Dept. of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany.
Dept. of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany.
Eur J Cancer. 2020 May;131:18-26. doi: 10.1016/j.ejca.2020.02.024. Epub 2020 Apr 2.
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.
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.
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.
抗 [程序性细胞死亡蛋白 1（PD-1）] 抗体纳武利尤单抗和帕博利珠单抗已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，联合抗 PD-1 加抗 [细胞毒性 T 淋巴细胞相关蛋白 4（CTLA4）] 阻断剂正在辅助和新辅助试验中进行研究。免疫检查点抑制剂已描述了类肉瘤样反应，很可能是药物诱导的。在临床黑色素瘤试验中，报告的类肉瘤/类肉瘤样反应的发生率<2%。我们观察到，在一项辅助临床试验中，接受免疫检查点抑制剂（ICI）治疗的黑色素瘤患者数量显著增加（45 例患者中有 10 例，22%），出现了药物诱导的类肉瘤样反应（DISR），类似于转移。
在我们的研究所，45 例 III 期黑色素瘤患者接受了辅助 ICI（单独使用纳武利尤单抗或联合使用伊匹单抗）治疗，在一项双盲临床试验中，10 例患者出现了 DISR。10 例患者中有 3 例为男性，中位年龄为 52 岁（范围，32-70 岁）。DISR 无症状，通常在治疗开始后首次放射影像学检查时（中位时间，2.8 个月）发现，并被描述为肿瘤进展的鉴别诊断。在 1 例患者中，在开始治疗后 13.1 个月和 ICI 治疗结束后 4 周才出现 DISR。10 例患者中有 8 例（仅作为唯一部位或除肺、皮肤和/或骨受累外）出现纵隔/肺门淋巴结病，1 例仅出现肺和皮肤受累，1 例仅出现皮肤 DISR。8/10 例患者进行了淋巴结、皮肤和骨活检，组织学证实为类肉瘤样反应（SLR）。由于患者无症状，无需治疗 DISR，仅 1 例因骨受累而停止研究治疗。所有患者的 DISR 均已缓解或处于缓解期。在中位随访时间为 15.3 个月（范围，12-17.6 个月）时，2 例患者出现黑色素瘤复发。
在大多数情况下，仅通过活检才能将类肉瘤与黑色素瘤进展区分开来。接受辅助 ICI 治疗的治疗医生和放射科医生必须意识到 DISR 发生率可能更高。需要进行彻底的跨学科评估，以区分真正的黑色素瘤进展，并决定是否继续辅助 ICI 治疗。
