各位好！今日与大家分享一篇大学阀William D. Travis发表在Modern pathology上有关浸润性肺腺癌的文章。在既往一系列文献的验证下，浸润性肺腺癌的新分级像一个风口，吹到了天上。但是大家知道，这片天空同样笼罩着两篇乌云，有两篇研究对IASLC的新分级提出了新的看法。作为理论的提出者，一起来看看Travis怎样用研究来驳斥想要进行在这个话题上进行微操的理论~！
Novel insights into the International Association for the Study of Lung Cancer grading system for lung adenocarcinoma
Kay See Tan PhD a, Allison Reiner MS a, Katsura Emoto MD, PhD b, Takashi Eguchi MD, PhD c, Yusuke Takahashi MD, PhD d, Rania G. Aly MD, PhD e, Natasha Rekhtman MD, PhD e, Prasad S. Adusumilli MD f g, William D. Travis MD e
Modern Pathology 21 May 2024
Background: The new grading system for lung adenocarcinoma (ADC) proposed by the International Association for the Study of Lung Cancer (IASLC) defines prognostic subgroups based on histologic patterns observed on surgical specimens. This study seeks to provide novel insights into the IASLC grading system, with a particular focus on recurrence-specific survival (RSS) and lung cancer–specific survival (LCSS) among patients with stage I ADC.
背景：国际肺癌研究协会(IASLC)提出的新的肺腺癌分级系统(ADC)根据手术标本上观察到的组织学类型定义了预后亚组。这项研究试图为IASLC分级系统提供新的见解，特别关注I期ADC患者的复发特异性生存率(RSS)和肺癌特异性生存率(LCS)。
METHODS: Under the IASLC grading system, tumors were classified as grade 1 (lepidic predominant with <20% high-grade patterns [micropapillary, solid, complex glandular]), grade 2 (acinar or papillary predominant with <20% high-grade patterns), or grade 3 (≥20% high-grade patterns). Kaplan-Meier survival estimates, pathologic features, and genomic profiles were investigated for patients whose disease was reclassified to a higher grade under the IASLC grading system on the basis of the hypothesis that they would strongly resemble patients with predominant high-grade tumors.
方法：根据IASLC分级系统，将肿瘤分为1级(以乳头型为主，高级别[微乳头、实体型、复杂腺体]<20%)，2级(腺泡或乳头为主，高级别<20%)，3级(≥高级别20%)。根据IASLC分级系统将疾病重新分类为更高级别的患者的Kaplan-Meier生存估计、病理特征和基因组图谱进行了研究，其基础是假设他们将与主要的高级别肿瘤患者非常相似。
RESULTS: Overall, 423 of 1443 patients (29%) with grade 1 or 2 tumors by the predominant pattern–based grading system had their tumors upgraded to grade 3 by the IASLC grading system. The RSS curves for patients with upgraded tumors were significantly different from those for patients with grade 1 or 2 tumors (log-rank p<0.001) but not from those for patients with predominant high-grade patterns (p=0.3). Patients with upgraded tumors had a similar incidence of visceral pleural invasion and spread of tumor through air spaces as patients with predominant high-grade patterns. In multivariable models, the IASLC grading system remained significantly associated with RSS and LCSS after adjustment for aggressive pathologic features such as visceral pleural invasion and spread of tumor through air spaces.
结果：总体而言，1443例患者中有423例(29%)的肿瘤通过IASLC分级系统升级到了3级。肿瘤升级组与1、2级组比较差异有统计学意义(p<0.001)，而与高级别组比较差异无统计学意义(p=0.30)。肿瘤升级的患者与以高级别为主的患者相比，脏层胸膜侵犯和肿瘤通过空气扩散的发生率相似。在多因素模型中，在校正了侵袭性病理特征后，IASLC分级系统仍然与RSS和LCS显著相关，如内脏胸膜侵犯和肿瘤通过空气腔扩散。
CONCLUSION: The IASLC grading system outperforms the predominant pattern–based grading system and appropriately reclassifies tumors into higher grades with worse prognosis, even after other pathologic features of aggressiveness are considered.
结论：IASLC分级系统优于主要亚型的分级系统，即使考虑到其他侵袭性的病理特征，也可以适当地将肿瘤重新分类为较高级别，预后较差。
1.世界是非黑即白么？肺腺癌病理一直在向乳腺病理学习经验，因此三分类的浸润性肺腺癌新分级一经提出就被许多学者追捧，验证。但是呢，偏偏有两个研究团队表示，你这标准定的也还行，但是还得再稍微微调下。
来自韩国的A团队表示Grade2需要细分，按照附壁型是否＞20%分为2a/2b。
来自加拿大的B团队表示Grade3里面高级别组织学模式仅计算为实体型和微乳头状成分的总和，即去除筛状型或复杂腺体型。
来自意大利的C团队表示别三分类了，搞个“低恶性潜能 ADC (LMP-ADC)”。满足以下标准：≤3 cm 大小、非粘液组织型、≥15% 贴壁型生长，并且不存在以下症状：高级别模式、>1 个有丝分裂/2 mm 2、坏死和血管/胸膜侵犯。
由于意大利选手没有在IASLC范围内讨论，William D. Travis选择性忽视了该团队的提议，并在文中对该提议表示缄默。
https://pathology.jhu.edu/breast/staging-grade/
10.1016/j.jtho.2020.06.001
10.1097/PAS.0000000000002151
2. 其次看细节。
①理念设计上目前针对I期肺腺癌的病理评估仍然是在衡量五种主要亚型对预后的影响程度，如何综合评估预后（even a minor percentage of micropapillary or solid pattern is associated with poor prognosis）？文章首先回顾了一下既往应用新分级开展的10项研究。再次确证了IASLC grade胜过以主要病理亚型的分类方式。
②方法上充分揭示了主要亚型模式和新分级升级的患者（Upgraded）在病理亚型上的分布差异。
③结果和讨论部分对A团队分类方法的验证显示在队列中Grade2a/2b并没有显著的生存差异，对B团队分类方法的验证显示AIC可能IASLC分类更优，考虑到系统的认识高级别成分，还是建议保留原来的定义，即将筛状型或复杂腺体型纳入高级别成分的评判中。
④充分肯定了不同地域肺癌亚型可能存在差异，譬如亚裔人群的Grade3相对少，而欧美人群Grade3相对多。在不同地区，应用不同分类造成的Upgrade也不尽相同。这种异质性似乎代表着histology的诊断极限，围绕早期病理亚型上的新分类将会带来更深刻的认识。如果想深入看看到底哪些因素可能对预后影响很重要，请收看TRACERx系列研究。
3. Grading system 本质上是为了同质化诊疗做出努力。但是究竟在多小的尺度下，Grading systyem不连续，不平滑。什么样的因素可能是隐藏在pattern背后的真相？
目录
1. INTRODUCTION
2. METHODS
2.1 Study Cohort
2.2 Histologic Evaluation and Grading Criteria
2.3 Recurrence and Follow-up
2.4 Statistical Analysis
3. Results
3.1 Summary of Patient Characteristics (Table 1)
3.2 Survival Outcomes Based on the Grading Systems (Figure 1)
3.3 Reclassification of Tumors Using the IASLC Grading System (Figure 2)(Supplementary Table 1)(Figure 3, Supplementary Figure 1)
3.4 Clinical Features of Patients with Upgraded Tumors (Table 2, Supplementary Table 2)
3.5 Performance of the Grading Systems (Supplementary Table 3)(Supplementary Figure 2)
3.6 Relationship Between the IASLC Grading System and Pathologic and Genomic Features (Supplementary Table 5)(Supplementary Figure 3)
3.7 Validation of Two Proposed Modified Grading Systems (Figure 4)
4. Discussion
— 图表汇总—
3.1 Summary of Patient Characteristics
Table 1. Patient characteristics (N=1443)
Data are median (interquartile range) or no. (%). IASLC, International Association for the Study of Lung Cancer.
3.2 Survival Outcomes Based on the Grading Systems
Figure 1. Recurrence-specific survival and lung cancer–specific survival using the predominant pattern–based grading system (A-B) and the International Association for the Study of Lung Cancer (IASLC) grading system (C-D). Survival patterns of patients whose tumors were upgraded to grade 3 by the IASLC grading system (E-F).
Patients with upgraded tumors (black dashed lines) are those with predominant lepidic, acinar, or papillary patterns but that include ≥20% high-grade patterns.
3.3 Reclassification of Tumors Using the IASLC Grading System
Figure 2. Reclassification from predominant pattern-based grading system to IASLC grading system.
Red box: 423 of 1443 patients (29%) with grade 1 or grade 2 tumors by the predominant pattern-based grading system had their tumors upgraded to grade 3 by the IASLC grading system.
Supplementary Table 1. Distribution of patients by the IASLC grading system and reclassification status from the recent literature, stratified by patient characteristics
Figure 3. Cumulative incidence of recurrence and lung cancer deaths using the predominant pattern–based grading system (A-B) and the International Association for the Study of Lung Cancer (IASLC) grading system (C-D). Survival patterns of patients whose tumors were upgraded to grade 3 by the IASLC grading system (E-F).
Patients with upgraded tumors (black dashed lines) are those with predominant lepidic, acinar, or papillary patterns but that include ≥20% high-grade patterns.
Supplementary Figure 1. Overall survival and recurrence-free survival using the predominant pattern–based grading system (A-B) and the International Association for the Study of Lung Cancer (IASLC) grading system (C-D). Survival patterns of patients whose tumors were upgraded to grade 3 by the IASLC grading system (E-F).
Patients with upgraded tumors (black dashed lines) are those with predominant lepidic, acinar, or papillary patterns but that include ≥20% high-grade patterns.
3.4 Clinical Features of Patients with Upgraded Tumors
Table 2. Patient characteristics by the IASLC grading system
Data are median (interquartile range) or no. (%). IASLC, International Association for the Study of Lung Cancer.
a Kruskal-Wallis rank-sum test; Pearson’s chi-squared test.
b Wilcoxon rank-sum test; Pearson’s chi-squared test.
Supplementary Table 2. Histopathologic features by the IASLC grading system
3.5 Performance of the Grading Systems
Supplementary Table 3. Multivariable Cox model for recurrence-specific survival using the predominant pattern–based grading system, the IASLC grading system, and the simplified IASLC grading system
Supplementary Table 4. Multivariable Cox model for lung cancer–specific survival using the predominant pattern–based grading system, the IASLC grading system, and the simplified IASLC grading system
Supplementary Figure 2. Calibration curves from multivariable models for recurrence-specific survival (RSS) and lung cancer–specific survival (LCSS) (See Supplementary Tables 3 and 4).
Calibration plots were created to compare the 5-year predicted RSS or LCSS with the observed 5-year RSS and LCSS. An ideal prediction model would yield a plot where the observed and predicted probabilities perfectly correspond and align along the 45-degree line. We present both the apparent (unadjusted) calibration curve (black connected plot) and the optimism-corrected estimates (blue crosses) based on 1000 bootstrap samples. IASLC, International Association for the Study of Lung Cancer; MVA, multivariable analysis.
