Pathology Unit, Maggiore Hospital, AUSL Bologna, Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
IRCCS Azienda Ospedaliero-Universitaria Policlinico di Sant'Orsola, University of Bologna, Bologna, Italy; Dermatology Unit, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
Pathol Res Pract. 2023 Jul;247:154564. doi: 10.1016/j.prp.2023.154564. Epub 2023 May 23.
One of the most relevant genetic alterations in cutaneous melanoma (CM) is the biallelic inactivation/loss-of-heterozygosis (LOH) of cyclin-dependent kinase inhibitor 2 A (CDKN2A), which results in the immunohistochemical loss of p16 frequently found in CM. However, we recently described a rare case of dermal/deep-seated melanoma arising in giant congenital nevus (DDM-GCN) with p16 overexpression combined with p53 loss and tumor protein 53 (TP53) mutation. Herein, we reported a case series of CM with p16 overexpression and analyzed their clinicopathologic features, immunohistochemical expression of the cell cycle regulatory molecules (CCRM: p53, p21, Cyclin D1, Rb), and mutational landscape.
We retrospectively tested for p16 all cases of CM diagnosed at our institution between January 1st 2019-April 1st 2022. In CM with p16 overexpression, we reported clinicopathologic features, immunohistochemical results for melanocytic markers and CCRM, and mutational landscape investigated with a next-generation sequencing (NGS) panel. In cases with zonal p16 overexpression, the immunohistochemical assessment for melanocytic markers and CCRM, as well as the NGS analysis have been performed in both components {with and without p16 overexpression [p16(+)c and p16(-)]}.
Overexpression of p16 was found in 10/2879 (0.35%) CM [5/10 (50%) diffuse and 5/10 (50%) zonal]. We combined the immunohistochemical results for CCRM and molecular data to classify the cases as follows: a) Group 1 with altered expression of at least one CCRM but no TP53 mutations [3/10 (30%), all with Rb altered/lost]; b) Group 2 with altered expression of at least one CCRM and TP53 mutations [4/10 (40%), all with p53 altered]; c) Group 3 with normal expression of CCRM and no TP53 mutations [3/10 (30%), all with mutations in MAPK pathway genes (NRAS and BRAF)]. In CM with zonal p16 overexpression, the histologic appearance of p16(+)c was heterogeneous, whereas combining CCRM profiles and molecular data the cases could be categorized as follows: a) cases with the same CCRM and molecular profiles in both p16(+)c and p16(-)c; b) cases with p16(+)c showing additional genetic mutations and/or modifications of CCRM expression.
p16 overexpression is a rare event, occurring in advanced-stage, clinically- and histologically-heterogeneous CM. These lesions may be classified into three different groups based on CCRM expression and mutational profiles (including TP53 mutation). The analysis of CM with zonal p16 overexpression suggests that, at least in a subset of cases, this phenomenon could represent a sign of "molecular progression" due to the acquisition of additional genetic mutations and/or modifications of the CCRM profile.
皮肤黑色素瘤 (CM) 中最相关的遗传改变之一是细胞周期蛋白依赖性激酶抑制剂 2A (CDKN2A) 的双等位基因失活/杂合性丢失 (LOH)，导致 p16 的免疫组织化学丢失，这在 CM 中经常发现。然而，我们最近描述了一例罕见的真皮/深部黑色素瘤起源于巨大先天性痣 (DDM-GCN)，表现为 p16 过表达，同时伴有 p53 缺失和肿瘤蛋白 53 (TP53) 突变。在此，我们报告了一组 p16 过表达的 CM 病例，并分析了它们的临床病理特征、细胞周期调节分子 (CCRM：p53、p21、Cyclin D1、Rb) 的免疫组织化学表达以及突变景观。
我们回顾性地检测了 2019 年 1 月 1 日至 2022 年 4 月 1 日期间在我们机构诊断为 CM 的所有病例中的 p16。在 p16 过表达的 CM 中，我们报告了临床病理特征、黑素细胞标志物和 CCRM 的免疫组织化学结果，以及使用下一代测序 (NGS) 面板进行的突变景观研究。在有区域性 p16 过表达的病例中，对黑素细胞标志物和 CCRM 的免疫组织化学评估，以及 NGS 分析，均在具有和不具有 p16 过表达 [p16(+)c 和 p16(-)] 的两个成分中进行。
在 2879 例 CM 中发现 10 例 (0.35%) p16 过表达 [5/10 (50%) 弥漫性和 5/10 (50%) 区域性]。我们结合 CCRM 的免疫组织化学结果和分子数据将病例分类如下：a) 至少一种 CCRM 表达改变但无 TP53 突变的组 1[3/10 (30%)，均为 Rb 改变/缺失]；b) 至少一种 CCRM 表达改变且 TP53 突变的组 2[4/10 (40%)，均为 p53 改变]；c) CCRM 表达正常且无 TP53 突变的组 3[3/10 (30%)，均为 MAPK 通路基因 (NRAS 和 BRAF) 突变]。在具有区域性 p16 过表达的 CM 中，p16(+)c 的组织学表现存在异质性，而结合 CCRM 谱和分子数据，这些病例可分为以下几类：a) 在 p16(+)c 和 p16(-)c 中具有相同 CCRM 和分子谱的病例；b) p16(+)c 显示额外遗传突变和/或 CCRM 表达改变的病例。
p16 过表达是一种罕见的事件，发生在晚期、临床上和组织学上具有异质性的 CM 中。这些病变可根据 CCRM 表达和突变谱 (包括 TP53 突变) 分为三组。对具有区域性 p16 过表达的 CM 的分析表明，至少在一部分病例中，这种现象可能代表由于获得额外的遗传突变和/或 CCRM 谱的改变而导致的“分子进展”的标志。
