Case Report: Unmasking Hypercalcemia in Patients With Neuroendocrine Neoplasms. Experience From Six Italian Referral Centers

BackgroundHypercalcemia is a common paraneoplastic syndrome which can occur in up to 10% of patients with advanced neoplasms. Paraneoplastic parathyroid hormone-related protein (PTHrP) represents the most frequent cause of this syndrome. In neuroendocrine neoplasms (NENs) paraneoplastic hypercalcemia is rare.Case SeriesThe present series includes all patients with NENs and paraneoplastic hypercalcemia from four Italian centres: (I) A 40-year-old man was hospitalized for repeated episodes of falls, hyposthenia and drowsiness. Severe hypercalcemia was found. Metastatic pancreatic G2 NEN and PTHrP-related hypercalcemia were diagnosed. The patient started therapy with somatostatin analogs (SSA) and Denosumab. After disease progression peptide receptor radionuclide therapy (PRRT) was started with an objective response associated with PTHrP reduction and normocalcemia. (II) A 45-year-old man was referred for pancreatic G2 NEN. SSA and subsequently everolimus were administered for metastases occurrence. Hypercalcemia occurred and PRRT and Denosumab were started for disease progression with the onset of bone metastases. Despite disease stability after four cycles of PRRT the patient’s performance status worsened until death. (III) A 49-year-old woman was hospitalized for psychic slowdown, confusional state, sensory dullness. A severe hypercalcemia, associated with a pancreatic G1 NEN was diagnosed and treated with haemodialysis, bisphosphonates injections and continuous infusion of calcitonin. 1,25-dihydroxyvitamin D was high, PTHrP was undetectable. After surgery serum calcium levels and 1,25-dihydroxyvitamin D were normalized. (IV) A 69-year-old man was hospitalized after the onset of shortness of breath and dyspnea, asthenia and weight loss. Computed Tomography (CT) and 68Ga DOTATOC Positron Emission Tomography (PET)-CT revealed a left pulmonary nodule. Hypercalcemia and markedly elevated PTHrP levels were detected. The histological examination revealed an atypical carcinoid. After surgery, calcium levels were normalized, PTHrP was significantly reduced with an improvement of general conditions.ConclusionIn our series, paraneoplastic PTHrP-related hypercalcemia occurred in pancreatic NEN and in one bronchial carcinoid representing the third case in the literature. Our case associated with 1,25-dihydroxyvitamin D secretion represents the fourth case in the literature. PTHrP secretion should be considered in NENs’ patients with hypercalcemia. Acute treatment should be focused on lowering calcium levels, and long-term control can be achieved by tumor cytoreduction inhibiting PTHrP release.

Paraneoplastic Hypercalcemia as the Initial Presenting Sign of Metastatic Renal Cell Carcinoma

Introduction: Malignant hypercalcemia can occur in patients with renal cell carcinoma as part of a paraneoplastic syndrome. The suggested mechanisms of malignant hypercalcemia include overproduction of parathyroid hormone-related peptide (PTHrP), interleukin-6 (IL-6), prostaglandins, and tumor necrosis factor-alpha (TNF-α). This report describes an unusual case of paraneoplastic hypercalcemia as the initial manifestation of metastatic renal cell carcinoma (RCC). Case presentation: A 44-year-old Caucasian male with no past medical history who presented to his PCP complaining of unintentional weight loss of 25 lbs, increasing fatigue, occasional right flank pain, and nausea. His family history is significant for multiple myeloma of his mother. The physical exam was unremarkable. Labs were remarkable for serum calcium of 11.5 mg/dL, Albumin of 4.5 g/dL, intact parathyroid hormone (PTH) of 9 pg/mL, undetectable PTHrP, 25 hydroxy VitD of 26.4 ng/mL, and 1, 25 hydroxy VitD of 18 pg/mL. Serum and urine protein electrophoresis and PSA were unremarkable. CXR revealed the right lower lobe noncalcified nodule of 15×11×7 mm. CT abdomen/Pelvis revealed a right renal mass of 13×14×12 cm without lymphadenopathy or local metastasis. The patient was referred to a medical oncologist and further workup including PET/CT scan that demonstrated increased uptake in right lung nodule of SUV 6, right renal mass uptake of SUV 72, and MRI brain without metastasis. The patient treated with right total nephrectomy that revealed a sarcomatoid renal cell carcinoma. Right lung nodule biopsy revealed a clear cell renal carcinoma. The patient further treated with two cycles of Gemcitabine/oxaliplatin and four cycles of nivolumab/ipilimumab. A repeated PET/CT scan showed a complete resolution of a right lung nodule. Repeated labs were unremarkable, including serum calcium of 8.7 mg/dL. Discussion: Hypercalcemia is a frequent occurrence in patients with RCC, but it is an unusual presenting symptom. The initial evaluation should focus on whether the hypercalcemia is parathyroid-dependent or medication-related. Basic laboratory investigations for hypercalcemia include PTH, PTHrP, and 1, 25(OH)2D. Bone-resorbing cytokines may be present in those patients in which the cause of the hypercalcemia is unclear. In our case, we could not determine the specific cytokine that caused hypercalcemia, as IL-6 and TNF-α were unavailable. If laboratory tests are unavailable, bone scan, CT scan, or PET-CT should be considered to evaluate for lytic bone lesions or underlying malignancy. Evaluation for carcinoma should be persistently pursued in a patient who has symptoms suggestive of paraneoplastic hypercalcemia. Finally, symptomatic malignant hypercalcemia can be treated with IV fluids and bisphosphonates. Approximately 50% of patients who undergo nephrectomy and/or tumor debulking will revert to normocalcemia.

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.

Paraneoplastic Hypercalcemia Secondary to Canine Mammary Tumors

Background: Paraneoplastic syndromes are complexes symptom that occur at a distinct site from the primary tumor or its metastasis by the production of hormone by the tissue in which the tumor appears. Paraneoplastic hypercalcemia is associated with an abnormal elevation of serum calcium levels and the mainly tumor related to this syndrome in canine is lymphoma, anal sac apocrine gland adenocarcinoma and multiple myeloma. In mammary tumors, the most frequent tumor that affect female dogs, this syndrome was also observed. The aims of this study were to evaluate serum calcium levels in female dogs with malignant mammary tumors and correlate calcium levels with clinicopathological parameters.Materials, Methods & Results: It was evaluated fifty-one female dogs with mammary carcinomas (simple carcinomas and carcinoma in mixed tumors) for serum calcium levels using colorimetric test. Clinical-histopathological data as spray status, pseudopregnancy, tumor size, ulceration, clinical staging, histopathological type and tumor grade were also evaluated in association with serum calcium levels. All dogs were treated with unilateral mastectomy. It was observed that 18 animals (35%) had calcium serum levels increased (>11.5 mg/dL) and 56% (10/18 cases) of these animals had serum calcium levels higher than 12 mg/dL. All dogs with hypercalcemia were asymptomatic, including two female dogs that presented the highest levels (13.43 mg/dL and 14.28 mg/dL). Hypercalcemia of malignancy was related to mammary carcinomas after the exclusion of other causes of hypercalcemia through laboratory tests (complete blood count and serum biochemistry) and abdominal ultrasound. No correlation was verified between the corrected serum calcium values with clinical and histopathological parameters evaluated.Discussion: In this study, it was observed a high incidence of paraneoplastic hypercalcemia associated with canine mammary tumors (35%). In humans, this syndrome is related in up to 10% of all patients with advanced cancer and with worse prognosis. The most frequent clinical signs of hypercalcemia are nonspecific and can be confused with other diseases, such as polyuria, polydipsia, anorexia, constipation, lethargy and weakness. The treatment of this syndrome is based on tumor resection and when necessary other treatments can be performed with fluid containing 0.9% sodium chloride, furosemide, prednisolone and calcitonin. Patients with asymptomatic or mildly symptomatic hypercalcemia (calcium levels <12 mg/ dL) do not require immediate treatment. Clinical signs occur more frequently with serum calcium levels higher than 15 mg/dL. Calcium levels higher than 18 mg/dL are considered a medical emergency and the clinical signs observed are trigger seizures, cardiac arrhythmia, acute renal failure and death. Most animals of this study presented mild hypercalcemia, that could justify the absence of clinical signs related to this syndrome, and the treatment for this syndrome was the tumor removal. The high serum calcium levels did not show correlation with more aggressive tumors and poorer prognosis, conditions evaluated by histological type, tumor grade and clinical stage. The evaluation of serum calcium levels is an important clinical test to be done in female dogs with mammary tumors, besides to be an affordable and technically simple test. The clinical signs related to this syndrome are nonspecific and may be confused with other diseases commonly observed in older dogs. The data suggest that there are no correlation between serum calcium levels with aggressiveness of canine mammary tumors and with other clinical features.

SMARCA4-Deficient Carcinoma of Unknown Primary Presenting with Fatal Paraneoplastic Hypercalcemia in a Heart Transplant Recipient: First Report in a Male Patient

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare SMARCA4-driven aggressive malignancy of young age characteristically associated with paraneoplastic hypercalcemia. Comparable neoplasms/presentations have not been reported in males. A 39-year-old male heart transplant recipient (HTX 40 months previously) presented with multiple liver nodules and hypercalcemic crisis. The serum parathyroid hormone-related protein (PTHrp) was significantly elevated (241 pg/ml; reference value < 57). Liver biopsy showed poorly differentiated partially rhabdoid neoplasm expressing pancytokeratin, CK20, and focally GATA3, SATB2, p63, and SALL4. The tumor cells showed dual loss of SMARCA4 and SMARCA2. He died of irreversible multiorgan failure one week after admission. To our knowledge, this is the first report highlighting the rare occurrence of paraneoplastic hypercalcemia associated with SMARCA4-deficient malignancies in males. Although the immunophenotype suggests urothelial or upper gastrointestinal tract origin, the exact primary tumor site could not be ascertained due to rapid death of the patient. SMARCA4 immunohistochemistry should be included in the workup of neoplasms associated with hypercalcemia irrespective of gender and site.