肺腺癌脑转移病理学特征及人类间变性淋巴瘤激酶和表皮生长因子受体诊断价值

doi:10.3969/j.issn.1672-6731.2021.04.008

摘要/Abstract

摘要：

目的总结肺腺癌脑转移的病理学特征，并探讨人类间变性淋巴瘤激酶（ALK）和表皮生长因子受体（EGFR）的诊断价值。方法收集2013年1月至2016年12月在复旦大学附属华山医院神经外科手术切取的86例非小细胞肺癌脑转移的脑组织标本，经HE染色和免疫组化染色进行病理学分析，经免疫组化染色检测ALK和EGFR阳性率。结果 86例非小细胞肺癌患者中74例（86.05%）发生肺腺癌脑转移，其病理分型为实体型44例（59.46%）、腺泡型9例（12.16%）、乳头型14例（18.42%）和微乳头型7例（9.46%），与文献报道的原发性肺腺癌的病理分型差异有统计学意义（χ²=97.858，P=0.000）。肺腺癌脑转移ALK阳性率为9.46%（7/74），不同病理分型差异无统计学意义（χ²=1.690，P=0.639）；EGFR阳性率为52.70%（39/74），不同病理分型差异有统计学意义（χ²=7.938，P=0.047）；突变型EGFR总体阳性率为33.78%（25/74），不同病理分型差异无统计学意义（χ²=1.721，P=0.632），其中EGFR-19阳性率为18.92%（14/74）、EGFR-21为16.22%（12/74）。肺腺癌脑转移患者ALK与EGFR的表达可能存在相互排斥（χ²=12.462，P=0.001）。结论肺腺癌实体型和微乳头型具有较高的脑转移率。肺腺癌脑转移ALK和EGFR表达与原发性肺腺癌相一致，且二者表达可能存在相互排斥。

关键词: 癌, 非小细胞肺, 肿瘤转移, 受体, 表皮生长因子, 淋巴瘤, 大细胞, 间变性, 免疫组织化学

Abstract:

Objective To analyze the clinical-pathological features of brain metastases of lung adenocarcinoma and detect the expressions of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) in order to guide the targeted drug therapy of patients with advanced lung cancer. Methods A total of 86 cases of brain metastases from non-small cell lung cancer (NSCLC) in Huashan Hospital, Fudan University from January 2013 to December 2016 were selected for pathological analysis by HE staining and immunolabeling, ALK and EGFR expression were detected by immunohistochemical staining. Results Among 86 cases of brain metastases from NSCLC, 74 cases (86.05%) were adenocarcinoma, 3 cases (3.49%) of squamous cell carcinoma, and 9 cases (10.47%) of neuroendocrine tumors. Among the 74 brain metastases from lung adenocarcinoma, there were 44 cases (59.46%) of solid type, 9 cases (12.16%) of acinar type, 14 cases (18.42%) of papillary type and 7 cases (9.46%) of micropapillary type, which were significantly different from the pathological subtypes of primary lung adenocarcinoma reported in the literature (χ²=97.858, P=0.000). The expression rate of ALK protein was 9.46% (7/74), the expression rates were not statistically significant in different pathological types (χ²=1.690, P=0.639). The expression rate of EGFR non-mutant protein was 52.70% (39/74), and the expression rates were statistically significant in different pathological types (χ²=7.938, P=0.047). Fourteen cases (18.92%, 14/74) showed positive staining by specific mutation antibody of exon 19 of EGFR gene, while 12 cases (16.22%, 12/74) having exon 21 of EGFR gene mutation, and the total positive rate was 33.78% (25/74), the expression rates were not statistically significant in different pathological types (χ²=1.721, P=0.632). The expression levels of ALK and EGFR in brain metastases from lung adenocarcinoma were mutually exclusive (χ²=12.462, P=0.001). Conclusions Among lung adenocarcinoma, the solid lung type and the micropapillary type have higher tendencies of brain metastasis. The expression rates of ALK and EGFR in brain metastases were consistent with those of primary lung adenocarcinoma, and their expression was mutually exclusive.

Key words: Carcinoma, non-small-cell lung, Neoplasm metastasis, Receptor, epidermal growth factor, Lymphoma, large-cell, anaplastic, Immunohistochemistry

李竹君, 毛璐宁, 熊佶, 王鑫, 卢韶华, 刘颖. 肺腺癌脑转移病理学特征及人类间变性淋巴瘤激酶和表皮生长因子受体诊断价值[J]. 中国现代神经疾病杂志, 2021, 21(4): 272-280.

LI Zhu-jun, MAO Lu-ning, XIONG Ji, WANG Xin, LU Shao-hua, LIU Ying. Histopathological features with anaplastic lymphoma kinase and epidermal growth factor receptor expression of brain metastases from lung adenocarcinoma[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2021, 21(4): 272-280.

http://journal11.magtechjournal.com/cjcnn/CN/Y2021/V21/I4/272

参考文献

[1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021[J]. CA Cancer J Clin, 2021, 71:7-33.
[2] Marx A, Chan JK, Coindre JM, Detterbeck F, Girard N, Harris NL, Jaffe ES, Kurrer MO, Marom EM, Moreira AL, Mukai K, Orazi A, Ströbel P. The 2015 World Health Organization Classification of Tumors of the Thymus:continuity and changes[J]. J Thorac Oncol, 2015, 10:1383-1395.
[3] Zappa C, Mousa SA. Non-small cell lung cancer:current treatment and future advances[J]. Transl Lung Cancer Res, 2016, 5:288-300.
[4] Page S, Milner-Watts C, Perna M, Janzic U, Vidal N, Kaudeer N, Ahmed M, McDonald F, Locke I, Minchom A, Bhosle J, Welsh L, O'Brien M. Systemic treatment of brain metastases in non-small cell lung cancer[J]. Eur J Cancer, 2020, 132:187-198.
[5] Rybarczyk-Kasiuchnicz A, Ramlau R, Stencel K. Treatment of brain metastases of non-small cell lung carcinoma[J]. Int J Mol Sci, 2021, 22:593.
[6] Ernani V, Stinchcombe TE. Management of brain metastases in non-small-cell lung cancer[J]. J Oncol Pract, 2019, 15:563-570.
[7] Wu SG, Liu YN, Tsai MF, Chang YL, Yu CJ, Yang PC, Yang JC, Wen YF, Shih JY. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients[J]. Oncotarget, 2016, 7:12404-12413.
[8] Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer[J]. Nature, 2007, 448:561-566.
[9] Wen M, Wang X, Sun Y, Xia J, Fan L, Xing H, Zhang Z, Li X. Detection of EML4-ALK fusion gene and features associated with EGFR mutations in Chinese patients with non-small-cell lung cancer[J]. Onco Targets Ther, 2016, 9:1989-1995.
[10] Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, Ho KK, Au JS, Chung LP, Pik Wong M; University of Hong Kong Lung Cancer Study Group. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS[J]. Cancer, 2009, 115:1723-1733.
[11] Wei L, Li X, Yu Z. Mutations of EGFR gene and EML4-ALK fusion gene in superficial lymph node of non-small cell lung cancer[J]. Zhonghua Yi Xue Za Zhi, 2015, 95:2070-2073.
[12] Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer[J]. Eur J Cancer, 2010, 46:1773-1780.
[13] Xie JY, Yang LL, Ju GL, Yang M, Xu YB. Improvement of preparation method and quality process of pathological large slices of brain tissue specimen[J]. Lin Chuang Yu Shi Yan Bing Li Xue Za Zhi, 2019, 35:866-867.[谢建英, 杨柳柳, 居根吕, 杨敏, 徐玉兵. 脑组织标本病理大切片的制作方法及质量流程改进[J]. 临床与实验病理学杂志, 2019, 35:866-867.]
[14] Zhang J, Shao JC, Zhu L. Interpretation of the WHO classification of lung tumor in 2015[J]. Zhonghua Bing Li Xue Za Zhi, 2015:619-624.[张杰, 邵晋晨, 朱蕾. 2015版 WHO肺肿瘤分类解读[J]. 中华病理学杂志, 2015:619-624.]
[15] Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma[J]. J Thorac Oncol, 2011, 6:244-285.
[16] Lu F, Li S, Dong B, Zhang S, Lv C, Yang Y. Identification of lung adenocarcinoma mutation status based on histologic subtype:retrospective analysis of 269 patients[J]. Thorac Cancer, 2016, 7:17-23.
[17] Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, Park BJ, Rusch VW, Travis WD. Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma:prognostic subgroups and implications for further revision of staging based on analysis of 514 stage Ⅰ cases[J]. Mod Pathol, 2011, 24:653-664.
[18] Yanagawa N, Shiono S, Abiko M, Ogata SY, Sato T, Tamura G. New IASLC/ATS/ERS classification and invasive tumor size are predictive of disease recurrence in stage Ⅰ lung adenocarcinoma[J]. J Thorac Oncol, 2013, 8:612-618.
[19] Xu CH, Wang W, Wei Y, Hu HD, Zou J, Yan J, Yu LK, Yang RS, Wang Y. Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification in stage IB lung adenocarcinoma[J]. Eur J Surg Oncol, 2015, 41:1430-1436.
[20] Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer[J]. Cell, 2007, 131:1190-1203.
[21] Kim B, Jang YJ, Park S, Lee JI, Kim HK, Han J. Histopathologic analysis of brain metastasis in pulmonary adenocarcinoma:necrosis is a new risk factor[J]. Pathol Res Pract, 2019, 215:807-815.
[22] Casteillo F, Guy JB, Dal-Col P, Karpathiou G, Pommier B, Bayle-Bleuez S, Fournel P, Vassal F, Forest F. Pathologic subtypes of lung adenocarcinoma brain metastasis is a strong predictor of survival after resection[J]. Am J Surg Pathol, 2018, 42:1701-1707.
[23] Zhang YG, Jin ML, Li L, Zhao HY, Zeng X, Jiang L, Wei P, Diao XL, Li X, Cao Q, Tian XX. Evaluation of ALK rearrangement in Chinese non-small cell lung cancer using FISH, immunohistochemistry, and real-time quantitative RT-PCR on paraffin-embedded tissues[J]. PLoS One, 2013, 8:e64821.
[24] Xia N, An J, Jiang QQ, Li M, Tan J, Hu CP. Analysis of EGFR, EML4-ALK, KRAS, and c-MET mutations in Chinese lung adenocarcinoma patients[J]. Exp Lung Res, 2013, 39:328-335.
[25] Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, Uhlmann EJ, Wong ET, Dahlberg SE, Huberman MS, Costa DB. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers[J]. Lung Cancer, 2015, 88:108-111.
[26] Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, Zhou C, Shreeve SM, Selaru P, Polli A, Schnell P, Wilner KD, Wiltshire R, Camidge DR, Crinò L. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases[J]. J Clin Oncol, 2015, 33:1881-1888.
[27] McLeer-Florin A, Moro-Sibilot D, Melis A, Salameire D, Lefebvre C, Ceccaldi F, de Fraipont F, Brambilla E, Lantuejoul S. Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice:a French study[J]. J Thorac Oncol, 2012, 7:348-354.
[28] Murakami Y, Mitsudomi T, Yatabe Y. A screening method for the ALK fusion gene in NSCLC[J]. Front Oncol, 2012, 2:24.
[29] Jokoji R, Yamasaki T, Minami S, Komuta K, Sakamaki Y, Takeuchi K, Tsujimoto M. Combination of morphological feature analysis and immunohistochemistry is useful for screening of EML4-ALK-positive lung adenocarcinoma[J]. J Clin Pathol, 2010, 63:1066-1070.
[30] Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA, Stubbs H, Law K, Lindeman N, Mark E, Janne PA, Lynch T, Johnson BE, Iafrate AJ, Chirieac LR. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population[J]. Clin Cancer Res, 2009, 15:5216-5223.
[31] Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy[J]. Science, 2004, 304:1497-1500.
[32] Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, Heeroma K, Itoh Y, Cornelio G, Yang PC. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER)[J]. J Thorac Oncol, 2014, 9:154-162.
[33] Kitamura A, Hosoda W, Sasaki E, Mitsudomi T, Yatabe Y. Immunohistochemical detection of EGFR mutation using mutation-specific antibodies in lung cancer[J]. Clin Cancer Res, 2010, 16:3349-3355.
[34] Cooper WA, Yu B, Yip PY, Ng CC, Lum T, Farzin M, Trent RJ, Mercorella B, Clarkson A, Kohonen-Corish MR, Horvath LG, Kench JG, McCaughan B, Gill AJ, O'Toole SA. EGFR mutant-specific immunohistochemistry has high specificity and sensitivity for detecting targeted activating EGFR mutations in lung adenocarcinoma[J]. J Clin Pathol, 2013, 66:744-748.
[35] Wen YH, Brogi E, Hasanovic A, Ladanyi M, Soslow RA, Chitale D, Shia J, Moreira AL. Immunohistochemical staining with EGFR mutation-specific antibodies:high specificity as a diagnostic marker for lung adenocarcinoma[J]. Mod Pathol, 2013, 26:1197-1203.
[36] Yoshida A, Tsuta K, Nakamura H, Kohno T, Takahashi F, Asamura H, Sekine I, Fukayama M, Shibata T, Furuta K, Tsuda H. Comprehensive histologic analysis of ALK-rearranged lung carcinomas[J]. Am J Surg Pathol, 2011, 35:1226-1234.
[37] Nishino M, Klepeis VE, Yeap BY, Bergethon K, Morales-Oyarvide V, Dias-Santagata D, Yagi Y, Mark EJ, Iafrate AJ, Mino-Kenudson M. Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas[J]. Mod Pathol, 2012, 25:1462-1472.
[38] Inamura K, Ninomiya H, Ishikawa Y, Matsubara O. Is the epidermal growth factor receptor status in lung cancers reflected in clinicopathologic features[J]? Arch Pathol Lab Med, 2010, 134:66-72.
[39] Sakuma Y, Matsukuma S, Yoshihara M, Nakamura Y, Noda K, Nakayama H, Kameda Y, Tsuchiya E, Miyagi Y. Distinctive evaluation of nonmucinous and mucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses for Japanese lung adenocarcinomas:confirmation of the correlations with histologic subtypes and gene mutations[J]. Am J Clin Pathol, 2007, 128:100-108.
[40] Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U, Settleman J, Kobayashi S, Mark EJ, Rodig SJ, Chirieac LR, Kwak EL, Lynch TJ, Iafrate AJ. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK[J]. J Clin Oncol, 2009, 27:4247-4253.
[41] Tiseo M, Gelsomino F, Boggiani D, Bortesi B, Bartolotti M, Bozzetti C, Sammarelli G, Thai E, Ardizzoni A. EGFR and EML4-ALK gene mutations in NSCLC:a case report of erlotinib-resistant patient with both concomitant mutations[J]. Lung Cancer, 2011, 71:241-243.

选择文件类型/文献管理软件名称

选择包含的内容

2 肺腺癌脑转移病理学特征及人类间变性淋巴瘤激酶和表皮生长因子受体诊断价值

Histopathological features with anaplastic lymphoma kinase and epidermal growth factor receptor expression of brain metastases from lung adenocarcinoma

RichHTML

PDF

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	任修德, 李涛, 范吉康, 王希森, 贾晓丹, 杨学军. 胶质母细胞瘤FGFR3-TACC3融合基因介导丙酮酸激酶M2入核促进DNA损伤修复基础研究[J]. 中国现代神经疾病杂志, 2023, 23(8): 745-757.
[2]	马晓丽, 童家杰, 张秀智, 杜倩, 隋爱霞, 赵焕芬. 表现为垂体腺瘤卒中的黄色瘤性垂体炎[J]. 中国现代神经疾病杂志, 2023, 23(7): 599-603.
[3]	刘敏婷, 戴利军, 张振斌, 邵媛, 赖名耀, 张笑坛. 转化生长因子-β联合CD3⁺、CD4⁺、CD8⁺T细胞检测胶质母细胞瘤免疫微环境初探[J]. 中国现代神经疾病杂志, 2023, 23(3): 247-253.
[4]	唐薇婷, 肖波. N-甲基-D-天冬氨酸受体GRIN2A基因变异与癫痫研究进展[J]. 中国现代神经疾病杂志, 2023, 23(2): 89-93.
[5]	王雪, 刘霄, 李志梅, 王群. 基于Nomogram模型的抗N-甲基-D-天冬氨酸受体脑炎合并急性症状性癫癎发作的危险因素分析[J]. 中国现代神经疾病杂志, 2022, 22(3): 179-186.
[6]	林晓雪, 刘颖元, 张淑华, 董钊. 偏头痛急性期和预防性治疗进展[J]. 中国现代神经疾病杂志, 2022, 22(2): 99-103.
[7]	梁恭博, 王卓才, 何文源, 赖续文, 王蔚. 罕见松果体区骨外黏液样软骨肉瘤[J]. 中国现代神经疾病杂志, 2022, 22(12): 1059-1067.
[8]	成白洁, 李海南, 邓达标, 许少强, 李智. 中枢神经系统原发性黑色素细胞肿瘤临床病理学特征[J]. 中国现代神经疾病杂志, 2021, 21(8): 670-678.
[9]	宋坤, 王娟, 柴学, 张玉梅, 严春燕, 周金宝, 朱海青. 脑膜瘤伴黑色素细胞移殖性增生[J]. 中国现代神经疾病杂志, 2021, 21(6): 485-492.
[10]	张锦浩, 刘沛东, 张辰, 李佳博, 任枭, 陈露露, 孙锦章, 王旭亚, 张亮, 杨学军. ACT001通过抑制P65磷酸化降低胶质母细胞瘤细胞程序性死亡蛋白配体1的表达[J]. 中国现代神经疾病杂志, 2021, 21(6): 502-510.
[11]	王月坤, 刘磊, 陈琬琦, 王裕, 马文斌. 脑转移瘤患者单纯手术治疗与手术联合术后脑部放疗对比分析[J]. 中国现代神经疾病杂志, 2021, 21(3): 162-169.
[12]	范冲竹, 李海南, 向璇, 邓达标, 李业海, 匡祖颖, 李智. 易误诊为脑肿瘤的颅内静脉窦血栓形成[J]. 中国现代神经疾病杂志, 2021, 21(12): 1089-1094.
[13]	刘梅, 穆宁, 马春华, 李金铎, 李林, 姜镕. 双倍剂量埃克替尼治疗EGFR基因敏感突变肺腺癌柔脑膜转移疗效初探[J]. 中国现代神经疾病杂志, 2021, 21(11): 1001-1006.
[14]	孙瑗璟, 范玉华. 常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病病理学及分子机制研究进展[J]. 中国现代神经疾病杂志, 2021, 21(10): 828-833.
[15]	谢聃, 宋赞民, 王霞, 张拥波. 先天性EDNRB基因缺陷对大鼠海马区神经细胞凋亡的影响[J]. 中国现代神经疾病杂志, 2021, 21(10): 881-886.

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

2 肺腺癌脑转移病理学特征及人类间变性淋巴瘤激酶和表皮生长因子受体诊断价值

Histopathological features with anaplastic lymphoma kinase and epidermal growth factor receptor expression of brain metastases from lung adenocarcinoma

RichHTML

PDF

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价