吴荻教授：原发部位不明黑色素瘤的临床病理特征、诊治现状及进展

编者按：原发部位不明黑色素瘤（Metastatic Melanoma of Unknown Primary, MUP）是一种少见的黑色素瘤类型，约占黑色素瘤的2~3%。MUP的特征是原发肿瘤位置未知，而转移灶通常主要出现在淋巴结、皮下组织或内脏器官。由于MUP的临床症状和影像学表现缺乏特异性，使得诊断过程相对复杂。目前，确诊MUP主要依赖于组织或细胞病理学活检、免疫组化检测以及分子病理学检测。

一、疾病特点

据估计，2020年全球黑色素瘤新发病例约32.5万人，死亡病例超过5.6万人^[1]。其中约2-3%黑色素瘤没有明确原发部位，主要累及淋巴结,最常涉及腋窝、腹股沟和腮腺淋巴结，其次皮下组织、内脏受累较多。患病年龄多处于40至50岁的年龄段，且男性患者数量多于女性^[2,3]。

二、诊断

根据1963年Das Gupta提出的诊断标准，MUP的诊断需明确组织病理学证实为转移性黑色素瘤，同时筛查全身各部位均不存在原发黑色素瘤^[4,5]。原发部位不明黑色素瘤（MUP）的诊断面临诸多挑战，主要由于其临床表现多样且缺乏特异性症状，导致早期诊断困难。尽管影像学检查有助于识别转移部位，但在确定原发灶方面存在局限^[6,7]。病理学诊断也较为复杂，常用免疫组化标志物在MUP中的表达可能不一致，需要与其他恶性肿瘤或良性病变进行区分^[8]。

三、发病机制

MUP的发病机制有三种主要假说。第一种假说认为黑色素瘤可能起源于淋巴结中的黑色素细胞痣或蓝痣^[9]，伴随着关键基因如BRAF、NRAS、PPP6C、TERT的突变，以及GNAQ和GNA11在蓝痣恶变中的作用^[10-21]；肿瘤细胞通过改变抗原表型和分泌免疫抑制因子逃避免疫监视^[22-26]。第二种假说提出原发灶可能在自身免疫介导下自发性消退，导致仅观察到转移灶^[27]。MUP患者的自发性消退现象与肿瘤的多个特征相关，如深度、大小和部位，这可能反映了宿主的免疫反应^[28,29]。第三种假说认为可能存在未记录的原发性黑色素瘤。这些理论为MUP的起源提供了可能的解释，但仍需通过进一步的临床研究和科学探索来加以证实。

四、治疗

（1）传统治疗方法

MUP患者治疗方法首选手术治疗，研究表明手术治疗患者5年生存率大约在47%到56%^[30-32]。然而，部分患者仍面临复发风险，与淋巴结转移的MUP患者相比，皮下转移的MUP患者复发率更高^[33]。因此，临床上广泛采用术后放疗或化疗作为治疗手段，但研究表明这些治疗与仅进行手术治疗相比，在预后上并没有显著差异^[34]。

（2）靶向治疗和免疫治疗

免疫治疗和靶向治疗可以显著提高MUP患者的生存率^[35-37]。一项回顾性研究中，Verver等纳入1032例MUP，其中有475名IV期MUP患者接受手术治疗联合或不联合化疗、放疗中位总生存期为4个月，557名IV期MUP患者接受免疫治疗或靶向治疗，靶向治疗中位总生存期延长至8个月，接受免疫治疗患者可达18个月^[38]。表明接受免疫治疗和靶向治疗有效延长MUP患者的生存期。

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