Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
J Cutan Pathol. 2023 Dec;50(12):1083-1093. doi: 10.1111/cup.14502. Epub 2023 Aug 11.
Melanocytic tumors driven by MAP2K1 in-frame deletions are among the most recently described class of melanocytic neoplasms. The reported range of diagnoses and associated genomic aberrations in these neoplasms is wide and includes melanomas, deep penetrating melanocytomas, and pigmented epithelioid melanocytoma. However, little is known about the characteristics of these tumors, especially in the absence of well-known second molecular "hits." Moreover, despite their frequent spitzoid cytomorphology, their potential categorization among the Spitz tumors is debatable.
We conducted a retrospective search through our molecular archives to identify sequenced melanocytic tumors with MAP2K1 in-frame deletions. We reviewed the clinical and histomorphological features of these tumors and compared them to similar neoplasms reported to date. In addition, we performed single-nucleotide polymorphism (SNP) array testing to identify structural chromosomal aberrations.
Of 27 sequenced tumors, 6 (22%) showed a pathogenic MAP2K1 in-frame deletion (with or without insertion) and were included in this series. Five (83%) were females with lesions involving the upper limb. Histopathologically, all neoplasms were compounded with plaque-like or wedge-shaped silhouettes, spitzoid cytomorphology, and impaired cytologic maturation. All cases showed background actinic damage with sclerotic stroma replacing solar elastosis, variable pagetoid scatter, and occasional dermal mitotic figures (range 1-2/mm ). Five cases (83%) had a small component of nevic-looking melanocytes. Biologically, these tumors likely fall within the spectrum of unusual nevi. Five cases (83%) had a relatively high mutational burden and four (67%) showed an ultraviolet radiation signature. Four cases (67%) showed in-frame deletion involving the p.I103_K104del locus while two cases (33%) showed in-frame deletion involving the p.Q58_E62del locus. SNP array testing showed structural abnormalities ranging from 1 to 5 per case. Five of these cases showed a gain of chromosome 15 spanning the MAP2K1 gene locus.
Melanocytic tumors with MAP2K1 in-frame deletion could represent another spectrum of melanocytic tumors with close genotypic-phenotypic correlation. They are largely characterized by a spectrum that encompasses desmoplastic Spitz nevus as shown in our series and Spitz and Clark nevus as shown by others. Evolutionary, they share many similarities with tumors with BRAF V600E mutations, suggesting they are better classified along the conventional pathway rather than the Spitz pathway despite the frequent spitzoid morphology.
由 MAP2K1 框内缺失驱动的黑色素细胞瘤是最近描述的黑色素细胞瘤中的一类。这些肿瘤报告的诊断范围和相关的基因组异常广泛，包括黑色素瘤、深部穿透性黑色素细胞瘤和色素性上皮样黑色素细胞瘤。然而，人们对这些肿瘤的特征知之甚少，尤其是在缺乏众所周知的第二个分子“打击”的情况下。此外，尽管它们具有频繁的棘皮样细胞形态学特征，但它们在 Spitz 肿瘤中的分类仍存在争议。
我们通过分子档案进行了回顾性搜索，以确定具有 MAP2K1 框内缺失的测序黑色素细胞瘤。我们回顾了这些肿瘤的临床和组织形态学特征，并将其与迄今为止报道的类似肿瘤进行了比较。此外，我们还进行了单核苷酸多态性 (SNP) 阵列测试，以识别结构染色体异常。
在 27 个测序的肿瘤中，有 6 个(22%)显示出致病性 MAP2K1 框内缺失(有或无插入)，并包含在本系列中。5 例(83%)为女性，病变累及上肢。组织病理学上，所有肿瘤均为复合性斑块状或楔形轮廓、棘皮样细胞形态学和细胞成熟受损。所有病例均显示背景性光化损伤，硬化基质取代了太阳弹性纤维变性，具有可变的 pagetoid 散布和偶尔的真皮有丝分裂图(范围 1-2/mm )。5 例(83%)有一小部分类似痣的黑素细胞。从生物学角度来看，这些肿瘤可能属于不寻常痣的范畴。5 例(83%)具有相对较高的突变负担，4 例(67%)显示紫外线辐射特征。4 例(67%)显示涉及 p.I103_K104del 位点的框内缺失，而 2 例(33%)显示涉及 p.Q58_E62del 位点的框内缺失。SNP 阵列测试显示每个病例的结构异常范围为 1 至 5。其中 5 例显示 15 号染色体获得，跨越 MAP2K1 基因座。
具有 MAP2K1 框内缺失的黑色素细胞瘤可能代表另一种黑色素细胞瘤谱，具有密切的基因型-表型相关性。它们的主要特征是一种谱，包括我们系列中显示的具有促结缔组织形成的 Spitz 痣和其他研究中显示的 Spitz 和 Clark 痣。从进化角度来看，它们与具有 BRAF V600E 突变的肿瘤有许多相似之处，这表明它们最好沿着常规途径分类，而不是 Spitz 途径，尽管它们具有频繁的棘皮样形态。
