Administration of glucocorticoids prior to liquid biopsy dramatically reduces the detection rate of MYD88 L265P mutation in cerebrospinal fluid of primary CNS lymphoma patients
Administration of glucocorticoids prior to liquid biopsy dramatically reduces the detection rate of MYD88 L265P mutation in cerebrospinal fluid of primary CNS lymphoma patients
复制标题
液体活检前给予糖皮质激素显着降低原发性中枢神经系统淋巴瘤患者脑脊液中MYD88 L265P突变的检出率
DOI：
10.1080/10428194.2023.2199895
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Fujii Y
中科院分区：
文献类型：
--
作者：
Takahashi H;Natsumeda M;On J;Watanabe J;Tada M;Shimizu H;Tsukamoto Y;Okada M;Oishi M;Takizawa J;Hayashi Y;Masaki Y;Kakita A;Fujii Y
我们[1，2]和其他人[3，4]已经报道了液体活检通过使用液滴数字PCR（ddPCr）检测脑脊液（CSF）中的无细胞循环肿瘤dNA（cctdNA）诊断原发性中枢神经系统淋巴瘤（PCNSL）的有效性。诊断PCNSL的金标准仍然是手术活检[5]，但由于组织取样困难，位置较深或较小的病变可能难以诊断。约85%的PCNSL携带MYD 88 L265 P突变;另一方面，这种突变很少在健康个体中发现[3，6]。此外，MYD 88 L265 P突变仅在B细胞恶性肿瘤如弥漫性大B细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症和igM单克隆丙种球蛋白病中描述[7]，在胶质母细胞瘤或其他转移性实体脑肿瘤中尚未描述。因此，在Mri和/或Ct显示疑似脑肿瘤的患者中，其检测可诊断PCNSL [8]。我们之前报道了MYD 88 L265 P突变可以在从CNS淋巴瘤患者的CSF中提取的cctdNA中可靠地检测到，并且在21名具有匹配的CSF和肿瘤样本的患者中发现MYD 88 L265 P状态的100%一致性[1]。液体活检可以作为无法接受手术活检的患者的替代诊断工具，但除了技术错误和正确的样本处理之外，还存在准确检测感兴趣的基因突变的陷阱。PCNSL对糖皮质激素（GC）高度敏感。由于在神经肿瘤会诊之前神经系统症状的快速进展，最初可以使用GC。GC诱导的细胞凋亡和肿瘤缩小可能导致形态学变化，已知术前给予GC会阻碍组织病理学诊断[9，10]。然而，尚不清楚液体活检前GC给药是否会影响PCNSL患者中MYD 88突变的检测。本回顾性研究旨在阐明PCNSL患者液体活检前GC给药的影响。本研究入组了6例于2020年12月至2022年4月在两个中心接受液体活检并在液体活检前接受GC给药的PCNSL患者。在每个中心获得机构审查委员会的批准（新泻大学批准# G2018-008，金泽医科大学批准# G183），并获得所有患者或其家属的书面同意。通过腰椎穿刺采集所有CSF样本，使用麦克斯韦rSC ccfdNA Plasma Kit（rSC; Promega，Leiden，the Netherlands）提取cctdNA，并通过ddPCR检测MYD 88 L265 P突变，如前所述[1，2]。还分别使用dNeasyBlood & tissueKit（Qiagen，瓦伦西亚，CA，USA）和QiAampFFPe tissueKit（Qiagen，瓦伦西亚，CA，USA）从冷冻组织或FFPe切片中提取肿瘤衍生组织dNA。对于每名患者，对术前和术后所有造影剂增强病变进行体积分析。
We [1, 2] and others [3, 4] have reported the usefulness of liquid biopsy to diagnose primary central nervous system lymphomas (PCNSL) by detecting cell free circulating tumor dNA (cctdNA) in cerebrospinal fluid (CSF) using droplet digital PCr (ddPCr). the gold standard for diagnosis of PCNSL still is surgical biopsy [5], but deeply located or small lesions can be challenging to diagnose because of the difficulty of tissue sampling. About 85% of PCNSLs harbor MYD88 L265P mutations; on the other hand, this mutation is rarely found in healthy individuals [3, 6]. Moreover, MYD88 L265P mutations have only been described in B cell malignancies such as diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia and igM monoclonal gammopathy [7], and has not been described in glioblastoma or in other metastatic solid brain tumors. thus, in patients with suspected brain tumor on Mri and/or Ct, its detection could be diagnostic for PCNSL [8]. We previously reported that MYD88 L265P mutations can be reliably detected in cctdNA extracted from CSF of CNS lymphoma patients, and found a 100% concordance in MYD88 L265P status in 21 patients with matched CSF and tumor samples [1]. Liquid biopsy can be an alternative diagnostic tool for patients who cannot undergo surgical biopsy, but there are pitfalls beyond technical error and proper sample handling to detect the genetic mutation of interest accurately. PCNSL is highly sensitive to glucocorticoids (GC). GCs can be administered initially because of the rapid progression of neurologic symptoms prior to neuro-oncology consultation. GC-induced apoptosis and shrinkage of the tumor may lead to morphological changes, and preoperative administration of GCs is known to hinder histopathological diagnosis [9, 10]. however, it is not known whether GC administration before liquid biopsy can affect the detection of MYD88 mutations in PCNSL patients. this retrospective study was conducted to clarify the impact of GC administration prior to liquid biopsy in PCNSL patients. Six PCNSL patients who underwent liquid biopsy in two centers from december 2020 to April 2022 and receiving GC administration prior to liquid biopsy were enrolled in the study. Approval of the institutional review board was attained at each center (approval# G2018-008 for Niigata University and# G183 for Kanazawa Medical University) and written consent was obtained from all patients or their families. All CSF samples were collected by lumbar puncture, cctdNA was extracted using the Maxwell rSC ccfdNA Plasma Kit (rSC; Promega, Leiden, the Netherlands), and MYD88 L265P mutations were detected by ddPCr as previously described [1, 2]. tumor derived tissue dNA was also extracted from frozen tissues or FFPe sections, using dNeasy Blood & tissue Kit (Qiagen, Valencia, CA, USA) and QiAamp FFPe tissue Kit (Qiagen, Valencia, CA, USA), respectively. For each patient, a volumetric analysis of all contrast enhancing lesions before and