A Rare Case of Humoral Hypercalcemia of Malignancy Caused by a Gallbladder Adenocarcinoma

Humoral hypercalcemia of malignancy (HHM) is a common paraneoplastic syndrome occurring secondary to oversecretion of parathyroid hormone-related peptide (PTHrP). It is usually seen in solid tumors particularly squamous cell carcinoma of the head, neck, and lungs. Gallbladder adenocarcinoma is an unusual cause of HHM. We present a rare case of hypercalcemia secondary to elevated PTHrP secretion in a patient with gallbladder adenocarcinoma.

Case Description:

A 65-year-old woman with a history of gallbladder adenocarcinoma (diagnosed 3 months prior to admission) presented to the hospital with fatigue, dizziness, and nausea. Initial labs revealed calcium of 15.1 (Normal: 8.5 - 10.2 mg/dL), Albumin 2.7 (Normal: 3.5-5.2 g/dL), Phosphorous 2.1 (Normal: 2.8 - 4.5 mg/dL), and creatinine 0.6 (Normal: 0.6 - 1.1 mg/dL). Further studies showed iPTH of 7 (Normal: 14-65 pg/ml), 25-Hydroxyvitamin D 10.1 (Normal: 20 - 40 ng/ml), Vitamin D 1,25 of 55 (Normal: 18- 78 pg/ml) and elevated PTHrP of 132 (Normal: < 2.5 pmol/L). Per oncology, the patient had non-resectable cancer. She was managed with intravenous (IV) fluids, calcitonin and received 4 mg IV zoledronic acid. Her calcium subsequently normalized to 10 mg/dL and she was discharged to a rehabilitation facility. She presented to the hospital a week later with similar complaints, and was found to have hypercalcemia with corrected calcium of 15 mg/dL. However, she expired before further treatment could be provided.

Discussion:

PTHrP-mediated hypercalcemia is commonly associated with squamous cell carcinomas, and portends a poor prognosis. Gallbladder adenocarcinoma is an aggressive form of cancer with a 5-year survival rate of approximately 19%. Cases of PTHrP-mediated hypercalcemia in gallbladder adenocarcinoma have been rarely reported. The management of HHM involves treatment of the underlying carcinoma along with other pharmacological agents to lower calcium such as IV bisphosphonate or denosumab. IV bisphosphonates are considered first line of treatment and in most patients serum calcium level normalizes within 4 to 7 days. This response lasts for 1 to 3 weeks. In our case, the patient returned within a week with hypercalcemia despite receiving bisphosphonates. A similar pattern was observed in a prior case report of a patient with gallbladder adenocarcinoma, where IV bisphosphonate therapy was unsuccessful. Given the paucity of such cases, it remains unclear if this cancer is less amenable to standard therapies for hypercalcemia of malignancy due to higher expression of PTHrP or due to a PTHrP independent mechanism.