2011年肺腺癌新分类在评估组织学类型与分子学改变相关性中的意义

Relevance of molecular alterations in histopathologic subtyping of lung adenocarcinoma based on 2011 International Multidisciplinary Lung Adenocarcinoma Classification

目的根据2011年国际肺癌研究学会、美国胸科学会和欧洲呼吸学会公布的肺腺癌国际多学科分类方案（简称新分类）评估不同组织学类型与表皮生长因子受体（EGFR）、KRAS、EML4-ALK突变的相关性。方法检测212例手术切除肺腺癌标本中EGFR第18～21号外显子（E18～21）、KRAS第12和13位密码子和EML4-ALK突变，并结合新分类与2004年WHO分类进行比较分析。结果按照新分类标准，EGFR突变常见于贴壁为主型、乳头为主型和微乳头为主型腺癌，不同组织学类型之间差异有统计学意义（P=0．008）；KRAS突变最常见于浸润性黏液腺癌（1／2），其次为胶样腺癌（3／7），在不同组织学类型之间差异有统计学意义（P=0．003）；EML4-ALK融合突变最常见于实体为主型腺癌伴黏液产生（6／39，15．4％），其次为胶样腺癌（1／7），在不同组织学类型之间差异无统计学意义（P=0．181）。EGFR突变的腺癌伴有甲状腺转录因子（TTF）-1高表达（P=0．008），KRAS突变的腺癌伴有TTF-1低表达（P=0．000），而EML4-ALK融合与TTF-1表达无相关性（P=0．274）。按照2004年WHO分类，KRAS和EMIA—ALK突变在不同组织学类型之间差异有统计学意义（P=0．002，P=0．000），而EGFR突变差异无统计学意义（P=0．502）。结论新分类结合TTF—1免疫标记有助于判断肺腺癌的分子学改变，TTF-1阳性的贴壁为主型、乳头为主型和微乳头为主型腺癌提示可能存在EGFR突变；而TTF-1阴性的浸润性黏液腺癌和胶样腺癌则可能存在KRAS突变，但对于判断EMIA—ALK融合突变无明显优势。

Objective To evaluate the relevance of molecular alterations and histopathological subtypes of lung adenoearcinoma according to 2011 International Association for the Study of Lung Cancer/ American Thoracic Society/European Respiratory Society International Muhidisciplinary Lung Adenocarcinoma Classification. Methods Mutations of epidermal growth factor receptor （ECFR） 18-21 exons （E18-21） , KRAS 12/13 eodons and EML4-ALK fusion in 212 cases of lung adenocareinoma which underwent complete tumor resection, were detected by immunohistoehemistry, PCR-amplifying and gene sequencing. The relevance of the molecular alterations to histopathologieal subtypes based on the new classification and 2004 WHO classification were further characterized. Results Mutations of EGFR were observed in 49.6% of lung adenocareinomas, involving mainly E21 （52.4% , 55/105） and E19 （36.2% , 38/105）. Mutations of KRAS were detected in 8% cases of adenocareinoma, involving mainly codon 12 （15/17）. EMIA-ALK fusions were found in 6. 1% of lung adenocarcinoma, the most common fusion mutation was type V1 （E13; A20） （7/13）, followed by type V3a/b （E6a/b; A20） （4/13）. Based on the new classification, 7/10 lepidic, 63.2% （48/76） papillary, and 5/8 mieropapillary predominant adenocarcinomas harbored EGFR mutations. EGFR mutations showed significant difference among different histological subtypes （ P = 0. 008 ）. KRAS mutations were most frequently found in iuvasive mueinous adenocarcinoma （1/2）, followed by colloid predominant adenocareinoma （3/7）. There was significant difference of KRAS mutations among different histological subtypes （ P = 0. 003 ）. EMIA-ALK fusions were most frequently found in the solid predominant with mucin production subtype （15.4% , 6/39） , followed by colloid predominant adenocarcinoma （1/7） , and no significant difference of EMIA-ALK fusions was found among different histological subtypes （ P = 0. 181 ） . Significant TTF-1 overexpression was observed in adenocarcinomas harbored EGFR mutations （ P = 0. 008 ） , and no or significantly lower level expression of TFF-1 was observed in adenocarcinomas harbored KRAS mutations （P = 0. 000）. However, there was no association between TTF-1 expression and EMIA-ALK fusions （P = 0. 274 ）. Based on the 2004 WHO classification, mutations of KRAS （ P = 0. 002 ） and EMIA-ALK （ P = 0. 000）, rather than EGFR （ P = 0. 502）, showed significant differences among different subtypes. According to both classification systems, the difference of ＂triple negative＂ adenocarcinomas was not significant among different subtypes （P = 0. 684, P = 0. 449, respectively ） . Conclusions The new classification, combined with TTF-1 immunomarker, can help to predict the molecular alterations of EGFR and KRAS genes, but can not indicate the EML4-ALK fusion in lung ade Lepidic, papillary, and micropapillary predominant adenocarcinomas with TTF-1 expression are closely related to the presence of EGFR mutation, and invasive mucinous adenocarcinoma, while colloid predominant adenocarcinoma without TTF-1 expression is closely related to the presence of KRAS mutation.