Kleist Britta, Kempa Marcel, Novy Michael, Oberkanins Christian, Xu Li, Li Guojun, Loland Christiane, Poetsch Micaela
Department of Pathology, Southern Hospital Trust Kristiansand, Norway.
Institute of Legal Medicine, University Hospital Essen Essen, Germany.
Int J Clin Exp Pathol. 2014 Aug 15;7(9):5927-39. eCollection 2014.
Neuroendocrine differentiation of tumor tissue has been recognized as an important prerequisite for new targeted therapies. To evaluate the suitability of colorectal cancer (CRC) tissue for these treatment approaches and to find a possible link to pretherapeutic conditions of other targeted strategies, we compared neuroendocrine differentiation and KRAS/NRAS/BRAF/PIK3CA/TP53 mutational status in primary and metastatic CRC. Immunohistochemical expression analysis of neuroendocrine markers chromogranin A and synaptophysin was performed on archival CRC tissue, comprising 116 primary tumors, 258 lymph node metastases and 72 distant metastases from 115 patients. All CRC samples but 30 distant metastases were subjected to mutation analysis of KRAS, NRAS, BRAF, PIK3CA, and TP53. Neuroendocrine marker expression was found significantly less frequently in lymph node metastases compared to primary tumors and distant metastases (20%, 31%, 28%, respectively, P = 0.044). KRAS mutation rates increased significantly from primary tumors to lymph node metastases and distant metastases within the neuroendocrine negative CRC group (44%, 53%, 64%, respectively, P = 0.042). Neuroendocrine differentiation was significantly less concordant than KRAS/NRAS/BRAF/PIK3CA/TP53 mutational status in primary tumor/lymph node metastases pairs (65% versus 88%-99%; P < 0.0001) and primary tumor/distant metastases pairs (64% versus 83%-100%; P = 0.027 and P < 0.0001, respectively). According to these data, therapeutic targeting of neuroendocrine tumor cells can be considered only for a subset of CRC patients and biopsies from the metastatic site should be used to guide therapy. A possible importance of lacking neuroendocrine differentiation for progression of KRAS mutant CRC should be further investigated.
肿瘤组织的神经内分泌分化已被认为是新的靶向治疗的重要前提条件。为了评估结直肠癌（CRC）组织对这些治疗方法的适用性，并寻找与其他靶向治疗策略的治疗前状况的可能联系，我们比较了原发性和转移性CRC中神经内分泌分化以及KRAS/NRAS/BRAF/PIK3CA/TP53的突变状态。对来自115例患者的存档CRC组织进行神经内分泌标志物嗜铬粒蛋白A和突触素的免疫组化表达分析，这些组织包括116个原发性肿瘤、258个淋巴结转移灶和72个远处转移灶。除30个远处转移灶外，所有CRC样本均进行了KRAS、NRAS、BRAF、PIK3CA和TP53的突变分析。发现神经内分泌标志物表达在淋巴结转移灶中的频率明显低于原发性肿瘤和远处转移灶（分别为20%、31%、28%，P = 0.044）。在神经内分泌阴性的CRC组中，KRAS突变率从原发性肿瘤到淋巴结转移灶和远处转移灶显著增加（分别为44%、53%、64%，P = 0.042）。在原发性肿瘤/淋巴结转移灶对（65%对88%-99%；P < 0.0001）和原发性肿瘤/远处转移灶对（64%对83%-100%；P = 0.027和P < 0.0001）中，神经内分泌分化的一致性明显低于KRAS/NRAS/BRAF/PIK3CA/TP53的突变状态。根据这些数据，仅对一部分CRC患者可考虑对神经内分泌肿瘤细胞进行靶向治疗，并且应使用来自转移部位的活检来指导治疗。KRAS突变型CRC进展过程中缺乏神经内分泌分化的可能重要性应进一步研究。
