Molecular Profiling of Pheochromocytoma and Abdominal Paraganglioma Stratified by the PASS Algorithm Reveals Chromogranin B as Associated With Histologic Prediction of Malignant Behavior
Molecular Profiling of Pheochromocytoma and Abdominal Paraganglioma Stratified by the PASS Algorithm Reveals Chromogranin B as Associated With Histologic Prediction of Malignant Behavior
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DOI：
10.1097/pas.0000000000001190
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发表时间：
2019-03-01
影响因子：
5.6
通讯作者：
Juhlin, C. Christofer
中科院分区：
文献类型：
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作者：
Stenman, Adam;Svahn, Fredrika;Juhlin, C. Christofer
嗜铬细胞瘤(PCCs)和腹部副神经节瘤(PGL)，统称为PPGL，被认为具有恶性潜能-但只有部分病例会显示出全面的恶性特征。肾上腺嗜铬细胞瘤评分(PASS)算法是一种被建议的组织学系统，用于检测潜在的攻击行为，但对其与潜在的分子遗传学的耦合知之甚少。在这项研究中，使用PASS标准对总共92例PPGL进行了组织学评估，这些PPGL以前的特征是易感基因状态和mRNA表达谱。共有32/92例PPGL(35%)的PPGL评分为4分，包括所有8例有恶性行为的患者(7例有已知转移，1例有广泛浸润性局部复发)。对表达数据和临床参数以及个别PASS标准的统计分析表明，嗜铬粒蛋白B(CHGB)、BRCA2、HIST1H3B、BUB1B和RET等与PASS和转移/局部复发之间存在显著的相关性，CHGB与PASS和转移/局部复发的相关性最强。在高通量和明显恶性行为的PPGL中观察到明显的CHGB下调，也与较短的疾病相关生存期有关。这一发现得到了定量实时聚合酶链式反应的验证，在定量实时聚合酶链式反应中，CHGB的表达与PASS和转移/局部复发都相关，与在TCGA队列中获得的一致的结果一致。此外，对肿瘤亚型的免疫组织化学分析表明，高分通过与CHGB蛋白表达阴性或微弱之间存在相关性。PPGLS患者术后及格分数较高，术前血浆CHGB水平也较低。这些数据共同指出，CHGB可能是PPGLS的术前和术后的标志物，具有潜在的攻击性行为。
Pheochromocytomas (PCCs) and abdominal paragangliomas (PGLs), collectively abbreviated PPGL, are believed to exhibit malignant potential-but only subsets of cases will display full-blown malignant properties. The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) algorithm is a proposed histologic system to detect potential for aggressive behavior, but little is known regarding the coupling to underlying molecular genetics. In this study, a total of 92 PPGLs, previously characterized for susceptibility gene status and mRNA expressional profiles, were histologically assessed using the PASS criteria. A total of 32/92 PPGLs (35%) exhibited a PASS score >= 4, including all 8 cases with malignant behavior (7 with known metastases and 1 with extensively infiltrative local recurrence). Statistical analyzes between expressional data and clinical parameters as well as individual PASS criteria yielded significant associations to Chromogranin B (CHGB), BRCA2, HIST1H3B, BUB1B, and RET to name a few, and CHGB had the strongest correlation to both PASS and metastasis/local recurrence of all analyzed genes. Evident CHGB downregulation was observed in PPGLs with high PASS and overtly malignant behavior, and was also associated with shorter disease-related survival. This finding was validated using quantitative real-time polymerase chain reaction, in which CHGB expression correlated with both PASS and metastasis/local recurrence with consistent findings obtained in the TCGA cohort. Moreover, immunohistochemical analyses of subsets of tumors showed a correlation between high PASS scores and negative or weak CHGB protein expression. Patients with PPGLs obtaining high PASS scores postoperatively, also exhibited low preoperative plasma levels of CHGB. These data collectively point out CHGB as a possible preoperative and postoperative marker for PPGLs with potential for aggressive behavior.