SUN-803 - Unraveling Hypercalcemia in Metastatic Esophageal Adenocarcinoma: Dual Pathogenic Mechanisms Beyond Elevated Parathyroid Hormone

Introduction:
Hypercalcemia affects approximately 1% of the population, with primary hyperparathyroidism (PHPT) and hypercalcemia of malignancy (HCM) accounting for 90% of cases. The initial approach involves distinguishing PTH-dependent from PTH-independent mechanisms. PHPT, characterized by elevated or inappropriately normal PTH levels, accounts for most outpatient presentations of mild hypercalcemia. Conversely, HCM, the most common cause in hospitalized patients, typically presents with suppressed PTH levels. When hypercalcemia develops in patients with known malignancy and elevated PTH, concomitant PHPT is the most likely diagnosis, as ectopic PTH secretion by tumors is extremely rare. Severe hypercalcemia (serum calcium ≥14 mg/dL) occurs more commonly with HCM than PHPT, making dual etiology particularly important to recognize in cancer patients presenting with marked hypercalcemia, as this necessitates aggressive treatment of acute hypercalcemia with bisphosphonates while addressing the underlying malignancy.
Clinical

Case:
A 69-year-old woman with T1bN2M1 esophageal adenocarcinoma and brain metastasis status post neoadjuvant chemotherapy and radiation presented with acute pulmonary embolism and severe hypercalcemia (serum calcium 15.6 mg/dL, PTH 173 pg/mL). Additional labs revealed leukocytosis (21.8 K/μL), acute kidney injury (creatinine 1.49 mg/dL from baseline 0.7-0.8 mg/dL), and elevated alkaline phosphatase (463 U/L). Chart review revealed mild hypercalcemia (11.1 mg/dL) and inappropriately elevated PTH of 143 pg/mL three months prior to presentation. Despite findings demonstrating preexisting PHPT, alternative causes of severe hypercalcemia were considered given the known malignancy. PTHrP was elevated at 24 pmol/L, confirming a dual etiology of hypercalcemia. PET imaging demonstrated disease progression with new pulmonary and hepatic metastases but no bone metastases, consistent with humoral HCM from PTHrP. Neck ultrasound failed to identify a parathyroid adenoma. The patient received aggressive intravenous hydration, calcitonin 4 units/kg twice daily for four doses, and zoledronic acid 4 mg intravenously. Serum calcium normalized by hospital day six, and she was discharged with a referral for surgical evaluation and consideration for definitive management.
Clinical Lesson:
This case highlights the importance of investigating PTH-independent mechanisms in cancer patients presenting with hypercalcemia, even when PTH-dependent PHPT is clearly documented. The presence of severe hypercalcemia should heighten suspicion for concurrent malignancy-related mechanisms. PTHrP-mediated hypercalcemia has been documented with esophageal adenocarcinoma and is associated with poor prognosis. Recognition of a dual etiology of hypercalcemia is essential for appropriate therapeutic management and prognostic counseling.

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