小细胞肺癌患者采用PD-L1抑制剂治疗致垂体炎1例报道并文献复习

doi:10.16150/j.1671-2870.2022.06.13

摘要/Abstract

摘要：

本文报道1例经细胞程序性死亡配体1（Programmed cell death-ligand 1，PD-L1）抑制剂治疗7个周期后导致免疫相关垂体炎（immune-related hypophysitis， irH）病例。患者表现为乏力、纳差、低血压，血清促肾上腺皮质激素（adrenocorticotropic hormone，ACTH）、促甲状腺激素水平较PD-L1抑制剂治疗前明显降低（分别由治疗前的正常值48 ng/L、4.64 μIU/mL降至3.8 ng/L、0.266 μIU/mL），予氢化可的松替代治疗20 d后，患者的临床症状及激素水平逐步好转。回顾近10年PubMed、万方及中国知网数据库收录的由免疫检查点抑制剂导致的300余例垂体炎病例，其中84例肺癌患者，由PD-L1抑制剂引起irH的肺癌患者为10例，患者主要表现为乏力、厌食、体重下降、低血压。与细胞毒性T淋巴细胞相关蛋白4抗体阻断剂相比， PD-1/PD-L1引起的irH发病率低，且发病相对较迟，且垂体MRI检查多无明显异常，但病情危重，甚至可危及生命，临床需引起重视。

关键词: 程序性死亡配体抑制剂, 小细胞肺癌, 免疫相关垂体炎

Abstract:

This paper reports a case of immune-related hypophysitis (irH) after 7 cycles of treatment with Duva-lizumab, a PD-L1 (programmed cell death-ligand 1) inhibitor in a patient with small cell lung cancer. The patient showed fatigue, anorexia, hypotension, with lower serum levels of adrenocorticotropic hormone (ACTH) (3.8 ng/L) and thyroid stimulating hormone（TSH）(0.266 μIU/mL) than those before treatment (48 ng/L, 4.64 μIU/mL). The patient′s condition gradually improved with hydrocortisone replacement treatment. PubMed, Wanfang, and CNKI databases were searched.A total of 316 cases have been reported in recent 10 years, including 10 cases with irH caused by PD-1/PD-L1 in 84 lung cancer patients, mainly manifested as fatigue, anorexia, weight loss, and hypotension. Compared with cytotoxic T lymphocyte associated protein 4 antibody blocker treatment, the incidence of PD-1/PD-L1 induced-irH is low, and onset of irH is later. Pituitary MRI images mostly showed no abnormality. However, the condition of the patients was often critical or even life-threatening, which need to pay attention to.

Key words: Programmed cell death-ligand 1 inhibitor, Small cell lung cancer, Immune-related hypophysitis

中图分类号:

R735

张美玲, 朱潇邦, 宋爱玲, 周剑平, 李庆云. 小细胞肺癌患者采用PD-L1抑制剂治疗致垂体炎1例报道并文献复习[J]. 诊断学理论与实践, 2022, 21(06): 741-745.

ZHANG Meiling, ZHU Xiaobang, SHONG Ailing, ZHOU Jianping, LI Qingyun. PD-L1 inhibitors-induced hypophysitis in a patient with small cell lung cancer: a case report and literatures review[J]. Journal of Diagnostics Concepts & Practice, 2022, 21(06): 741-745.

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检测项目	ICI治疗前	irH确诊时	糖皮质激素治疗irH 20 d	糖皮质激素停药15 d	参考值
垂体-肾上腺轴激素皮质醇（nmol/L）
8 AM	406.0	39^a）	148.5	224.5	133~537
4 PM	402.1	37.8^a）	/		68.2~327
0 AM	400.6	39.6^a）	/	258.4	/
促肾上腺皮质激素（ACTH）（ng/L）
8 AM	48	3.8^a）	2.89^a）	<1.0^a）	7.2~63.3
4 PM	/	1.72^a）	/	2.46^a）	5.0~40.0
0 AM	/	1.52^a）	/	1.19^a）	5.0~10.0
垂体-甲状腺轴激素
促甲状腺激素（TSH）（μIU/mL）	4.64	0.266^a）	3.71	0.948	0.27~4.2
总甲状腺素（TT₄）（nmol/L）	78.29	59.48^a）	80.44	53.16^a）	66~181
三碘甲状腺原氨酸（TT₃）（nmol/L）	1.38	0.632^a）	1.01^a）	1.00^a）	1.3~3.1
游离甲状腺素（FT₄）（pmol/L）	13.56	10.68^a）	16.79	13.41	12.0~22.0
游离三碘甲状腺原氨酸（FT₃）（pmol/L）	14.92	2.44^a）	2.99^a）	2.61^a）	3.1~6.8
垂体-性腺轴激素
黄体生成素（LH）（mIU/mL）	/	19.31^a）	/	5.05	1.24~8.62
卵泡刺激素（FSH）（mIU/mL）		39.19^a）		22.45	2.64~13.13
泌乳素（PRL）（ng/mL）		0.55^a）		11.23	2.64~13.13
孕酮（P）（ng/mL）		0.03^a）		0.05^a）	0.14~2.06
睾酮（T）（ng/mL）		2.29		0.61^a）	1.75~7.81
雌二醇（S）（pg/mL）		17.91		22.36	15~38.95

参考文献	年龄（岁）	性别	诊断	使用药物	发生时间	临床症状	MRI 表现	激素及电解质水平									激素恢复情况
参考文献	年龄（岁）	性别	诊断	使用药物	发生时间	临床症状	MRI 表现	ACTH	F	TSH	FT₄	FSH/LH	GH	PRL	钠	钾	激素恢复情况
[15]	69	女	ADE	Nivolumb	16周	乏力、纳差	前叶萎缩，垂体高度2.2 mm	↓	↓	↓	↑	-	-	-	-	-	NA
[16]	75	男	ADE	Nivolumb	26周	乏力、纳差、低血压	垂体无明显异常	↓	↓	↑	-	-	-	↓	-	-	TSH、PRA 恢复，ACTH 未恢复
[17]	63	男	ADE	Nivolumb	15周	纳差、乏力、低血压、发热	垂体无明显异常	↓	↓	-	-	-	-	-	↓	-	NA
[18]	58	女	SCLC	Nivolumb+ ipilimab	6周	头痛、恶心呕吐、纳差	垂体增大1.5 cm，垂体柄增粗4 mm	↓	↓	↓	-	↓	-	↑	-	-	NA
[19]	65	男	NSCLC	Atezolizumab	56周	乏力、纳差	垂体前叶萎缩	↓	↓	-	-	-	-	-	-	-	24个月后 ACTH 未恢复
[19]	70	男	NSCLC	Atezolizumab	54周	乏力、纳差	垂体无明显异常	↓	↓	-	-	↑	-	-	-		13个月后 ACTH 未恢复
[20]	55	男	NSCLC	Nivolumab	66周	乏力、体重下降	垂体无明显异常	↓	↓	↓	↑	-	-	-	-	-	TSH恢复
[21]	59	男	NSCLC	Pembrolizumab	16周	乏力、纳差、发热	垂体无明显异常	↓	↓	↑	↓	-	-	-	↓	-	NA
[22]	79	男	SCC	Nivolumab	20周	乏力、纳差、低血压	垂体无明显异常	↓	↓	-	-	-	-	-	↓	-	ACTH恢复
[23]	61	男	SCLC	Nivolumab	13周	乏力、纳差、低血压	垂体无明显异常	↓	↓	-	-	↑	-	↑	-	-	10个月 ACTH未恢复