Can Thyroid Cancer Produce PTHrP?
Yes, thyroid cancer can produce parathyroid hormone-related peptide (PTHrP), though this is not a characteristic feature of the most common thyroid cancer types and is more typically associated with other malignancies causing humoral hypercalcemia of malignancy.
Evidence for PTHrP Production in Malignancies
PTHrP is well-established as the major pathogenic factor in humoral hypercalcemia of malignancy (HHM), occurring in 10-25% of cancer patients, particularly those with squamous cell lung cancer 1, 2, 3. The peptide shares considerable homology with parathyroid hormone and binds to the PTH type 1 receptor (PTH1R) with high affinity, mimicking PTH actions on bone and kidney while suppressing endogenous PTH production 1, 4.
PTHrP Expression Across Tumor Types
Research demonstrates that PTHrP mRNA is expressed in the majority of various cancer cell lines, including gastric, breast, lung, colon, cervical, and renal cancers 5. Importantly, PTHrP expression has been documented at both the mRNA and protein levels across a wide variety of tumor types, suggesting it could serve as a common target molecule in immunotherapy for multiple cancer types 5.
Thyroid Cancer and PTHrP: Limited Direct Evidence
The provided guidelines on thyroid cancer management do not specifically mention PTHrP production as a characteristic feature of differentiated thyroid cancer (papillary or follicular) or medullary thyroid cancer 6.
- Medullary thyroid cancer (MTC) is specifically noted to produce calcitonin and CEA from parafollicular C cells, with elevated serum calcitonin serving as the primary tumor marker 6
- The thyroid cancer guidelines focus on calcitonin production rather than PTHrP when discussing peptide secretion 6
Clinical Implications and Diagnostic Approach
When hypercalcemia occurs in the context of malignancy, the diagnostic workup should include:
- Measurement of serum intact PTH (which will be suppressed in PTHrP-mediated hypercalcemia) 1, 2, 3
- Measurement of serum PTHrP levels (elevated in HHM) 2, 3
- PTHrP-mediated hypercalcemia is characterized by suppressed iPTH levels and low or normal calcitriol levels 1, 3
Plasma PTHrP concentrations are elevated in the majority of patients with cancer-associated hypercalcemia, with normal subjects having mean levels of 1.9 pmol/L and HHM patients having mean levels of 20.9 pmol/L 7.
Important Clinical Pitfall
While thyroid cancer can theoretically produce PTHrP (as many tumor types express this peptide), it is not a defining characteristic of thyroid malignancies. If a patient with thyroid cancer presents with hypercalcemia, consider alternative causes including:
- Concurrent primary hyperparathyroidism 1
- Bone metastases with local osteolytic activity 2, 3
- Other malignancies producing PTHrP 4, 5
The median survival after discovery of malignant hypercalcemia is approximately 1 month in lung cancer patients, emphasizing the prognostic significance when PTHrP-mediated hypercalcemia does occur 2, 3.