SAT-LB23 Paraneoplastic Hypercalcemia in a PTH Producing Adrenocortical Carcinoma - a Rare and Deadly Condition

Background: Hypercalcemia is a commonly encountered paraneoplastic manifestation of certain cancers with or without endocrine differentiation. However, the association between adrenocortical carcinoma (ACC) with paraneoplastic hypercalcemia is very rare, and therefore little is known about the cause and its relevance in the disease. Clinical Case: A 40-year-old woman presented in the hospital with a 5-month history of progressive flank pain with unintentional weight loss of 6 kg. MRI revealed a mass of 9x8.1x4.8 cm of the right adrenal gland with inhomogeneous contrast enhancement. Biochemical investigations provided evidence of endogenous hypercortisolism (24-hour urinary cortisol excretion [490 µg, n<236 µg/l], 1mg dexamethasone suppression test [199 nmol/l, n<50 nmol/l], ACTH [28 ng/l, n<61 ng/l]) although the patient did not show any specific clinical sign of overt hypercortisolism. In addition, laboratory testing revealed an exceptionally high plasma level of calcium [max 3.67 mmol/l (albumin-corrected)] and low phosphate [min 0.26 mmol/l] in the setting of low PTH [6.4 ng/l, n>15 ng/l] and PTHrP levels [<0.50 pmol/l]. However, subsequent dilution unmasked a highly elevated PTH concentration of 2171.5 ng/l with persistent low PTHrP levels, indicating false low values due to a hook effect in the initial measurement. Levels of 1,25-dihydroxy vitamin D and 25-hydroxy vitamin D were in the normal range. A PET-CT provided no indications of metabolically active (osseous) metastases. After correction of the serum calcium towards tolerable values, the tumor was removed by open en bloc adrenalectomy. Histologic evaluation confirmed an ACC (TNM pT4 pN1 (2/3), L1, V1, high grade) despite missing immunohistochemically expression of classical adrenal markers (diagnosis of exclusion). Supplemental quantitative RT-PCR studies support the diagnosis of ACC by detecting significant SF-1 and CYP11B2 expression in the tumor cells. Further analyses provided evidence that the mRNA expression of PTH, but not PTHrP, was moderately increased in the ACC sample compared to NCI H295R cells. Upon tumor resection, serum calcium levels swiftly normalized indicating the tumor as the sole source of PTH secretion. Despite initiation of adjuvant mitotane- and salvage chemo-therapy, the patient died 3 months later upon of a massive tumor relapse with a recurrence of severe hypercalcemia. Conclusion: This case demonstrates paraneoplastic hypercalcemia in a PTH producing ACC. PTH may induce hypercalcemia, impair adrenal steroid synthesis and act as an autocrine growth factor in ACC, as described in few individual cases for PTHrp producing ACC [1]. This suggests a poor prognosis for this rare entity. 1. Rizk-Rabin, M., et al., Differential Expression of Parathyroid Hormone-Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells. 2008.