Abstract

Ameloblastoma is a rare odontogenic tumor which may be complicated by hypercalcemia in advanced disease. Tumoral parathyroid hormone-related peptide (PTHrP) production and local osteolysis from paracrine factors have been proposed as mechanisms. Mitogen-activated protein kinase (MAPK) inhibitors have been successfully used in ameloblastomas with BRAF V600E mutation to reduce symptoms and decrease tumor burden. Serum calcium has been observed to normalize following treatment with MAPK inhibitors; however, the response of PTHrP and markers of bone turnover has not been reported. We describe a case of a 55-year-old female with PTHrP-mediated hypercalcemia secondary to BRAF V600E-positive ameloblastoma with pulmonary metastases. Following treatment with dabrafenib and trametinib, the patient experienced the regression of pulmonary lesions and normalization of serum calcium, PTHrP, and markers of bone turnover. Tissue samples of ameloblastoma carrying BRAF V600E mutation are more likely to express PTHrP than tissue samples carrying wild-type BRAF. In our case, resolution of PTHrP-mediated hypercalcemia following initiation of BRAF/MEK inhibition provides additional evidence that the MAPK pathway contributes to PTHrP synthesis. It also raises the question of whether MAPK inhibitors would be effective in treating PTHrP-mediated hypercalcemia associated with other malignancies harboring BRAF V600E mutation.

中文翻译：

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BRAFV600E 阳性转移性成釉细胞瘤接受 BRAF/MEK 双重抑制治疗后 PTHrP 介导的高钙血症得到缓解

摘要

成釉细胞瘤是一种罕见的牙源性肿瘤，晚期可能并发高钙血症。肿瘤甲状旁腺激素相关肽（PTHrP）的产生和旁分泌因子的局部骨质溶解已被认为是机制。丝裂原激活蛋白激酶 (MAPK) 抑制剂已成功用于治疗 BRAF V600E 突变的成釉细胞瘤，以减轻症状并减轻肿瘤负荷。使用 MAPK 抑制剂治疗后，观察到血清钙恢复正常；然而，PTHrP 和骨转换标志物的反应尚未见报道。我们描述了一名 55 岁女性的病例，她患有 PTHrP 介导的高钙血症，继发于 BRAF V600E 阳性成釉细胞瘤并伴有肺转移。接受达拉非尼和曲美替尼治疗后，患者肺部病变消退，血清钙、PTHrP 和骨转换标志物恢复正常。携带 BRAF V600E 突变的成釉细胞瘤组织样本比携带野生型 BRAF 的组织样本更有可能表达 PTHrP。在我们的案例中，BRAF/MEK 抑制开始后 PTHrP 介导的高钙血症的解决提供了 MAPK 途径有助于 PTHrP 合成的额外证据。它还提出了一个问题：MAPK 抑制剂是否能有效治疗与其他携带 BRAF V600E 突变的恶性肿瘤相关的 PTHrP 介导的高钙血症。