融合基因阳性肺腺癌的病理组织学特征及与砂粒体的相关性研究

A comprehensive study on histological features of fusion-positive lung adenocarcinomas and their association with psammoma bodies

背景与目的:间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)、c-ros原癌基因1酪氨酸激酶(c-ros oncogene 1 receptor tyrosine kinase,ROS1)和RET融合基因被陆续证实为肺腺癌的驱动基因突变,并可在靶向治疗中获益。该研究旨在阐述融合基因阳性肺腺癌病理组织学特征,并探讨砂粒体与融合基因阳性肺腺癌的相关性。方法:收集复旦大学附属肿瘤医院原发肺腺癌患者手术切除新鲜标本和石蜡固定标本,检测肺腺癌标本中表皮生长因子受体(epidermal growth factor receptor,EGFR)、鼠类肉瘤病毒癌基因(Kirsten rat sarcoma viral oncogene,K-ras)、ALK、RET和ROS1基因突变状态。选取融合基因阳性肺腺癌病例44例(9例ROS1阳性,20例K-ras阳性,15例RET阳性)和融合基因阴性肺腺癌111例(20例EGFR突变,20例K-ras突变,71例未检测出基因突变)用于本项研究。根据2015年世界卫生组织(World Health Organization,WHO)肺腺癌新分类评估融合基因组与无融合基因组的病理组织学形态特征,并观察肺腺癌组织中砂粒体的数量及其分布的特征,并探讨砂粒体与融合基因阳性肺腺癌的相关性。结果:融合基因组中主要组织学亚型为腺泡状亚型(19/44,43.2%)和实体亚型(13/44,29.5%),无融合基因组主要组织学亚型为腺泡状亚型(50/111,45.0%)。实体亚型更多见于融合基因组,但两组间主要组织学亚型差异无统计学意义(P=0.060)。含印戒细胞成分、微乳头结构、黏液筛状结构及细胞外黏液分泌在融合基因组中阳性率均显著高于无融合基因组(P=0.000,P=0.044,P=0.000,P=0.010)。砂粒体在融合基因组阳性率显著高于无融合基因组(P=0.000),并且砂粒体与微乳头及黏液筛状结构具有显著相关性(P=0.000)。结论:实体亚型及腺泡状亚型常见于融合基因阳性肺腺癌。砂粒体、微乳头、细胞外黏液分泌、黏液筛状结构及含印戒细胞成分等特征性组织学形态与融合基因阳性肺腺癌密切相关,并且砂粒体与微乳头结构和(或)黏液筛状结构往往同时存在。通过对肺腺癌的特征性形态学观察对肺腺癌基因检测的优先性筛选具有指导意义。

Background and purpose： Gene fusions have been identified as recurrent oncogenic events in lung adenocarcinoma. Our purpose are to study the histologic features of anaplastic lymphoma kinase （ALK）, c-ros oncogene 1 receptor tyrosine kinase （ROS 1） and RET proto-oncogene fusion-positive lung adenocarcinomas and to evaluate the correlation between psammoma bodies and fusion-positive lung adenocarcinomas. Methods： In this study, we performed a comprehensive histologic analysis of 44 fusion-positive （including 15 RET, 20 ALK and 9 ROS1） lung adenocarcinomas and 111 fusion-negative [including 20 epidermal growth factor receptor （EGFR）, 20 Kirsten rat sarcoma viral oncogene （K-ras）, 71 pan-negative] lung adenocarcinomas. Results： ALK, RET and ROS1 fusionpositive lung adenocarcinomas were more prevalent in solid or acinar predominant adenocarcinoma. Multivariate analysis showed that tumors harboring a fusion gene had significantly higher prevalence of the presence of signet ring cells （P=0.000）, micropapillary component （P=0.044）, mucinous cribriform pattern （P=0.000） and extracellular mucin （P=0.010）. The incidence of psammoma bodies was higher in the lung adenocarcinomas with a gene fusion than in tumors without gene fusions （P=0.000）. Psammoma bodies were more likely to be found in tumors with any micropapillary component and/or mucinous cribriform pattern than in tumors lacking a micropapillary component and/or mucinous cribriform pattern （P=0.000）. Conclusion： Our data showed that the presence of psammoma bodies, micropapillary component, mucinous cribriform pattern, extracellular mucin or signet ring cells may be either sensitive or specific to predict tumors harboring a fusion gene. These distinct morphologic features may be helpful in selecting cases for further accurate molecular testing.