Humoral Hypercalcemia of Malignancy Is a Rare Complication of Bladder Carcinoma

Introduction : Humoral hypercalcemia of malignancy (HHM) accounts for approximately 80% of hypercalcemia caused by malignancies. We present an unusual case of squamous cell carcinoma (SCC) of the bladder as the etiology of HHM.

Case Description : A 76-year-old female with recently diagnosed poorly differentiated SCC of the bladder presented to the emergency department with complaints of worsening weakness and fatigue over one week.  Admission laboratories were notable for serum calcium of 12.1 mg/dL (8.6-10.3), albumin level 2.1 g/dL (3.5-5.7), and corrected calcium 13.6 mg/dL.  Serum calcium level corrected for low albumin was 10.8 mg/dL approximately a week before hospital admission.  Parathyroid hormone (PTH) level was suppressed at 10 pg/mL (12-88), and PTH related peptide (PTHrP) was unequivocally elevated at 80.6 pM (0.0-3.4), indicating HHM.  Saline hydration and calcitonin (4 IU/kg/dose for four doses) improved corrected calcium level to 12.5 mg/dL.  Due to impaired renal function (eGFR 34 mL/min/1.73m²), the patient was also treated with denosumab 120 mg.  Eucalcemia was achieved six days after administration of denosumab, and corrected calcium level at hospital discharge, 17 d after administration of denosumab, was 8.7 mg/dL.

Discussion : Bladder carcinoma is the sixth most common cancer in the United States and hypercalcemia of malignancy (HCM) is reported in 20-30% of cancer patients at some point during the course of disease, but HCM is a rare complication of bladder carcinoma.  Urothelial (transitional cell) carcinoma accounts for more than 90% of bladder cancers in the United States, and PubMed searches of “urothelial carcinoma and hypercalcemia” and “transitional cell carcinoma and hypercalcemia” return a total of 12 reported cases of HCM; a search of “squamous cell carcinoma bladder and hypercalcemia” fails to generate any publications.  Parathyroid-independent hypercalcemia is reported in all 12 cases of bladder cancer complicated by hypercalcemia, with PTHrP first identified as the causative factor in 1994.  One urothelial carcinoma complicated by HHM was reported to have squamous cell features.  The prevalence of bladder SCC in the United States is approximately 3%, though this appears to be the first reported case of bladder SCC complicated by HHM.  Prompt diagnosis and treatment of HCM is necessary to prevent cognitive impairment and renal failure that may occur due to severe hypercalcemia.  High dose denosumab is an effective treatment alternative to parenteral bisphosphonates such as zoledronic acid for treatment of HCM, including patients with low GFR.