Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Mod Pathol. 2024 Jan;37(1):100352. doi: 10.1016/j.modpat.2023.100352. Epub 2023 Oct 13.
In this study, we performed a comprehensive molecular analysis of paired skin and peripheral blood/bone marrow (BM) samples from 17 patients with cutaneous myeloid or cutaneous histiocytic-dendritic neoplasms. The cutaneous manifestations included 10 patients with cutaneous acute myeloid leukemia (c-AML), 2 patients with full or partial Langerhans cell differentiation, 2 patients with blastic plasmacytoid dendritic cell neoplasms (BPDCN), 1 patient with both Langerhans cell differentiation and BPDCN, and 2 patients with full or partial indeterminate dendritic cell differentiation. Seven of the 10 c-AML patients (70%) exhibited concurrent or subsequent marrow involvement by acute myeloid leukemia, with all 7 cases (100%) demonstrating shared clonal mutations in both the skin and BM. However, clonal relatedness was documented in one additional case that never had any BM involvement. Nevertheless, NPM1 mutations were identified in 7 of the 10 (70%) of these c-AML cases while one had KMT2A rearrangement and one showed inv(16). All 3 patients (100%) with Langerhans cell neoplasms, 2 patients with BPDCN (100%), and one of the 2 patients (50%) with other cutaneous dendritic cell neoplasms also demonstrated shared mutations between the skin and concurrent or subsequent myeloid neoplasms. Both BM and c-AML shared identical founding drivers, with a predominance of NPM1, DNMT3A, and translocations associated with monocytic differentiation, with common cutaneous-only mutations involving genes in the signal transduction and epigenetic pathways. Cutaneous histiocytic-dendritic neoplasms shared founding drivers in ASXL1, TET2, and/or SRSF2. However, in the Langerhans cell histiocytosis or histiocytic sarcoma cases, there exist recurrent secondary RAS pathway hits, whereas cutaneous BPDCN cases exhibit copy number or structural variants. These results enrich and broaden our understanding of clonally related cutaneous manifestations of myeloid neoplasms and further illuminate the highly diverse spectrum of morphologic and immunophenotypic features they exhibit.
在这项研究中，我们对 17 例皮肤髓系或皮肤组织细胞-树突状肿瘤患者的配对皮肤和外周血/骨髓（BM）样本进行了全面的分子分析。皮肤表现包括 10 例皮肤急性髓系白血病（c-AML）患者、2 例具有完全或部分朗格汉斯细胞分化的患者、2 例母细胞性浆细胞样树突细胞肿瘤（BPDCN）患者、1 例同时具有朗格汉斯细胞分化和 BPDCN 的患者以及 2 例具有完全或部分未确定树突状细胞分化的患者。10 例 c-AML 患者中的 7 例（70%）表现为同时或随后骨髓受累的急性髓系白血病，所有 7 例（100%）皮肤和 BM 均存在共享的克隆突变。然而，在一个从未有过 BM 受累的病例中，也记录到克隆相关性。然而，7 例（70%）c-AML 病例中存在 NPM1 突变，1 例存在 KMT2A 重排，1 例存在 inv(16)。所有 3 例（100%）朗格汉斯细胞肿瘤患者、2 例 BPDCN 患者（100%）和 2 例其他皮肤树突状细胞肿瘤患者中的 1 例（50%）皮肤和同时或随后的髓系肿瘤之间也存在共享突变。BM 和 c-AML 共享相同的起始驱动因素，以 NPM1、DNMT3A 和与单核细胞分化相关的易位为主，常见的仅皮肤突变涉及信号转导和表观遗传途径中的基因。皮肤组织细胞-树突状肿瘤共享 ASXL1、TET2 和/或 SRSF2 的起始驱动因素。然而，在朗格汉斯细胞组织细胞增多症或组织细胞肉瘤病例中，存在反复的继发 RAS 通路打击，而皮肤 BPDCN 病例则表现为拷贝数或结构变异。这些结果丰富并拓宽了我们对髓系肿瘤克隆相关皮肤表现的认识，并进一步阐明了它们表现出的高度多样化的形态和免疫表型特征。
