肺腺癌组织学亚型与预后和EGFR突变相关性研究
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摘要
目的：探讨肺腺癌组织学亚型与预后及EGFR突变的相关性。
方法：1.收集中国人民解放军总医院病理科1995年10月至2007年8月期间158例细支气管肺泡癌和2005年4月至2011年9月期间已进行EGFR突变检测的282例肺腺癌手术病例,按照新的国际肺癌研究协会、美国胸科协会和欧洲呼吸学会肺腺癌分类标准对组织切片重新进行评估,使用5%增量记录每种组织学成分,按全面组织学亚型进行组织学分型,并对158例细支气管肺泡癌进行随访。2.应用直接DNA测序技术在石蜡组织中检测EGFR基因18、19、20及21号外显子的突变情况。3、运用SPSS统计软件(13.0)对所获得的实验数据进行统计学分析。
结果：1.158例细支气管肺泡癌中,男、女各79例,平均年龄59.7岁(31-84岁),不吸烟者122(77.2%)人,Ⅰ期病人占大部分(n=126,79.7%)。重新分类后微浸润腺癌最多(45,28.4%),其次是贴壁为主腺癌(39,24.6%)。腺泡状为主腺癌有26例,原位腺癌有13例,乳头状为主腺癌有20例,微乳头状为主腺癌有1例,实性为主腺癌有3例。浸润性腺癌的变异型包括黏液腺癌11例,胶样腺癌1例。随访时间为64-206个月,失访5例。各组织学亚型预后不同。原位腺癌、微浸润腺癌的5年无病生存率和5年总生存率均为100%。贴壁为主、腺泡状为主和乳头状为主腺癌的预后中等,5年总生存率分别为87.5%、73.9%和77.8%。实性为主腺癌和浸润性腺癌的变异型预后差,5年总生存期为33.3%、41.7%。分期(P=0.000)和肿瘤大小(P=0.000)与预后相关。2.282例腺癌中,男性145例,女性137例,平均年龄60.4岁(20-86岁),全部为中国人。不吸烟者198人,Ⅰ期112例,Ⅱ期79例,Ⅲ期74例,Ⅳ期17例。检测282例样本中EGFR突变共165例,突变率为58.5%,突变类型如下：19号外显子检测到85例突变,突变率是51.5%；20外显子检测到9例突变,突变率为5.4%；21外显子检测到69例,突变率为41.8%。突变主要集中在19号外显子的缺失和21号外显子的点突变。女性突变率(66.4)比男性(51,0%)高,差别具有统计学意义(P=0.009)。不吸烟组患者突变率(64.9%)高于曾吸烟组(52.2)和目前吸烟组(41.5%),差别也具有统计学意义。年龄、肿瘤大小、分期与EGFR突变发生率无关。最常见的组织学亚型是腺泡状为主型腺癌93(33.0%)。乳头状腺癌发生EGFR突变(8/10,80%)比其它亚型(157/271,57.7%)更常见,其次是贴壁状为主腺癌(78.7%),实性为主腺癌发生突变率较低(32.1%)。组织学亚型与EGFR突变有明显相关性(P=0.000)。
结论：1.停止使用BAC这一术语是合理的、重要的。2.根据肺腺癌新分类,各组织学亚型临床结果不同,原位腺癌和微浸润腺癌预后最好；实性为主型腺癌、粘液腺癌和胶样腺癌预后差；贴壁状为主腺癌、腺泡状为主腺癌和乳头状腺癌预后介于前两组之间。3.组织学亚型与EGFR突变状态密切相关,微乳头状为主型腺癌EGFR突变率最高,粘液腺癌EGFR突变率最低。同时,不吸烟的患者比吸烟者患者的EGFR突变率高,女性患者比男性患者的EGFR突变发生率高。
Objective:To investigate the relationship among histological subtypes, EGFR mutation and prognosis of lung adenocarcinoma.
Methods:1. All cases of lung adenocacinoma were collected from the archives of the Department of Pathology, Chinese PLA General Hospital including two series.158cases of BAC were between October1995and August2007, and another282cases of adenocarcinoma between April2005and December2011of which EGFR mutation were detected. All patients'slides were reviewed and reclassificated according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma, using comprehensive histological subtyping, recording the percentage, in5%increments,of each histological component.2. EGFR gene mutations of exons18through21were detected by direct DNA sequencing.3. Data were analyzed with Statistical Standard Package Service Solution software (13.0).
Results:1. Among158cases of BAC,79cases were female and79cases were male, with an average age of59.7yrs (range:31-84),122(77.2%) cases were non-smokers, and majority of patients were stage I (n=126,79.7%). After reclassification, minimally invasive adenocarcinoma (MIA) was the most common subtype (28.4%), followed by lepidic predominant adenocarcinoma (LPA,24.6%). The time of follow-up was64-206months. The prognosis of each subtype was different. Both AIS and MIA had100%5-year disease-free survival rate and100%5-year overall survival rate. Lepidic, acinar, and papillary had intermediate prognosis with87.5%,73.9%and77.8%5-year overall survival rate respectively. Solid and variants of invasive adenocarcinoma cases had poor prognosis with33.3%,41.7%5-year overall survival rate respectively. Higher stage (P=0.000) and age (tumor P=0.000) were associated with worse disease-free survival.2. Among282cases of lung adenocarcinoma, There were145men and137women aged 20to86years (mean,60.4years). All patients were Chinese. There were198never smokers,48former smokers, and36current smokers. Pathologic stages were stage I in112patients, stage Ⅱ in19patients, and stage Ⅲ in74patients, stage Ⅳ in17patients. Epidermal growth factor receptor mutations were detected in165of a total of282cases (58.5%). Exons with mutations were as follows:of a total of165mutated carcinomas,85(51.5%) were in exon19,9(5.4%) in exon20, and69(41.8%) in exon21. The most common mutation was in-frame deletions in exon19and the second most common mutation was point mutations in exon21. Epidermal growth factor receptor mutations were detected more frequently in women (66.4%) than in men (51.0%), the difference was statistically significant (P=0.009). EGFR mutations were more frequent in never smokers (64.9%) than in former smokers (52.2%) and current smokers (41.5%; P=0.003). Age, tumor size, and pathologic stage did not show significant associations with frequency of EGFR mutations. The most frequent subtype was acinar predominant. Epidermal growth factor receptor mutations were significantly more frequent in the micropapillary predominant subtype (8/10,80%) than in the other subtypes (157/272,57.7%), the second was LPA (78.7%), In contrast, EGFR mutations were less frequent in the solid predominant subtype (32.1%). The histopathologic subtypes correlated with EGFR mutations (P=0.000).
Conclusions:1.Discontinuing the use of the term "BAC" is reasonable and important.2The prognosis of each subtype was different. Both AIS and MIA had good prognosis, but Solid and variants of invasive adenocarcinoma had poor prognosis3. The histopathologic subtypes correlated with EGFR mutations, Epidermal growth factor receptor mutations were significantly more frequent in the micropapillary predominant subtype (8/10,80%) than in the other subtypes. Meantime, Epidermal growth factor receptor mutations were detected more frequently in women and never smokers.
方法：1.收集中国人民解放军总医院病理科1995年10月至2007年8月期间158例细支气管肺泡癌和2005年4月至2011年9月期间已进行EGFR突变检测的282例肺腺癌手术病例,按照新的国际肺癌研究协会、美国胸科协会和欧洲呼吸学会肺腺癌分类标准对组织切片重新进行评估,使用5%增量记录每种组织学成分,按全面组织学亚型进行组织学分型,并对158例细支气管肺泡癌进行随访。2.应用直接DNA测序技术在石蜡组织中检测EGFR基因18、19、20及21号外显子的突变情况。3、运用SPSS统计软件(13.0)对所获得的实验数据进行统计学分析。
结果：1.158例细支气管肺泡癌中,男、女各79例,平均年龄59.7岁(31-84岁),不吸烟者122(77.2%)人,Ⅰ期病人占大部分(n=126,79.7%)。重新分类后微浸润腺癌最多(45,28.4%),其次是贴壁为主腺癌(39,24.6%)。腺泡状为主腺癌有26例,原位腺癌有13例,乳头状为主腺癌有20例,微乳头状为主腺癌有1例,实性为主腺癌有3例。浸润性腺癌的变异型包括黏液腺癌11例,胶样腺癌1例。随访时间为64-206个月,失访5例。各组织学亚型预后不同。原位腺癌、微浸润腺癌的5年无病生存率和5年总生存率均为100%。贴壁为主、腺泡状为主和乳头状为主腺癌的预后中等,5年总生存率分别为87.5%、73.9%和77.8%。实性为主腺癌和浸润性腺癌的变异型预后差,5年总生存期为33.3%、41.7%。分期(P=0.000)和肿瘤大小(P=0.000)与预后相关。2.282例腺癌中,男性145例,女性137例,平均年龄60.4岁(20-86岁),全部为中国人。不吸烟者198人,Ⅰ期112例,Ⅱ期79例,Ⅲ期74例,Ⅳ期17例。检测282例样本中EGFR突变共165例,突变率为58.5%,突变类型如下：19号外显子检测到85例突变,突变率是51.5%；20外显子检测到9例突变,突变率为5.4%；21外显子检测到69例,突变率为41.8%。突变主要集中在19号外显子的缺失和21号外显子的点突变。女性突变率(66.4)比男性(51,0%)高,差别具有统计学意义(P=0.009)。不吸烟组患者突变率(64.9%)高于曾吸烟组(52.2)和目前吸烟组(41.5%),差别也具有统计学意义。年龄、肿瘤大小、分期与EGFR突变发生率无关。最常见的组织学亚型是腺泡状为主型腺癌93(33.0%)。乳头状腺癌发生EGFR突变(8/10,80%)比其它亚型(157/271,57.7%)更常见,其次是贴壁状为主腺癌(78.7%),实性为主腺癌发生突变率较低(32.1%)。组织学亚型与EGFR突变有明显相关性(P=0.000)。
结论：1.停止使用BAC这一术语是合理的、重要的。2.根据肺腺癌新分类,各组织学亚型临床结果不同,原位腺癌和微浸润腺癌预后最好；实性为主型腺癌、粘液腺癌和胶样腺癌预后差；贴壁状为主腺癌、腺泡状为主腺癌和乳头状腺癌预后介于前两组之间。3.组织学亚型与EGFR突变状态密切相关,微乳头状为主型腺癌EGFR突变率最高,粘液腺癌EGFR突变率最低。同时,不吸烟的患者比吸烟者患者的EGFR突变率高,女性患者比男性患者的EGFR突变发生率高。
Objective:To investigate the relationship among histological subtypes, EGFR mutation and prognosis of lung adenocarcinoma.
Methods:1. All cases of lung adenocacinoma were collected from the archives of the Department of Pathology, Chinese PLA General Hospital including two series.158cases of BAC were between October1995and August2007, and another282cases of adenocarcinoma between April2005and December2011of which EGFR mutation were detected. All patients'slides were reviewed and reclassificated according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma, using comprehensive histological subtyping, recording the percentage, in5%increments,of each histological component.2. EGFR gene mutations of exons18through21were detected by direct DNA sequencing.3. Data were analyzed with Statistical Standard Package Service Solution software (13.0).
Results:1. Among158cases of BAC,79cases were female and79cases were male, with an average age of59.7yrs (range:31-84),122(77.2%) cases were non-smokers, and majority of patients were stage I (n=126,79.7%). After reclassification, minimally invasive adenocarcinoma (MIA) was the most common subtype (28.4%), followed by lepidic predominant adenocarcinoma (LPA,24.6%). The time of follow-up was64-206months. The prognosis of each subtype was different. Both AIS and MIA had100%5-year disease-free survival rate and100%5-year overall survival rate. Lepidic, acinar, and papillary had intermediate prognosis with87.5%,73.9%and77.8%5-year overall survival rate respectively. Solid and variants of invasive adenocarcinoma cases had poor prognosis with33.3%,41.7%5-year overall survival rate respectively. Higher stage (P=0.000) and age (tumor P=0.000) were associated with worse disease-free survival.2. Among282cases of lung adenocarcinoma, There were145men and137women aged 20to86years (mean,60.4years). All patients were Chinese. There were198never smokers,48former smokers, and36current smokers. Pathologic stages were stage I in112patients, stage Ⅱ in19patients, and stage Ⅲ in74patients, stage Ⅳ in17patients. Epidermal growth factor receptor mutations were detected in165of a total of282cases (58.5%). Exons with mutations were as follows:of a total of165mutated carcinomas,85(51.5%) were in exon19,9(5.4%) in exon20, and69(41.8%) in exon21. The most common mutation was in-frame deletions in exon19and the second most common mutation was point mutations in exon21. Epidermal growth factor receptor mutations were detected more frequently in women (66.4%) than in men (51.0%), the difference was statistically significant (P=0.009). EGFR mutations were more frequent in never smokers (64.9%) than in former smokers (52.2%) and current smokers (41.5%; P=0.003). Age, tumor size, and pathologic stage did not show significant associations with frequency of EGFR mutations. The most frequent subtype was acinar predominant. Epidermal growth factor receptor mutations were significantly more frequent in the micropapillary predominant subtype (8/10,80%) than in the other subtypes (157/272,57.7%), the second was LPA (78.7%), In contrast, EGFR mutations were less frequent in the solid predominant subtype (32.1%). The histopathologic subtypes correlated with EGFR mutations (P=0.000).
Conclusions:1.Discontinuing the use of the term "BAC" is reasonable and important.2The prognosis of each subtype was different. Both AIS and MIA had good prognosis, but Solid and variants of invasive adenocarcinoma had poor prognosis3. The histopathologic subtypes correlated with EGFR mutations, Epidermal growth factor receptor mutations were significantly more frequent in the micropapillary predominant subtype (8/10,80%) than in the other subtypes. Meantime, Epidermal growth factor receptor mutations were detected more frequently in women and never smokers.
引文
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