Department of Dermatology, Dermatopathology, Columbia University Medical Center, New York, NY, USA.
Department of Pathology and Laboratory Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, BC, USA.
Hum Pathol. 2020 Dec;106:32-38. doi: 10.1016/j.humpath.2020.09.002. Epub 2020 Sep 15.
Primary dermal melanoma (PDM) is a rare variant of melanoma which simulates metastatic melanoma to the skin. Diagnosis of PDM cannot be established on histologic grounds alone but requires absence of evidence of melanoma elsewhere by clinical history and/or imaging studies. Despite this entity being clinically well documented, limited data on molecular characterization are available. We performed comprehensive mutation and copy number variation analysis in a series of PDMs in search for distinctive molecular features.Studies were approved by respective institutional review boards. Six cases fulfilling strict histologic criteria of PDM were identified in patients with absent history of melanoma elsewhere, negative sentinel lymph node biopsies and imaging studies. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue, and five cases passed quality control measures and were subjected to targeted exon sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets 410 panel. Two of five PDM carried NRAS hotspot mutations characteristic of cutaneous melanoma (CM) genomic subtypes. One case showed a probable low-activating NRAS mutation in combination with additional aberrations in other mitogen-activated protein kinase (MAPK) pathway effectors. Hotspot mutations were also identified in the TERT promoter region, and one tumor showed a mutation in the SWI/SNF remodeling complex. No oncogenic mutations were identified in one case. Furthermore, none of the tumors analyzed showed activating mutations in Gα subunits, including GNAQ and GNA11. Copy number alterations included deletions of Chr 9p, characteristic of CM.Despite PDM showing mutational heterogeneity, our findings suggest predominance of MAPK pathway aberrations in agreement with the mutational profile of CMs in general. Given the absence of genetic overlap with other distinct primary dermal melanocytic proliferations, mutational profiling will unlikely aid in the difficult differential diagnosis of PDM versus melanoma metastasis. Thorough metastatic workup remains crucial in establishing this rare diagnosis.
原发性皮肤黑素瘤（PDM）是一种罕见的黑素瘤变体，其模拟皮肤转移的黑素瘤。PDM 的诊断不能仅基于组织学依据，而是需要通过临床病史和/或影像学研究排除其他部位黑素瘤的证据。尽管这种疾病在临床上有充分的记录，但关于分子特征的有限数据。我们对一系列 PDM 进行了全面的突变和拷贝数变异分析，以寻找独特的分子特征。这些研究均获得了相应机构审查委员会的批准。在没有其他部位黑素瘤病史、阴性前哨淋巴结活检和影像学研究的患者中，我们确定了符合严格组织学标准的 PDM 病例。从福尔马林固定石蜡包埋（FFPE）组织中提取 DNA，其中 5 例通过质量控制措施，使用 Memorial Sloan Kettering 综合可操作癌症靶标突变分析 410 面板进行靶向外显子测序。5 例 PDM 中有 2 例携带特征性的皮肤黑素瘤（CM）基因组亚型的 NRAS 热点突变。1 例显示可能的低激活 NRAS 突变，同时其他丝裂原活化蛋白激酶（MAPK）通路效应物也存在额外的异常。热点突变也在 TERT 启动子区域被识别，1 个肿瘤显示 SWI/SNF 重塑复合物突变。1 例肿瘤未发现致癌突变。此外，分析的肿瘤均未发现 Gα 亚基，包括 GNAQ 和 GNA11 的激活突变。拷贝数改变包括 Chr9p 的缺失，这是 CM 的特征。尽管 PDM 表现出突变异质性，但我们的发现表明 MAPK 通路异常占主导地位，这与一般 CM 的突变谱一致。鉴于与其他不同的原发性皮肤黑素细胞增殖缺乏遗传重叠，突变谱分析不太可能有助于 PDM 与黑素瘤转移的困难鉴别诊断。彻底的转移研究对于确立这一罕见诊断仍然至关重要。
