色素瘤去分化（DedM）存在重大的诊断挑战。我们旨在调查DedM的临床、组织病理和分子特征。在一个亚组中进行了甲基化标记（MS）和拷贝数分析（CNP）。在EORTC（欧洲肿瘤研究和治疗组织）黑色素瘤组织中心检索的61名患者的78个DedM组织样本进行了回顾性调查。检索了临床和组织病理特征。在部分患者中，通过Infinium甲基化微阵列和CNP分析进行了基因分型。大部分患者（60/61）患有转移性DedM，其中最常见的是未分类的多形性、纺锤形细胞或类似未分化软组织肉瘤的小圆形细胞形态，很少与异种元素相关。总的来说，在成功分析的16名患者的20个组织样本中，只有7个组织样本发现保留的类似于黑色素瘤的MS，而在13个组织样本中观察到了非黑色素瘤的MS。在两名分析了多个标本的患者中，一些样本仍保持着皮肤黑色素瘤的MS，而其他标本则表现出向间充质/肉瘤样基因型的表观遗传学转变，与组织学特征相匹配。在这两位患者中，尽管其表观基因组发生了显著的改变，但他们的CNP在所有分析的样本中基本相同，与共同的克隆起源相一致。我们的研究进一步强调了DedM的真实诊断挑战。虽然MS和基因组CNP可以帮助病理学家诊断DedM，但我们提供了证明，黑色素瘤的去分化通常与表观遗传学的改变相关。版权所有©2023 Elsevier Ltd。

Dedifferentiated melanoma (DedM) poses significant diagnostic challenges. We aimed to investigate the clinical, histopathological and molecular features of DedM. Methylation signature (MS) and copy number profiling (CNP) were carried out in a subgroup of cases.A retrospective series of 78 DedM tissue samples from 61 patients retrieved from EORTC (European Organisation for Research and Treatment of Cancer) Melanoma Group centres were centrally reviewed. Clinical and histopathological features were retrieved. In a subgroup of patients, genotyping through Infinium Methylation microarray and CNP analysis was carried out.Most patients (60/61) had a metastatic DedM showing most frequently an unclassified pleomorphic, spindle cell, or small round cell morphology akin to undifferentiated soft tissue sarcoma, rarely associated with heterologous elements. Overall, among 20 successfully analysed tissue samples from 16 patients, we found retained melanoma-like MS in only 7 tissue samples while a non-melanoma-like MS was observed in 13 tissue samples. In two patients from whom multiple specimens were analysed, some of the samples had a preserved cutaneous melanoma MS while other specimens exhibited an epigenetic shift towards a mesenchymal/sarcoma-like profile, matching the histological features. In these two patients, CNP was largely identical across all analysed specimens, in line with their common clonal origin, despite significant modification of their epigenome.Our study further highlights that DedM represents a real diagnostic challenge. While MS and genomic CNP may help pathologists to diagnose DedM, we provide proof-of-concept that dedifferentiation in melanoma is frequently associated with epigenetic modifications.Copyright © 2023 Elsevier Ltd. All rights reserved.