Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.
Department of Clinical Medicine and Surgery, University "Federico II", Naples, Italy.
Front Endocrinol (Lausanne). 2021 May 19;12:665698. doi: 10.3389/fendo.2021.665698. eCollection 2021.
Hypercalcemia 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.
The present series includes all patients with NENs and paraneoplastic hypercalcemia from four Italian centres: 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. 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. 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. A 69-year-old man was hospitalized after the onset of shortness of breath and dyspnea, asthenia and weight loss. Computed Tomography (CT) and Ga 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.
In 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.
高钙血症是一种常见的副瘤综合征，可发生于多达 10%的晚期肿瘤患者中。副瘤甲状旁腺激素相关蛋白（PTHrP）是该综合征最常见的原因。在神经内分泌肿瘤（NENs）中，副瘤性高钙血症较为罕见。
本系列包括来自意大利四个中心的所有患有 NENs 和副瘤性高钙血症的患者：一名 40 岁男性因反复跌倒、虚弱和嗜睡而住院。发现严重高钙血症。诊断为转移性胰腺 G2 NEN 和 PTHrP 相关高钙血症。患者开始接受生长抑素类似物（SSA）和地舒单抗治疗。疾病进展后，开始进行肽受体放射性核素治疗（PRRT），并伴有与 PTHrP 降低和正常钙水平相关的客观反应。一名 45 岁男性因胰腺 G2 NEN 而被转介。给予 SSA，随后给予依维莫司，以治疗转移灶的发生。发生高钙血症，并开始进行 PRRT 和地舒单抗治疗，以疾病进展伴骨转移。尽管在 PRRT 四个周期后疾病稳定，但患者的一般状况仍恶化直至死亡。一名 49 岁女性因精神迟钝、意识模糊、感觉迟钝而住院。诊断为严重高钙血症，伴胰腺 G1 NEN，并进行血液透析、双膦酸盐注射和降钙素持续输注治疗。1,25-二羟维生素 D 升高，PTHrP 不可检测。手术后血清钙水平和 1,25-二羟维生素 D 恢复正常。一名 69 岁男性因呼吸急促、呼吸困难、乏力和体重减轻而住院。计算机断层扫描（CT）和 Ga DOTATOC 正电子发射断层扫描（PET）-CT 显示左肺结节。检测到高钙血症和明显升高的 PTHrP 水平。组织学检查显示为不典型类癌。手术后，钙水平正常，PTHrP 显著降低，一般情况改善。
在我们的系列中，副瘤 PTHrP 相关高钙血症发生在胰腺 NEN 和一例支气管类癌中，这是文献中的第三个病例。我们的病例与 1,25-二羟维生素 D 分泌有关，是文献中的第四个病例。在患有高钙血症的 NEN 患者中应考虑 PTHrP 分泌。急性治疗应侧重于降低钙水平，长期控制可通过肿瘤细胞减灭术抑制 PTHrP 释放来实现。
