Department of Histopathology, Bristol Royal Infirmary, BS2 8HW Bristol, UK.
Hum Pathol. 2012 Oct;43(10):1651-60. doi: 10.1016/j.humpath.2011.12.006. Epub 2012 Mar 19.
The overexpression of carbonic anhydrase IX, a hypoxia-induced enzyme, is associated with an adverse prognosis in many cancers. However, carbonic anhydrase IX expression in neuroblastoma, the most common extracranial pediatric tumor, has not been reported. Membranous and/or strong cytoplasmic carbonic anhydrase IX expression, assessed by immunohistochemistry, was present in 21 (23%) of 91 neuroblastomas but was absent in ganglioneuromas (n = 9). The proportion of neuroblastomas showing membranous carbonic anhydrase IX expression was higher in neuroblastomas with 1p deletion and MYCN amplification. Nuclear carbonic anhydrase IX expression was seen in less than 10% of ganglion cells in all ganglioneuromas. Of 91 neuroblastomas, 16 (18%) showed nuclear carbonic anhydrase IX expression in 10% or more tumoral cells. The proportion of neuroblastomas showing nuclear carbonic anhydrase IX expression was significantly higher in patients with adverse clinical (increasing stage and high-risk group), pathologic (unfavorable group and high mitosis-karyorrhexis-index), and biologic (MYCN-amplification and 1p deletion) factors. Carbonic anhydrase IX total protein levels, quantified by enzyme-linked immunosorbent assay, were higher in neuroblastomas (n = 49; geometric mean, 0.47 pg/µg; range, 0.0-6.52 pg/µg) than in ganglioneuromas (n = 6; geometric mean, 0.20 pg/µg; range, 0.09-0.47 pg/µg) and were significantly higher in MYCN-amplified neuroblastomas. Nuclear carbonic anhydrase IX expression was associated with a poorer overall survival (P = .003) and event-free survival (P = .004), although the relationships were no longer significant when adjusted for high-risk disease. There was no significant association of membranous carbonic anhydrase IX expression or higher-than-median total protein levels with overall survival or event-free survival. Carbonic anhydrase IX is expressed at significantly higher levels in neuroblastomas from patients with adverse clinicopathologic and biologic factors indicating that it is a biomarker of aggressive disease in neuroblastomas.
碳酸酐酶 IX 的过表达与许多癌症的不良预后相关，碳酸酐酶 IX 是一种缺氧诱导的酶。然而，神经母细胞瘤（最常见的颅外小儿肿瘤）中的碳酸酐酶 IX 表达尚未报道。通过免疫组织化学评估，21 例（23%）91 例神经母细胞瘤中存在膜性和/或强细胞质碳酸酐酶 IX 表达，但神经节细胞瘤（n = 9）中不存在。在 1p 缺失和 MYCN 扩增的神经母细胞瘤中，显示膜性碳酸酐酶 IX 表达的神经母细胞瘤比例较高。在所有神经节细胞瘤的神经节细胞中，核碳酸酐酶 IX 表达不到 10%。在 91 例神经母细胞瘤中，16 例（18%）有 10%或更多肿瘤细胞显示核碳酸酐酶 IX 表达。在具有不良临床（分期增加和高危组）、病理（不良组和高有丝分裂-核碎裂指数）和生物学（MYCN 扩增和 1p 缺失）因素的患者中，显示核碳酸酐酶 IX 表达的神经母细胞瘤比例显著更高。通过酶联免疫吸附试验定量检测碳酸酐酶 IX 总蛋白水平，神经母细胞瘤（n = 49；几何均数为 0.47 pg/µg；范围为 0.0-6.52 pg/µg）高于神经节细胞瘤（n = 6；几何均数为 0.20 pg/µg；范围为 0.09-0.47 pg/µg），并且在 MYCN 扩增的神经母细胞瘤中显著更高。核碳酸酐酶 IX 表达与总生存率（P =.003）和无事件生存率（P =.004）较差相关，尽管在调整高危疾病后，这些关系不再显著。膜性碳酸酐酶 IX 表达或高于中位数的总蛋白水平与总生存率或无事件生存率无显著相关性。在具有不良临床病理和生物学因素的神经母细胞瘤患者中，碳酸酐酶 IX 的表达水平显著升高，这表明它是神经母细胞瘤侵袭性疾病的生物标志物。
