Objective: To investigate the applicability of the 2021 WHO classification of thoracic tumors' new grading system for invasive pulmonary adenocarcinoma (IPA) with different clinical stages and its correlation with the characteristics of targeted genes' variation. Methods: A total of 2 467 patients with surgically resected primary IPA in Shanghai Pulmonary Hospital, Shanghai, China from September to December 2020 were retrospectively analyzed. Eligible cases were graded using the new grading system of IPA of the 2021 WHO classification of thoracic tumors. The clinicopathological data and targeted-gene abnormality were collected. The utility of new grading system of IPA in different clinical stages was investigated. The correlation of clinicopathological features and targeted-gene abnormality in different grades of IPA were compared. Results: All 2 311 cases of IPA were included. There were 2 046 cases of stage Ⅰ IPA (88.5%), 169 cases of stage Ⅱ (7.3%), and 96 cases of stage Ⅲ (4.2%). According to the new classification system of IPA, 186 cases (9.1%), 1 413 cases (69.1%) and 447 cases (21.8%) of stage-Ⅰ adenocarcinoma were classified as Grade 1, Grade 2 and Grade 3, respectively. However, there were no Grade 1 adenocarcinomas in stages Ⅱ and Ⅲ cases. Among stage-Ⅱ and Ⅲ IPA cases, there were 38 Grade 2 cases (22.5%) and 131 Grade 3 cases (77.5%), and 3 Grade 2 cases (3.1%) and 93 Grade 3 cases (96.9%), respectively. In stage-Ⅰ cases, no tumor cells spreading through airspace (STAS), vascular invasion or pleural invasion was found in Grade 1 of IPA, while the positive rates of STAS in Grade 2 and 3 IPA cases were 11.3% (159/1 413) and 73.2% (327/447), respectively. There was a significant difference among the three grades (P<0.01). Similarly, the rates of vascular and pleural invasion in Grade 3 IPA cases were 21.3% (95/447) and 75.8% (339/447), respectively, which were significantly higher than those of 1.3% (19/1 413) and 3.0% (42/1 413) in Grade 2 (P<0.01). EGFR mutational rates in Grades 1, 2 and 3 IPA were 65.7% (94/143), 76.4% (984/1 288) and 51.3% (216/421), respectively. The differences among the three grades were statistically significant (P<0.01). No fusion genes were detected in Grade 1 IPA, while the positive rates of ROS1 and ALK fusion genes in Grade 3 were 2.4% (10/421) and 8.3% (35/421), respectively, which were significantly higher than that of 0.5% (7/1 288) and 1.6% (20/1 288) in Grade 2 (P<0.01). In stage-Ⅱ cases, only EGFR mutation rate in Grade 2 adenocarcinoma (31/37, 83.8%) was higher than that in Grade 3 adenocarcinoma (71/123, 57.7%; P<0.01). However, the correlation between the new grade system of IPA and the distribution characteristics of targeted-gene variation cannot be evaluated in stage Ⅲ cases. Conclusions: The new grading system for IPA is mainly applicable to clinical stage-Ⅰ patients. Tumor grades of IPA are strongly correlated with the high-risk factors of prognosis and the distribution features of therapeutic targets. It is of great significance and clinical value to manage postoperative patients with early-stage IPA.
目的： 探讨2021版WHO胸部肿瘤分类浸润性肺腺癌新分级系统在不同临床分期中的应用情况及与靶向基因变异分布特征的相关性。 方法： 回顾性分析上海市肺科医院2020年9—12月手术切除病理诊断明确的原发浸润性肺腺癌2 467例，按照WHO胸部肿瘤分类浸润性肺腺癌新分级标准判读入组病例。收集患者临床信息和病理资料，以及靶向基因变异情况，比较浸润性肺腺癌新分级系统在不同临床分期中的应用情况，并进一步分析新分级与靶向基因变异分布特征的关系。 结果： 共入组浸润性肺腺癌2 311例。临床分期中，Ⅰ期2 046例（88.5%）、Ⅱ期169例（7.3%）和Ⅲ期96例（4.2%）。按照浸润性肺腺癌新分级标准，临床Ⅰ期腺癌中，1级186例（9.1%）、2级1 413例（69.1%）和3级447例（21.8%）。在Ⅱ期和Ⅲ期病例中均无1级腺癌，而2级和3级腺癌分别为38例（22.5%）、131例（77.5%）和3例（3.1%）、93例（96.9%）。在Ⅰ期病例中，1级腺癌均未发现肿瘤细胞沿肺泡腔播散（STAS）、脉管和胸膜侵犯，而在2级和3级腺癌中STAS的阳性率分别为11.3%（159/1 413）和73.2%（327/447），3组之间差异有统计学意义（P<0.01）；相似的，3级腺癌中脉管和胸膜侵犯的阳性率分别为21.3%（95/447）和75.8%（339/447），显著高于2级腺癌中的1.3%（19/1 413）和3.0%（42/1 413；P<0.01）。1级、2级和3级腺癌中表皮生长因子受体（EGFR）基因突变的阳性率分别为65.7%（94/143）、76.4%（984/1 288）和51.3%（216/421），3组之间差异有统计学意义（P<0.01）。1级腺癌中未检测到融合基因，而3级腺癌中ROS1和间变性淋巴瘤激酶（ALK）融合基因的阳性率分别2.4%（10/421）和8.3%（35/421），显著高于2级腺癌中0.5%（7/1 288）和1.6%（20/1 288；P<0.01）。在Ⅱ期病例中，仅有EGFR在2级腺癌中的突变率（31/37，83.8%）高于3级腺癌（71/123，57.7%；P<0.01）。而在Ⅲ期病例中无法评估腺癌新分级与基因变异分布特征的关系。 结论： 浸润性肺腺癌新分级系统主要适用于临床Ⅰ期患者。不同分级与影响患者预后的高危因素及靶向基因变异分布特征密切相关。新分级系统能够有效辅助早期肺腺癌术后患者的治疗管理，具有重要的临床意义和推广应用价值。.