Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
Department of Dermatology, Paracelsus Medical University, Salzburg, Austria.
J Eur Acad Dermatol Venereol. 2019 Apr;33(4):667-675. doi: 10.1111/jdv.15302. Epub 2018 Nov 26.
Primary melanoma ulceration is an unfavourable prognostic factor included in current staging systems. Yet, the immunological and molecular alterations responsible for this adverse outcome have not been fully elucidated.
We aimed to identify immunological differences between ulcerated and non-ulcerated primary melanomas concerning both innate and adaptive immunity and to correlate these with clinical outcome.
Formalin-fixed paraffin-embedded primary melanomas from 112 patients (pts) were analysed by immunohistochemistry. The expression of various markers identifying tumour-infiltrating lymphocytes, macrophages and dendritic cells was evaluated semi-quantitatively by three independent investigators. Tumour cell expression of programmed death-ligand 1 (PD-L1), transporter of antigen processing 1 and the MxA protein was also analysed.
Recurrence occurred in 21/56 pts (37.5%) with ulcerated vs. 14/56 pts (25.0%) with non-ulcerated tumours (P = 0.15). Tumour ulceration was associated with more frequent development of brain metastasis (17.6 vs. 3.6% of pts, P = 0.015). Immunohistochemistry showed an association of ulceration with the presence of intratumoural CD68 macrophages (P = 0.028) as well as with increased numbers of intratumoural CD11c dendritic cells (P = 0.014) and CD163 macrophages (P = 0.001). PD-L1 positivity (expression in >1% of tumour cells) was more frequent in ulcerated than non-ulcerated tumours [40 (72.7%) vs. 25 (44.6%), P = 0.003]. A positive correlation between intratumoural CD11c (Spearman's correlation coefficient ρ: 0.42) and CD163 (ρ: 0.31) cell count and frequency of tumour cell PD-L1 expression was detected.
Our results confirm the adverse clinical outcome associated with primary melanoma ulceration, particularly concerning the risk of recurrence and subsequent development of brain metastases. The observed immunological differences suggest a conceivable role of increased intratumoural macrophage and dendritic cell counts associated with enhanced tumour cell PD-L1 expression potentially contributing to the immunosuppressive, growth-promoting microenvironment of ulcerated primary melanomas.
原发性黑色素瘤溃疡是当前分期系统中包含的一个不利预后因素。然而，导致这种不良结果的免疫学和分子改变尚未完全阐明。
我们旨在确定原发性黑色素瘤溃疡和非溃疡之间在固有免疫和适应性免疫方面的免疫学差异，并将这些差异与临床结果相关联。
对 112 例患者（pts）的福尔马林固定石蜡包埋原发性黑色素瘤进行免疫组织化学分析。通过三位独立的研究者对鉴定肿瘤浸润淋巴细胞、巨噬细胞和树突状细胞的各种标志物的表达进行半定量评估。还分析了肿瘤细胞程序性死亡配体 1（PD-L1）、抗原处理转运体 1 和 MxA 蛋白的表达。
在 56 例 pts 中，21 例（37.5%）出现溃疡，56 例 pts 中 14 例（25.0%）出现非溃疡肿瘤（P=0.15）。肿瘤溃疡与更频繁发生脑转移有关（17.6%与 3.6%的 pts，P=0.015）。免疫组织化学显示溃疡与肿瘤内 CD68 巨噬细胞的存在相关（P=0.028），以及肿瘤内 CD11c 树突状细胞（P=0.014）和 CD163 巨噬细胞（P=0.001）数量增加相关。与非溃疡肿瘤相比，PD-L1 阳性（肿瘤细胞表达>1%）在溃疡肿瘤中更为常见[40（72.7%）与 25（44.6%），P=0.003]。检测到肿瘤内 CD11c（Spearman 相关系数 ρ：0.42）和 CD163（ρ：0.31）细胞计数与肿瘤细胞 PD-L1 表达频率之间的正相关。
我们的结果证实了原发性黑色素瘤溃疡与不良临床结果相关，特别是与复发风险和随后脑转移的发展相关。观察到的免疫学差异表明，与增强的肿瘤细胞 PD-L1 表达相关的肿瘤内巨噬细胞和树突状细胞计数增加可能发挥作用，有助于促进溃疡原发性黑色素瘤的免疫抑制、生长促进微环境。
