Humoral Hypercalcemia in a Patient with Cholangiocellular Carcinoma – Effective Therapy with Denosumab

Abstract

Patient: Male, 65Final Diagnosis: Humoral hypercalcemiaSymptoms: SyncopeMedication: —Clinical Procedure: Establishing diagnosis • lowering hypercalcemia with denosumabSpecialty: Endocrinology and MetabolicObjective:Educational purpose (only if useful for a systematic review or synthesis)Background:Hypercalcemia in cholangiocellular carcinoma is a highly uncommon event, mainly reported in Asian patients. In the absence of bone metastases, humoral hypercalcemia of malignancy (HHM) can be assumed. This is mostly the consequence of an elevated parathormone-related peptide (PTHrP) level. The standard therapeutic options in HHM are sometimes limited by the underlying disease or concomitant diseases.Case Report:We report the case of a 65-year-old Caucasian male. A syncope due to a hypercalcemia of 4.16 mmol/L (normal range, 2.19–2.54 mmol/L) was the initial symptom that eventually led to the diagnosis of cholangiocellular carcinoma. He had no metastatic bone disease; HHM was suspected. PTHrP was moderately elevated. Since there were contraindications for the standard therapeutic options, a therapy with 120 mg denosumab was initiated and proved effective, safe, and restored the patient’s quality of life for 11 months.Conclusions:The moderate elevation of parathyroid hormone-related peptide (PTHrP) in this case is addressed in context with the recent insights of a substantial underestimation of this parameter by many commercial assays which can explain our observation. Denosumab, a human monoclonal antibody which acts as a RANKL-inhibitor (receptor activator of nuclear factor kappaB ligand) was recently suggested as a therapeutic alternative. In this case, the therapy of the hypercalcemia with denosumab due to contraindications for other therapies led to an effective and long-standing remission of hypercalcemia. Its effectivity should be studied in larger case samples.

Recurrent distal cholangiocarcinoma and humoral hypercalcemia of malignancy: report of a rare case and literature review

“…In 17 of 25 patients, including the present patient, the details of the hypercalcemia and its treatment have been described [5, 6, 8-16, 19, 22-24]. In 15 of 17 patients (88%), including the present one, the Ca concentrations were initially normalized in response to bisphosphonate [5, 6, 8-14, 16, 19], denosumab [15,22], or tumor volume reduction surgery [24]. However, 8 of these 17 patients showed persistent or recurrent hypercalcemia [9,13,14,19,[22][23][24].…”

“…In 15 of 17 patients (88%), including the present one, the Ca concentrations were initially normalized in response to bisphosphonate [5, 6, 8-14, 16, 19], denosumab [15,22], or tumor volume reduction surgery [24]. However, 8 of these 17 patients showed persistent or recurrent hypercalcemia [9,13,14,19,[22][23][24]. Sixteen of the 17 patients died within 3 months of the initial diagnosis or recurrence of HHM, and 8 of these 16 died within 3 months, despite their Ca concentrations being normalized by the treatments [5,6,8,[10][11][12]15].…”

“…Two of the previously reported patients were administered denosumab, which successfully controlled their serum Ca concentrations (Table 2) [15,22]. One patient was administered denosumab because of contraindications to the standard treatment for HHM, and they maintained a normal serum Ca concentration for 11 months [22]. Another patient was administered denosumab because of recurrent hypercalcemia, despite chemotherapy and the administration of the standard treatment for HHM.…”

“…Denosumab inhibits the interaction between RANKL and RANK receptor, which suppresses bone resorption and hypercalcemia [15]. Two of the previously reported patients were administered denosumab, which successfully controlled their serum Ca concentrations (Table 2) [15,22]. One patient was administered denosumab because of contraindications to the standard treatment for HHM, and they maintained a normal serum Ca concentration for 11 months [22].…”

“…(i) In a retrospective study of the prevalence of hypercalcemia in patients with various malignancies, the survival time was shorter in patients with hypercalcemia than in those with normocalcemia [46]. Of the patients with HHM secondary to CC, most died within 3 months when the hypercalcemia was persistent or relapsed despite treatment [9,13,14,19,[22][23][24]. (ii) PTHrP may affect the prognosis of patients, independent of hypercalcemia [7,8,15].…”