is considered unlikely in cancer patients based on biochemical profiling 1

Clinical Differentiation: Primary Hyperparathyroidism vs. Paraneoplastic Syndrome

When a breast cancer patient presents with hypercalcemia and elevated intact PTH, this represents concurrent primary hyperparathyroidism, not a paraneoplastic syndrome 2. A case report documented a 69-year-old woman with invasive breast cancer and hypercalcemia (3.4 mmol/L) who had:

• Markedly elevated intact PTH (793 ng/L) 2
• Negative bone scan for metastases 2
• Parathyroid adenoma confirmed on imaging and pathology 2
• Normalization of calcium and PTH after parathyroid adenoma resection 2

This case demonstrates that elevated intact PTH in breast cancer patients indicates a separate benign parathyroid disorder, not tumor-mediated PTH production 2.

PTHrP as the True Paraneoplastic Mediator

PTHrP expression in breast cancer has significant clinical implications:

• Strong correlation exists between PTHrP levels and serum calcium (r = 0.75, p < 0.001) in patients with solid cancers 1
• PTHrP expression correlates with histological tumor grade and bone metastasis 5
• Estrogen and tamoxifen can stimulate PTHrP secretion, potentially explaining transient hypercalcemia during hormonal therapy 4
• PTHrP-positive breast cancers have significantly shorter overall survival in multivariate analysis 5

Diagnostic Approach to Hypercalcemia in Breast Cancer

When evaluating hypercalcemia in a breast cancer patient:

1. Measure intact PTH and PTHrP levels simultaneously 1
2. If PTH is elevated: Suspect concurrent primary hyperparathyroidism; perform parathyroid imaging (ultrasound and scintigraphy) 2
3. If PTH is suppressed and PTHrP is elevated: Diagnose humoral hypercalcemia of malignancy 1
4. Obtain bone scan to evaluate for osteolytic metastases 2

Common Pitfall

The critical error is attributing elevated intact PTH to paraneoplastic secretion by breast cancer. This misdiagnosis delays appropriate treatment of a curable parathyroid adenoma while incorrectly suggesting more advanced malignancy 2. Primary hyperparathyroidism should always be considered when intact PTH is elevated in the setting of negative bone imaging and only mildly deteriorated bone mineral density 2.