60% 的甲状腺髓样癌 (MTC) 病例涉及 RET 突变。与之前的多激酶治疗相比，RET 选择性酪氨酸激酶抑制剂 selpercatinib 具有前所未有的疗效。朗格汉斯细胞组织细胞增多症 (LCH) 是一种克隆性组织细胞肿瘤，通常由体细胞 BRAF 突变驱动，导致 MAPK 信号传导失调。我们描述了一名 22 岁女性，其 MTC 转移至区域淋巴结、肺和肝。肿瘤组织含有体细胞致病性 RET 变异 p.(M918T)，并开始使用 selpercatinib。她经历了持续的临床、生化和放射学反应。两年后，她出现了快速进展的肺尖结节，需要进行活检。组织病理学证明 LCH 具有罕见的 BRAF 变异 p.(V600_K601>D)。吸入皮质类固醇后肺结节得到改善。我们假设 RET 阻断产生的选择性压力可能激活了下游体细胞 BRAF 突变，导致肺 LCH。我们建议在接受选择性 RET 抑制的患者中，继续警惕由下游 MAPK 信号失调引起的肿瘤。具有 RET 改变的 MTC 的患者可以通过选择性 RET 阻断（selpercatinib）经历疾病快速改善和持续的疾病稳定性。 LCH是一种由MAPK激活驱动的克隆性肿瘤，其最常见的机制是BRAF突变。 MTC 和肺 LCH 都是由 MAPK 信号通路激活失调驱动的。我们假设 RET 特异性抑制剂 selpercatinib 可能导致休眠 LCH 继发于选择压力和克隆增殖的激活。

RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition.Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib). LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation. Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation. We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.