BACKGROUND Anti-[programmed cell death protein 1 (PD-1)] antibodies nivolumab and pembrolizumab were approved for adjuvant treatment of melanoma as they demonstrated improved relapse-free survival. Currently, combined anti-PD-1 plus anti-[cytotoxic T-lymphocyte-associated protein 4 (CTLA4)] blockade is being investigated in adjuvant and neoadjuvant trials. Sarcoidosis-like reactions have been described for immune checkpoint inhibitors and are most likely drug-induced. The reported rate of sarcoidosis/sarcoidosis-like reactions within clinical melanoma trials is <2%. We observed that a remarkably higher number of melanoma patients (10/45 patients, 22%) treated with immune checkpoint inhibitor (ICI) within an adjuvant clinical trial-developed drug induced sarcoidosis-like reaction (DISR) mimicking metastasis. CASE PRESENTATION Of 45 stage III melanoma patients who were treated at our institute with adjuvant ICI (either nivolumab alone or in combination with ipilimumab) within a two-armed, blinded clinical trial, ten developed a DISR. Three of the ten patients were men, median age was 52 years (range, 32-70 years). DISRs were asymptomatic and generally detected radiographically at first radiographic imaging after the start of therapy (median time, 2.8 months) and described as a differential diagnosis to tumour progression. In one patient, DISR was only apparent 13.1 months after start of therapy and 4 weeks after the end of ICI treatment. DISR presented as mediastinal/hilar lymphadenopathy in 8/10 patients (as only site or in addition to lung, skin and/or bone involvement), one patient had only lung and cutaneous, one patient only cutaneous DISR. Biopsies from lymph nodes, skin and bone were taken in 8/10 patients, and histology confirmed sarcoidosis-like reactions (SLRs). As patients were asymptomatic, no treatment for DISR was required, and study treatment was stopped for DISR in only one patient due to bone involvement. DISRs have resolved or are in remission in all patients. At a median follow-up time of 15.3 months (range, 12-17.6 months), two patients experienced melanoma relapse. CONCLUSIONS In most cases, sarcoidosis could only be differentiated from melanoma progression on biopsy. Treating physicians as well as radiologists have to be aware of the potentially higher rate of DISR in patients receiving adjuvant ICI. A thorough interdisciplinary workup is required to discriminate from true melanoma progression and to decide on continuation of adjuvant ICI treatment.

中文翻译：

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辅助免疫治疗中药物诱导的类结节病样反应：转移率和转移率增加。

背景技术抗[程序性细胞死亡蛋白1（PD-1）]抗体nivolumab和pembrolizumab被批准用于黑色素瘤的辅助治疗，因为它们显示出改善的无复发生存率。目前，在辅助和新辅助试验中正在研究联合使用的抗PD-1和抗[细胞毒性T淋巴细胞相关蛋白4（CTLA4）]阻断剂。结节病样反应已被描述为免疫检查点抑制剂，很可能是药物诱导的。在临床黑色素瘤试验中，结节病/类结节病样反应的报告率<2％。我们观察到在佐剂临床试验开发的模仿转移的药物诱发的类结节病样反应（DISR）中，接受免疫检查点抑制剂（ICI）治疗的黑素瘤患者（10/45患者，22％）显着增加。病例介绍在我们的研究所进行的两臂，双盲临床试验中，有45例III期黑色素瘤患者接受了辅助ICI（单独使用nivolumab或与ipilimumab联合治疗），其中10例发生了DISR。十名患者中有三名是男性，中位年龄为52岁（范围32-70岁）。DISR无症状，一般在治疗开始后（中位时间为2.8个月）在首次放射影像学上通过放射学检查发现，并被描述为对肿瘤进展的鉴别诊断。在一名患者中，仅在治疗开始后13.1个月和ICI治疗结束后4周出现了DISR。DISR在8/10名患者中表现为纵隔/肺门淋巴结肿大（仅累及肺，皮肤和/或骨骼，或者仅累及肺，皮肤和/或骨骼），一名患者只有肺和皮肤，一名患者只有皮肤DISR。从8/10例患者的淋巴结，皮肤和骨骼中取活检，组织学证实为结节病样反应（SLR）。由于患者无症状，因此不需要进行DISR的治疗，并且由于骨骼受累，只有一名患者停止了DISR的研究治疗。所有患者的DISR均已缓解或正在缓解。在中位随访时间为15.3个月（范围12-17.6个月）中，两名患者经历了黑色素瘤复发。结论在大多数情况下，结节病只能通过活检与黑素瘤进展区分开来。治疗医生和放射科医生必须意识到接受辅助ICI的患者中DISR的潜在可能性更高。需要进行全面的跨学科检查，以区别于真正的黑色素瘤进展，并决定继续进行辅助ICI治疗。