背景:在过去的10年中,用抗PD(L)1和抗CTLA4抗体进行的免疫检查点抑制显着改变了癌症治疗。然而,通过免疫检查点抑制增强免疫系统可导致免疫相关的不良事件,影响不同的器官系统,其中内分泌系统受影响最大。然而,关于免疫相关不良事件的关联描述很少,一些人的病理生理学仍然缺乏。这里,我们报道了一名70岁的高加索患者,在颈部黑色素瘤独特复发切除后,接受nivolumab(抗PD1单克隆抗体)治疗,并出现干燥综合征。极度疲劳,和体重减轻6个月后开始抗PD1治疗。血液检查显示,由于孤立的促肾上腺皮质激素缺乏,低血糖和继发性皮质醇减少。有趣的是,脑蛋氨酸正电子发射断层扫描/磁共振显示脑垂体的生理代谢,没有增加尺寸,未发现垂体转移。干燥综合征调查显示缺乏抗SSA/SSB抗体,而唇腺活检显示淋巴浆细胞浸润,焦点评分为1分。为了提供抗PD1相关唾液腺炎的病理生理学的新见解,我们通过对唇腺腺泡的免疫染色研究了水通道蛋白5的分布,并将这种分布与原发性干燥综合征中表达的分布进行了比较。与原发性干燥综合征患者(水通道蛋白5主要在基底外侧表达)相反,但与没有唾液腺炎的患者相似,我们观察到顶端水通道蛋白5的表达。这一新发现值得在其他抗PD1相关性唾液腺炎患者中得到证实。由于这些免疫相关的不良事件,抗PD1被停止;尽管如此,患者在1年后(2020年3月)颈部出现新的复发,通过放射治疗。从那以后,未发现黑色素瘤复发(放疗后1.5年),但患者仍需要垂体置换治疗.唾液腺炎部分缓解。
结论:我们报告了唾液腺炎和垂体炎的组合,解释了在抗PD1辅助治疗的黑色素瘤复发患者的极度疲劳。
BACKGROUND: Immune checkpoint inhibition with anti-PD(L)1 and anti-CTLA4 antibodies has significantly changed cancer treatment during the last 10 years. Nevertheless, boosting the immune system with immune checkpoint inhibition can result in immune-related adverse events, affecting different organ systems, among which the endocrine system is the most affected. However, there are few descriptions of the association of immune-related adverse events, and the pathophysiology of some is still lacking. Here, we report a 70-year-old Caucasian patient treated with nivolumab (anti-PD1 monoclonal antibody) after resection of a unique relapse of melanoma in the neck region who presented with sicca syndrome, extreme fatigue, and weight loss 6 months after the start of anti-PD1 therapy. Blood tests revealed hypoglycemia and secondary hypocortisolism due to isolated adrenocorticotrophic hormone deficiency. Interestingly, brain methionine positron emission tomography/magnetic resonance revealed physiological metabolism of the pituitary gland, which was not increased in size, and no hypophyseal metastasis was detected. The sicca syndrome investigation revealed the absence of anti-SSA/SSB antibodies, while the labial salivary gland biopsy showed lymphoplasmatocytic infiltrates with a focus score of 1. To provide new insights into the physiopathology of the anti-PD1-related sialadenitis, we investigated the distribution of
aquaporins 5 by immunostaining on the labial salivary gland acini, and compared this distribution with the one expressed in the primary Sjögren\'s syndrome. Contrary to patients with primary Sjögren\'s syndrome (in whom
aquaporins 5 is mainly expressed at the basolateral side), but similar to the patients with no sialadenitis, we observed expression of
aquaporins 5 at the apical pole. This new finding deserves to be confirmed in other patients with anti-PD1-related sialadenitis. Owing to these immune-related adverse events, anti-PD1 was stopped; nevertheless, the patient developed a new relapse 1 year later (March 2020) in the neck region, which was treated by radiotherapy. Since then, no relapse of melanoma was seen (1.5 years after radiotherapy), but the patient still requires hypophyseal replacement therapy. The sialoadenitis resolved partially.
CONCLUSIONS: We report a combination of sialoadenitis and hypophysitis explaining extreme fatigue in a patient who was treated in the adjuvant setting with anti-PD1 for a melanoma relapse.