Erdem Zeynep Betul, Ameline Baptiste, Bovée Judith V M G, van Boven Hester, Baumhoer Daniel, Chrisinger John S A, Fritchie Karen J
Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel and University of Basel, Basel, Switzerland.
Histopathology. 2025 Jan;86(2):247-259. doi: 10.1111/his.15309. Epub 2024 Sep 2.
Melanomas are recognised for their remarkable morphological plasticity. Some tumours may lose conventional features and/or acquire non-melanocytic characteristics, referred to as undifferentiated, dedifferentiated and transdifferentiated melanoma. Despite this phenotypical variability, melanomas typically maintain their cancer driver aberrations, affecting genes such as BRAF, NRAS and NF1. Currently, little is known about whether the DNA methylation profile follows the loss or change of differentiation or is retained despite extensive morphological transformation.
In this study we analysed 11 melanoma cases, comprising six males and five females, with a median age of 67 years, including five undifferentiated, four trans-differentiated and two de-differentiated melanomas. Undifferentiated and trans-differentiated tumours either arose in a patient with known melanoma and/or presented in the groin/axilla with molecular alterations consistent with melanoma. Cases with heterologous differentiation resembled chondrosarcoma, osteosarcoma, angiosarcoma and rhabdomyosarcoma both morphologically and immunohistochemically, while undifferentiated tumours resembled undifferentiated pleomorphic sarcoma. Methylome profiling was performed, and unsupervised clustering analysis revealed nine cases (five undifferentiated, three trans-differentiated and one de-differentiated) to cluster closely together with conventional melanomas from a reference set. Two cases clustered separately with a distinct group of conventional melanomas exhibiting H3K27me3 loss.
Despite loss of differentiation and phenotypical plasticity, methylation patterns seem to be retained in undifferentiated, de-differentiated and trans-differentiated melanomas and represent useful diagnostic tools to enhance diagnostic precision in these diagnostically challenging cases.
黑色素瘤以其显著的形态可塑性而闻名。一些肿瘤可能会失去传统特征和/或获得非黑素细胞特征，即所谓的未分化、去分化和转分化黑色素瘤。尽管存在这种表型变异性，但黑色素瘤通常会保留其癌症驱动畸变，影响诸如BRAF、NRAS和NF1等基因。目前，关于DNA甲基化谱是否随着分化的丧失或变化而改变，或者尽管发生了广泛的形态转变仍保持不变，我们知之甚少。
在本研究中，我们分析了11例黑色素瘤病例，包括6例男性和5例女性，中位年龄为67岁，其中包括5例未分化、4例转分化和2例去分化黑色素瘤。未分化和转分化肿瘤要么发生在已知患有黑色素瘤的患者身上，和/或出现在腹股沟/腋窝，伴有与黑色素瘤一致的分子改变。具有异源性分化的病例在形态和免疫组化上类似于软骨肉瘤、骨肉瘤、血管肉瘤和横纹肌肉瘤，而未分化肿瘤类似于未分化多形性肉瘤。进行了甲基化组分析，无监督聚类分析显示9例（5例未分化、3例转分化和1例去分化）与参考集中的传统黑色素瘤紧密聚集在一起。2例与一组表现出H3K27me3缺失的独特传统黑色素瘤单独聚类。
尽管存在分化丧失和表型可塑性，但甲基化模式似乎在未分化、去分化和转分化黑色素瘤中得以保留，并且是提高这些诊断具有挑战性病例诊断准确性的有用诊断工具。
