Pheochromocytomas and paragangliomas (PHEOs/PGLs) represent diagnostically challenging and complex neuroendocrine tumors (NETs). Current biomarker tests for PHEOs/PGLs are technically complex or limited. We assessed the diagnostic utility of a NET-specific 51-marker gene blood assay (NETest) in patients with PHEOs/PGLs (n = 81), including ten pediatric patients, and age-/gender-matched controls (n = 142) using a prospective case:control (1:2) analysis. mRNA was measured (qPCR), and results were scaled from 0 to 100 (upper limit of normal < 20). Receiver operating curve (ROC) and non-parametric (Mann-Whitney) tests were used for analyses (two-tailed). All data are presented as mean ± s.e.m. NETest accuracy for PHEO/PGL diagnosis was 100%. PHEO/PGL scores were 70 ± 3 vs 8.5 ± 1 in controls (P < 0.0001), and ROC analysis was 0.99 ± 0.004 (P < 0.0001). Diagnostic metrics were 94% accurate, 100% sensitive, and 92% specific. Imaging correlation with 68Ga-PET-SSA was 100%. NETest levels in PHEOs (n = 26) were significantly (P < 0.0001) elevated (83 ± 4) vs 66 ± 4 in PGLs (n = 40) and mixed PHEOs/PGLs (n = 5: 37 ± 3). Adrenal-derived tumors (n = 30) exhibited higher scores (76 ± 5) than extra-adrenal-derived tumors (66 ± 4, P < 0.05). Cluster 2 tumors exhibited significantly (P = 0.034) elevated NETest levels (n = 4: 92 ± 2) vs cluster 1 tumors (n = 35: 69 ± 4). Regulatory pathway analysis identified elevated RAS-RAF, metastatic, pluripotential, neural and secretory gene cluster levels (P < 0.05) in PHEOs compared to PGLs. Cluster 2 PPGLs exhibited elevated (P = 0.046) levels of growth factor signaling genes compared to cluster 1. The PHEOs/PGLs in the pediatric cohort (n = 10) were all NETest-positive (81 ± 8) and exhibited a gene expression profile spectrum analogous to adults. Circulating NET transcript analysis identifies PHEOs/PGLs with 100% efficacy and is likely to have clinical utility in the diagnosis and management of PHEO/PGL patients.

中文翻译：

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一种新型液体活检 (NETest) 可以高精度识别副神经节瘤和嗜铬细胞瘤。

嗜铬细胞瘤和副神经节瘤 (PHEOs/PGLs) 代表了诊断上具有挑战性和复杂的神经内分泌肿瘤 (NETs)。目前针对 PHEO/PGL 的生物标志物测试在技术上复杂或有限。我们评估了 NET 特异性 51 标志物基因血液检测 (NETest) 在 PHEO/PGL 患者（n = 81）中的诊断效用，包括 10 名儿科患者和年龄/性别匹配的对照（n = 142），使用前瞻性病例：对照（1:2）分析。测量 mRNA (qPCR)，并将结果从 0 缩放到 100（正常上限 < 20）。接受者操作曲线 (ROC) 和非参数 (Mann-Whitney) 检验用于分析（双尾）。所有数据均表示为平均值 ± sem NETest，对于 PHEO/PGL 诊断的准确度为 100%。PHEO/PGL 得分为 70 ± 3 vs 8.5 ± 1 (P < 0.0001)，ROC 分析为 0.99 ± 0.004 (P < 0.0001)。诊断指标准确率为 94%，敏感性为 100%，特异性为 92%。与 68Ga-PET-SSA 的成像相关性为 100%。PHEO (n = 26) 中的 NETest 水平显着 (P < 0.0001) 升高 (83 ± 4)，而 PGL (n = 40) 和混合 PHEO/PGL (n = 5: 37 ± 3) 中的 NETest 水平为 66 ± 4。肾上腺源性肿瘤 (n = 30) 的评分 (76 ± 5) 高于肾上腺外源性肿瘤 (66 ± 4, P < 0.05)。与集群 1 肿瘤 (n = 35: 69 ± 4) 相比，集群 2 肿瘤表现出显着 (P = 0.034) 升高的 NETest 水平 (n = 4: 92 ± 2)。调节通路分析发现，与 PGL 相比，PHEO 中的 RAS-RAF、转移性、多能性、神经和分泌基因簇水平升高（P < 0.05）。与集群 1 相比，集群 2 PPGL 的生长因子信号基因水平升高（P = 0.046）。儿科队列 (n = 10) 中的 PHEO/PGL 均为 NETest 阳性 (81 ± 8) 并表现出与成人相似的基因表达谱谱。循环 NET 转录本分析鉴定 PHEO/PGL 具有 100% 的疗效，并且可能在 PHEO/PGL 患者的诊断和管理中具有临床实用性。