在临床实践中，与皮肤鳞状角化病同时发生的Lynch综合征（LS）相关的胶质母细胞瘤（GBM）较为罕见。本研究分析了LS相关GBM与并发的鳞状角化病的临床病理学和遗传学特征，并评估了LS相关GBM的肿瘤免疫微环境（TIME）。采用免疫组化染色确认病理诊断，评估MMR和PD-1/PD-L1状态，并鉴定免疫细胞亚群。采用荧光原位杂交（FISH）检测EGFR和PDGFRA扩增以及1p/19q和CDKN2A的缺失。靶向下一代测序（NGS）分析体细胞突变、微卫星不稳定性（MSI）和肿瘤突变负荷（TMB）状态，全外显子测序和Sanger测序用于分析种系突变。在LS家族中，有三名成员（I:1、II:1和II:4）受到GBM的影响。失去MSH2和MSH6表达的GBM显示巨型和多核奇异细胞，以及ARID1A、TP53、ATM和NF1基因的突变。所有的GBM都具有高负荷的TMB但不具有MSI-H。CD8+T细胞和CD163+巨噬细胞在每个GBM组织中都很丰富。II:1的初发和复发性GBM显示高表达PD-L1的间充质特征。家族成员携带了MSH2和FDPS基因的新颖杂合性种系突变，确认了LS和浸润性浅表性光化性鳞状角化病的诊断。LS相关GBM在临床病理学和分子遗传学特征上呈现出多样性，并具有抑制性TIME。MMR缺陷和高TMB的存在可能作为GBM对免疫检查点抑制剂治疗反应的预测因子。LS相关GBM的鉴定对患者及其家庭成员具有重要好处，包括准确的诊断、遗传咨询和适当的筛查或监测方案。我们的研究提醒临床医生和病理学家在个体或家庭中考虑可能存在的并发遗传综合征的可能性。版权所有 © 2023 Yao、Hua、Yin、Xue、Hou、Nie、Zheng、Zhao、Guo、Ma、Li、Wang、Liu和Zhang。

Lynch syndrome (LS)-associated glioblastoma (GBM) is rare in clinical practice, and simultaneous occurrence with cutaneous porokeratosis is even rarer. In this study, we analyzed the clinicopathological and genetic characteristics of LS-associated GBMs and concurrent porokeratosis, as well as evaluated the tumor immune microenvironment (TIME) of LS-associated GBMs.Immunohistochemical staining was used to confirm the histopathological diagnosis, assess MMR and PD-1/PD-L1 status, and identify immune cell subsets. FISH was used to detect amplification of EGFR and PDGFRA, and deletion of 1p/19q and CDKN2A. Targeted NGS assay analyzed somatic variants, MSI, and TMB status, while whole-exome sequencing and Sanger sequencing were carried out to analyze the germline mutations.In the LS family, three members (I:1, II:1 and II:4) were affected by GBM. GBMs with loss of MSH2 and MSH6 expression displayed giant and multinucleated bizarre cells, along with mutations in ARID1A, TP53, ATM, and NF1 genes. All GBMs had TMB-H but not MSI-H. CD8+ T cells and CD163+ macrophages were abundant in each GBM tissue. The primary and recurrent GBMs of II:1 showed mesenchymal characteristics with high PD-L1 expression. The family members harbored a novel heterozygous germline mutation in MSH2 and FDPS genes, confirming the diagnosis of LS and disseminated superficial actinic porokeratosis.LS-associated GBM exhibits heterogeneity in clinicopathologic and molecular genetic features, as well as a suppressive TIME. The presence of MMR deficiency and TMB-H may serve as predictive factors for the response to immune checkpoint inhibitor therapy in GBMs. The identification of LS-associated GBM can provide significant benefits to both patients and their family members, including accurate diagnosis, genetic counseling, and appropriate screening or surveillance protocols. Our study serves as a reminder to clinicians and pathologists to consider the possibility of concurrent genetic syndromes in individuals or families.Copyright © 2023 Yao, Hua, Yin, Xue, Hou, Nie, Zheng, Zhao, Guo, Ma, Li, Wang, Liu and Zhang.