Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Mod Pathol. 2021 Apr;34(4):688-700. doi: 10.1038/s41379-020-00701-w. Epub 2020 Oct 19.
Homozygous deletion (HD) of CDKN2A is one of the most promising biomarkers for predicting poor prognosis of IDH-mutant diffuse gliomas. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recommendations propose that IDH-mutant lower-grade astrocytomas with CDKN2A/B HD be classified as grade IV tumors. Loss of methylthioadenosine phosphorylase (MTAP) immunohistochemistry staining has been proposed as a surrogate of CDKN2A HD in various tumors but its performance has not been fully investigated in diffuse glioma. This study determined whether MTAP immunoreactivity could serve as a proxy for CDKN2A HD in adult-type diffuse glioma, thereby contributing to stratifying patient outcome. MTAP immunohistochemistry staining using clone EPR6893 was scored in 178 diffuse glioma specimens consisting of 77 IDH-mutant astrocytomas, 13 IDH-mutant oligodendrogliomas, and 88 IDH-wildtype glioblastomas. The use of MTAP immunohistochemical deficiency to predict CDKN2A HD was good for IDH-mutant astrocytomas (sensitivity, 88%; specificity, 98%) and IDH-wildtype glioblastomas (sensitivity, 89%; specificity, 100%), but poor for IDH-mutant oligodendrogliomas (sensitivity, 67%; specificity, 57%). Both CDKN2A HD and MTAP immunohistochemical deficiency were significant adverse prognostic factors of overall survival for IDH-mutant astrocytoma (P < 0.001 each), but neither were prognostically significant for oligodendroglioma or IDH-wildtype glioblastoma. IDH-mutant lower-grade astrocytoma with CDKN2A HD and deficient MTAP immunoreactivity exhibited overlapping unfavorable outcome with IDH-mutant glioblastoma. MTAP immunostaining was easily interpreted in 61% of the cases tested, but scoring required greater care in the remaining cases. An alternative MTAP antibody clone (2G4) produced identical scoring results in all but 1 case, and a slightly larger proportion (66%) of cases were considered easy to interpret compared to using EPR6893. In summary, loss of MTAP immunoreactivity could serve as a reasonable predictive surrogate for CDKN2A HD in IDH-mutant astrocytomas and IDH-wildtype glioblastomas and could provide significant prognostic value for IDH-mutant astrocytoma, comparable to CDKN2A HD.
CDKN2A 纯合缺失 (HD) 是预测 IDH 突变型弥漫性神经胶质瘤预后不良的最有前途的生物标志物之一。脑肿瘤分子诊断和实践途径联盟（Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy，cIMPACT-NOW）建议，将 IDH 突变型低级别星形细胞瘤伴有 CDKN2A/B HD 归类为 4 级肿瘤。在各种肿瘤中，甲基硫腺苷磷酸化酶（methylthioadenosine phosphorylase，MTAP）免疫组化染色缺失已被提议作为 CDKN2A HD 的替代物，但在弥漫性神经胶质瘤中的性能尚未得到充分研究。本研究旨在确定 MTAP 免疫反应是否可作为成人型弥漫性神经胶质瘤中 CDKN2A HD 的替代物，从而有助于分层患者的预后。使用克隆 EPR6893 对 178 例弥漫性神经胶质瘤标本进行了 MTAP 免疫组化染色评分，其中包括 77 例 IDH 突变型星形细胞瘤、13 例 IDH 突变型少突胶质细胞瘤和 88 例 IDH 野生型胶质母细胞瘤。MTAP 免疫组织化学缺乏预测 CDKN2A HD 的效果对 IDH 突变型星形细胞瘤（敏感性为 88%，特异性为 98%）和 IDH 野生型胶质母细胞瘤（敏感性为 89%，特异性为 100%）均良好，但对 IDH 突变型少突胶质细胞瘤（敏感性为 67%，特异性为 57%）效果不佳。CDKN2A HD 和 MTAP 免疫组织化学缺乏均是 IDH 突变型星形细胞瘤总生存期的显著不良预后因素（均 P < 0.001），但在少突胶质细胞瘤或 IDH 野生型胶质母细胞瘤中均无预后意义。IDH 突变型低级别星形细胞瘤伴有 CDKN2A HD 和 MTAP 免疫反应缺失与 IDH 突变型胶质母细胞瘤具有重叠的不良预后。MTAP 免疫染色在 61%的测试病例中易于解释，但在其余病例中评分需要更加小心。另一种 MTAP 抗体克隆（2G4）在除 1 例外的所有病例中产生相同的评分结果，与使用 EPR6893 相比，有稍大比例（66%）的病例更容易解释。总之，MTAP 免疫反应缺失可作为 IDH 突变型星形细胞瘤和 IDH 野生型胶质母细胞瘤中 CDKN2A HD 的合理预测替代物，并可为 IDH 突变型星形细胞瘤提供有意义的预后价值，与 CDKN2A HD 相当。
