Objectives

The grading system proposed by the International Association for the Study of Lung Cancer is based on a combination of predominant histologic subtypes and the proportion of high-grade components with a cutoff of 20%. We aimed to examine the clinical implications of the grading system beyond the discrimination of patient prognosis, while assessing the biological differences among high-grade subtypes.

Methods

We retrospectively reviewed 648 consecutive patients with resected lung adenocarcinomas and examined their clinicopathologic, genotypic, and immunophenotypic features and treatment outcomes. Besides the differences among grades, the clinical impact of different high-grade components: micropapillary (MIP) and solid (SOL) patterns, was individually evaluated.

Results

Survival outcomes were well-stratified according to the grading system. Grade 3 tumors exhibited aggressive clinicopathologic features, while being an independent prognostic factor in multivariable analysis. A small proportion (<20 %) of high-grade components in grade 2 had a negative prognostic impact. The prognostic difference bordering on the 20 % cutoff of the MIP proportion was validated; however, the proportion of SOL component did not affect prognosis. A survival benefit from adjuvant chemotherapy was observed in grade 3 tumors regardless of histologic subtype, but not in grade 1–2 tumors. The molecular and immunophenotypic features were different among grades, but still heterogeneous in grade 3, with MIP harboring frequent EGFR mutation and SOL exhibiting high PD-L1 expression. The treatment outcome after recurrence was worse in grade 3, but tumors with MIP pattern had an equivalent prognosis to that of grade 1–2 tumors, reflecting the high frequency of molecular targeted therapy.

Conclusions

In addition to stratifying patient prognosis, the current grading system could discriminate clinical course, therapeutic effects of adjuvant chemotherapy, and molecular and immunophenotypic features. Further stratification based on biological heterogeneity in grade 3 remains necessary to enhance the role of the grading system in guiding patient management.

中文翻译：

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微乳头状和实性成分作为肺腺癌 IASLC 分级系统中的高级模式：临床意义和治疗

目标

国际肺癌研究协会提出的分级系统基于主要组织学亚型和高级别成分的比例（截止值为 20%）的组合。我们的目的是检查分级系统在区分患者预后之外的临床意义，同时评估高级别亚型之间的生物学差异。

方法

我们回顾性分析了 648 名连续切除肺腺癌的患者，并检查了他们的临床病理学、基因型和免疫表型特征以及治疗结果。除了等级之间的差异外，还单独评估了不同高级组件：微乳头（MIP）和实体（SOL）模式的临床影响。

结果

生存结果根据分级系统进行了良好分层。3级肿瘤表现出侵袭性的临床病理特征，同时是多变量分析中的独立预后因素。2 级中一小部分（<20%）的高级成分具有负面的预后影响。验证了接近 MIP 比例 20% 截止值的预后差异；然而，SOL成分的比例并不影响预后。无论组织学亚型如何，在 3 级肿瘤中观察到辅助化疗带来的生存获益，但在 1-2 级肿瘤中则不然。不同级别之间的分子和免疫表型特征有所不同，但在 3 级中仍然存在异质性，MIP 具有频繁的EGFR突变，而 SOL 则表现出高 PD-L1 表达。3级复发后的治疗效果较差，但MIP模式的肿瘤与1-2级肿瘤的预后相当，反映出分子靶向治疗的高频率。

结论

除了对患者预后进行分层之外，当前的分级系统还可以区分临床病程、辅助化疗的治疗效果以及分子和免疫表型特征。为了增强分级系统在指导患者管理中的作用，仍然有必要根据 3 级生物异质性进行进一步分层。