Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Italy.
Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
Cancer Treat Rev. 2020 Aug;88:102060. doi: 10.1016/j.ctrv.2020.102060. Epub 2020 Jun 23.
Phenotypic plasticity of malignant melanoma is a well-known phenomenon. Several translational studies and small case series have reported this clinical and biological entity, particularly in metastatic melanoma, showing frequent aberrant expression of non-melanocytic differentiation markers of different lineages, posing remarkable challenges due to several alternative differential diagnoses including undifferentiated carcinoma and sarcomas. When melanoma loses its typical morpho-phenotype by routinely used diagnostic immunohistochemical markers, it is defined as "dedifferentiated melanoma". Historically, this process was closely related to diagnostic interpretative difficulties. In recent years, however, dedifferentiation has been increasingly recognized as an important biological phenomenon that demonstrates the phenotypic and genetic plasticity of melanoma, and specifically the non-irreversibility of the multistep cancerogenesis. Furthermore, dedifferentiation emerged as a general hallmark of cancer evolution and a common denominator of cross-resistance to both targeted and immunotherapy. In this review, we summarize the histopathological features, the genetic and epigenetic bases underlying the dedifferentiated phenotype in melanomas and provide additional support that dedifferentiation is a mechanism of resistance to immunotherapy and targeted therapy.
恶性黑色素瘤的表型可塑性是一种众所周知的现象。几项转化研究和小病例系列报告了这种临床和生物学实体，特别是在转移性黑色素瘤中，表现出不同谱系的非黑色素细胞分化标志物的频繁异常表达，由于包括未分化癌和肉瘤在内的几个替代鉴别诊断，这带来了显著的挑战。当黑色素瘤通过常规使用的诊断免疫组织化学标志物失去其典型的形态表型时，它被定义为“去分化黑色素瘤”。从历史上看，这个过程与诊断解释的困难密切相关。然而，近年来，去分化已被越来越多地认为是一种重要的生物学现象，它展示了黑色素瘤的表型和遗传可塑性，特别是多步骤癌变的非不可逆性。此外，去分化已成为癌症进化的一般标志和对靶向治疗和免疫治疗交叉耐药的共同特征。在这篇综述中，我们总结了黑色素瘤中去分化表型的组织病理学特征、遗传和表观遗传基础，并提供了额外的证据表明去分化是对免疫治疗和靶向治疗产生耐药性的机制。
