各位好！今日与大家分享一篇近期发表在JTO上分析第九版TNM分期委员会对残留肿瘤分级的综述。研究对残留肿瘤的分度的历史沿革、循证数据、前沿展望进行了系统阐述。在这个大家大谈特谈MRD（minimal residual disease）的时代，本文所提到的外科R分期可以算作一种Macro Residual Disease了。一起来学习下！
The IASLC Lung Cancer Staging Project: Proposals for Revision of the Classification of Residual Tumor after Resection for the Forthcoming (9th) Edition of the TNM Classification of Lung Cancer
Frank C. Detterbeck, MD, Marcin Ostrowski, MD, Hans Hoffmann, MD, Ramón Rami-Porta, MD, FETCS, Ray U. Osarogiagbon, M.B.B.S., Jessica Donnington, MD, MSCR, Maurizio Infante, MD, Mirella Marino, MD, Edith M. Marom, MD, Jun Nakajima, MD, Andrew G. Nicholson, DM, FRCPath, Paul van Schil, MD, William D. Travis, MD, Ming S. Tsao, MD, John G. Edwards, PhD, FRCS(C/Th), Hisao Asamura, MD, and the Members of the Staging and Prognostic Factors Committee and Advisory Boards.
Journal of Thoracic Oncology 25 March 2024
Objectives: The goal of surgical resection is to completely remove a cancer; it is useful to have a system to describe how well this was accomplished. This is captured by the residual tumor (R) classification, which is separate from the TNM classification that describes the anatomic extent of a cancer independent of treatment. The traditional R-classification designates as R0 a complete resection, as R1 a macroscopically complete resection but with microscopic tumor at the surgical margin, and as R2 a resection that leaves gross tumor behind. For lung cancer, an additional category encompasses situations in which the presence of residual tumor is uncertain.
目的：手术切除的目标是彻底切除肿瘤；有一个系统来描述这一过程的完成情况是很有用的。这是由残存肿瘤(R)分类记录的，该分类与描述独立于治疗的癌症解剖范围的TNM分类是分开的。传统的R分类将R0标示为完全切除，将R1标示为大体完全切除但在手术边缘有微小肿瘤，而将R2标示为留下肉眼肿瘤的切除。对于肺癌，另一个类别包括残存肿瘤不确定的情况。
Methods: This paper represents a comprehensive review of evidence regarding these R categories and the descriptors thereof, focusing on studies published after the year 2000 and with adjustment for potential confounders.
方法：本文对这些R分类的证据及其描述因素进行了全面的综述，重点是2000年后发表的研究，并对潜在的混杂因素进行了调整。
Results: Consistent discrimination between complete, uncertain, and incomplete resection is demonstrated with respect to overall survival. Evidence regarding specific descriptors is generally somewhat limited and only partially consistent; nevertheless, the data suggests retaining all descriptors but with clarifications to address ambiguities.
结果：就总体存活率而言，完全切除、不确定切除和不完全切除之间的区别是一致的。关于具体描述词的证据通常有限，而且只有部分一致；然而，数据表明保留了所有描述词，但需要加以澄清，以解决含糊之处。
Conclusions: Based on this review, the R-classification for the 9th edition of stage classification of lung cancer is proposed to retain the same overall framework and descriptors, with more precise definitions of descriptors. These refinements should facilitate application as well as further research.
结论：在此基础上，建议第9版肺癌分期R分类保留相同的总体框架和描述符，并对描述符进行更精确的定义。这些改进应该有利于临床应用和进一步的研究。
Keywords: Lung Cancer; surgery；complete resection；residual disease
1.首先了解肺癌R分期的朋友们应当能看出来，R分期是独立于TNM之外的描述因子，既往定义上R(un)包括了淋巴结清扫不彻底、最高站淋巴结阳性、支气管切缘原位癌、胸腔灌洗液脱落细胞学阳性。
某种意义上可以说是Residual factor就是个大箩筐，啥都往里装。不过uncertain这个词用的是真好，来了么？如来；悟什么？悟空。
有趣的公布的R factor一直是John Edwards。说好的是JE，怎么Frank C. Detterbeck来牵头啊，这不兴抢戏的啊。
2.上细节：
首先文章细节架构就是①用数据来确证做实R(un)的各个点上有哪些循证证据的更新（老夫当年的策论英明神武）；②用接地气的话解释每个描述因子目前临床实践和研究中可能面临的现况（但回头看也就那么回事，不过如此）；③点开这个细分领域目前尚难深入研究的点（再怎样还得照老夫思路做）。
其次，简单说下R分委会对R factor的几个发展点。①淋巴结清扫上坚决推荐3站N1+3站N2（必须包括7区），对肺叶特异性清扫的执行细节态度不置可否（看下日本人怎么秀JCOG1413）。②最高站淋巴结的定义和预后意义目前并不明确，列了一些研究就开始了未来可期。③R1（Tis）最难的就是数据量少、回顾性数据记录差无法分析。④R1（cy+）比较有意思的点是病灶切除后冲洗脱落细胞学检出阳性的预后意义大于病灶切除前的，并且特意提及这并不是说cy+患者切除病灶无意义。⑤淋巴结包膜外侵犯中提了3种判断包膜外侵犯切缘程度的临床场景，严谨程度值得学习。
再者颇为有趣的是，文中多次强调在分析R因素的研究要纳入校正因素（肿瘤、地域、合并症、治疗因素）。而多数研究无法对治疗因素进行很好的校正（辅助治疗、手术方式）。SPFC对亚肺叶的相关预后因子、STAS、circulating tumor cells, cell-free DNA仍然保有期待。
3.Residual Disease的定义更多聚焦于复杂的外科切除临床场景。R分委会还挺想要鼓动寡转移、放射治疗领域的学者进一步探索类似描述的预后价值（复刻一下大箩筐如何变凤凰）。
目录
1. INTRODUCTION
2. Methods
3. Results
3.1 R-Status Categories
3.1.1 Definitions
3.1.2 Validation (Table 1, Figure 1)
3.2 Specific R(un) Descriptors
3.2.1 R0(un) - Limited Node Assessment (Table 2, Figure 2)
3.2.2 R0(un) - Highest Node Station Involvement (Table 3)
3.2.3 R1(is) - Carcinoma-in-Situ at the Bronchial Margin
3.2.4 R1(cy+) – Positive Pleural Lavage Cytology (Table 4)(Figure S1)(Figure 3)
3.3 Specific R1 Descriptors
3.3.1 R1 – Microscopically Positive Resection Margin (Table 5)
3.3.2 R1 – Extracapsular Extension of Involved Lymph Nodes (Table 6)
3.3.3 R1 – Malignant Pleural or Pericardial Effusion (Figure 3)
3.4 R2 Descriptors
3.5 Proposed 9th Edition R-Classification (Table 7)
4. DISCUSSION
5. Summary
— 图表汇总—
3. Results
3.1 R-Status Categories
3.1.1 Definitions
3.1.2 Validation
Table 1: Studies Evaluating the R(un) Category
Figure 1: Prognostic Impact of R-Classification Categories
Overall survival in studies of the R-Classification. A) 3,361 patients, 2009-19, Mid-South Quality of Surgical Resection database;11 B and D) 11,218 and 3,494 patients, respectively, 1999-2010, IASLC 8th edition database; C) 5,293 patients, 2009-13, Shanghai Pulmonary Hospital.
IASLC, International Association for the Study of Lung Cancer
3.2 Specific R(un) Descriptors
3.2.1 R0(un) - Limited Node Assessment
Table 2: Studies Evaluating the Limited Node Assessment R0(un) Descriptor
Figure 2: Prognostic Impact of Extent of Node Evaluation
Overall survival of patients by extent of node evaluation at the time of resection. A) 3,359 patients, 2009-19, Mid-South Quality of Surgical Resection database; B) 5,117 patients, 2008-16, Samsung Medical Center, Seoul, South Korea, and C) cohort characteristics of the cases in B. The impact of a more limited node evaluation is diametrically opposed in the two studies. The dramatically better survival in all groups in B compared with those in A suggests that the tumors involved in A and B are fundamentally different; the variable incidence of characteristics in C suggests that confounding by these characteristics may explain the better survival of the NX vs the compliant cohorts in B.
Adeno, adenocarcinoma; Fully compliant = 6-station minimum as recommended by the 8th edition R-classification; Partially compliant = some nodes assessed but less than the 6-station minimum; Non-compliant = no nodes sampled.
3.2.2 R0(un) - Highest Node Station Involvement
Table 3: Studies Evaluating the Highest Node Station Positive R0(un) Descriptor
3.2.3 R1(is) - Carcinoma-in-Situ at the Bronchial Margin
3.2.4 R1(cy+) – Positive Pleural Lavage Cytology
Table 4: Studies Evaluating the Positive Pleural Lavage R1(cy+) Descriptor
Figure S1: Comparison of Pre- and Post-Resection Pleural Lavage Cytology
Prospective study of pre- and post-resection pleural lavage, 2,178 patients, 1992-2006, National Cancer Center Hospital East, Chiba, Japan.
A) Overall survival of patients by pleural lavage cytology results;
B) relative proportion of patients by pre- and post-resection lavage results.
neg, negative; NS, not significant; pos, positive; Post, post-resection; pre, pre-resection
Figure 3: Overall Survival of R0, R1(cy+) and Pleural Dissemination Cohorts
Overall survival of patients undergoing R0 resection with negative pleural lavage cytology, or resection in the face of a positive lavage cytology or evidence of pleural dissemination (malignant pleural nodules or effusion).
A) 1,572 consecutive surgical patients, 1991-2009, Tokyo Cancer Institute Hospital;
B) 1,000 consecutive surgical patients, 1987-2001, Hyogo Medical Center;
C) 1,317 surgical patients, 1987-2004, Kobe University and Hyogo Cancer Center;
D) 1,025 retrospective surgical patients, 1993-2005, Kurashiki Central Hospital.
PD/PE, pleural dissemination/pleural effusion; PLC, Pleural lavage cytology; Pre, pre-resection;
3.3 Specific R1 Descriptors
3.3.1 R1 – Microscopically Positive Resection Margin
Table 5: Studies Evaluating the Microscopically Positive Margin R1 Descriptor
3.3.2 R1 – Extracapsular Extension of Involved Lymph Nodes
Table 6: Studies Evaluating the Extranodal Extension Descriptor
3.3.3 R1 – Malignant Pleural or Pericardial Effusion
Figure 3: Overall Survival of R0, R1(cy+) and Pleural Dissemination Cohorts
Overall survival of patients undergoing R0 resection with negative pleural lavage cytology, or resection in the face of a positive lavage cytology or evidence of pleural dissemination (malignant pleural nodules or effusion).
A) 1,572 consecutive surgical patients, 1991-2009, Tokyo Cancer Institute Hospital;
B) 1,000 consecutive surgical patients, 1987-2001, Hyogo Medical Center;
C) 1,317 surgical patients, 1987-2004, Kobe University and Hyogo Cancer Center;
D) 1,025 retrospective surgical patients, 1993-2005, Kurashiki Central Hospital.
PD/PE, pleural dissemination/pleural effusion; PLC, Pleural lavage cytology; Pre, pre-resection;
3.4 R2 Descriptors
3.5 Proposed 9th Edition R-Classification
Table 7. Residual Tumor after Surgical Resection
