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High-risk features associated with recurrence in stage I lung adenocarcinoma

Cameron N. Fick, MD,a Elizabeth G. Dunne, MD,a Stijn Vanstraelen, MD,a Nicolas Toumbacaris, MSPH,b Kay See Tan, PhD,b Gaetano Rocco, MD,a,c Daniela Molena, MD,a,c James Huang, MD,a,c Bernard J. Park, MD,a,c Natasha Rekhtman, MD, PhD,d William D. Travis, MD,d Jamie E. Chaft, MD,e,f Matthew J. Bott, MD,a,c Valerie W. Rusch, MD,a,c Prasad S. Adusumilli, MD,a,c Smita Sihag, MD,a,c James M. Isbell, MD,a,c and David R. Jones, MDa,c

JTCVS 21 May 2024

Objective: There is a lack of knowledge regarding the use of prognostic features in stage I lung adenocarcinoma (LUAD). Thus, we investigated clinicopathologic features associated with recurrence after complete resection for stage I LUAD.

背景：I期肺腺癌（LUAD）预后特征的使用场景仍然缺乏相应临床只是。因此，本研究对I期LUAD完全切除后与复发相关的临床病理特征进行了研究。

METHODS: We performed a retrospective analysis of patients with pathologic stage I LUAD who underwent R0 resection from 2010 to 2020. Exclusion criteria included history of lung cancer, induction or adjuvant therapy, noninvasive or mucinous LUAD, and death within 90 days of surgery. Fine and Gray competing-risk regression assessed associations between clinicopathologic features and disease recurrence.

方法：我们对2010年至2020年间接受R 0切除术的病理I期LUAD患者进行了回顾性分析。排除标准包括肺癌史、诱导或辅助治疗、非侵入性或粘液性LUAD以及手术后90天内死亡。Fine和Gray竞争风险回归评估了临床病理特征与疾病复发之间的关联。

RESULTS: In total, 1912 patients met inclusion criteria. Most patients (1565 [82%]) had stage IA LUAD, and 250 developed recurrence: 141 (56%) distant and 109 (44%) locoregional only. The 5-year cumulative incidence of recurrence was 12% (95% CI, 11%-14%). Higher maximum standardized uptake value of the primary tumor (hazard ratio [HR], 1.04), sublobar resection (HR, 2.04), higher International Association for the Study of Lung Cancer grade (HR, 5.32 [grade 2]; HR, 7.93 [grade 3]), lymphovascular invasion (HR, 1.70), visceral pleural invasion (HR, 1.54), and tumor size (HR, 1.30) were independently associated with a hazard of recurrence. Tumors with 3 to 4 high-risk features had a higher cumulative incidence of recurrence at 5 years than tumors without these features (30% vs 4%; P < .001).

结果：总共有1912名患者符合入选标准。大多数患者（1565例[82%]）为IA LUAD期，250例复发：141例（56%）为远处复发，109例（44%）仅局部复发。5年累计复发发生率为12%（95%CI，11%-14%）。原始肿瘤的最大标准化吸收值更高（风险比[HR]，1.04），叶下切除术（HR，2.04），国际肺癌研究协会较高等级（HR，5.32 [2级]; HR，7.93 [3级]），淋巴血管侵犯（HR，1.70）、脏层胸膜侵犯（HR，1.54）和肿瘤大小（HR，1.30）与复发风险独立相关。具有3至4个高危特征的肿瘤5年时的累积复发率高于没有这些特征的肿瘤（30% vs 4%; P < .001）。

CONCLUSION: Recurrence after resection for stage I LUAD remains an issue for select patients. Commonly reported clinicopathologic features can be used to define patients at high risk of recurrence and should be considered when assessing the prognosis of patients with stage I disease.

结论：I期LUAD切除术后的复发对于某些患者来说仍然是一个问题。常见报告的临床病理特征可用于定义复发风险高的患者，并在评估I期疾病患者的预后时应予以考虑。

Prognostic Value of the International Association for the Study of Lung Cancer Grading System and its Association with the Tumor Microenvironment in Stage I EGFR-muted Lung Adenocarcinoma

Shoko Kubota a b c, Tetsuro Taki a Tomohiro Miyoshi b, Kenta Tane b, Joji Samejima b, Keiju Aokage b, Masashi Wakabayashi d, Nomura Kotaro b, Michiko Nagamine a, Motohiro Kojima a e, Shingo Sakashita a e, Naoya Sakamoto a e, Masahiro Tsuboi b, Genichiro Ishii a c f

European Journal of Cancer 24 June 2024

Background: The International Association for the Study of Lung Cancer (IASLC) grading system predicts early lung adenocarcinoma outcomes.

背景：国际肺癌研究协会（IASLC）分级系统可预测早期肺腺癌结局。

METHODS: The purpose of this study is to examine prognostic value of the IASLC grading system and its association with the tumor microenvironment (TME) in Stage I EGFR-muted lung adenocarcinoma. Based on the IASLC grading system, we compared the clinicopathological characteristics of EGFR-mutated lung adenocarcinoma (n=296). In addition, we examined the expression level of E-cadherin in tumor cells and counted the number of tumor-infiltrating lymphocytes (TILs; CD8, CD20, CD138, and Foxp3), tumor-associated macrophages (TAMs; CD204), and cancer-associated fibroblasts (CAFs; podoplanin) using semi-automatic digital pathology image analysis.

方法：本研究的目的是检查IASLC分级系统的预后价值及其与I期EGFR突变肺腺癌肿瘤微环境（TME）的关系。基于IASLC分级系统，我们比较了EGFR突变肺腺癌（n=296）的临床病理特征。此外，我们检查了肿瘤细胞中E-钙粘蛋白的表达水平，并使用半自动数字病理图像分析计算了肿瘤浸润性淋巴细胞（TLR; CD 8、CD 20、CD 138和Foxp 3）、肿瘤相关巨噬细胞（TAMS; CD 204）和癌症相关成纤维细胞（CAF; podoplanin）的数量。

RESULTS: Recurrence-free survival (RFS) curve showed that survival of grade 3 was significantly shorter than that of grade 1 (P < 0.01) and grade 2 (P = 0.03). Multivariate analysis of RFS revealed the invasive size, lymphatic permeation, and grade 3 (P < 0.01) as independent poor prognostic factors. The number of CD204+TAMs and PDPN+CAFs was significantly higher in grade 3 than in grade 1 or 2 (all P < 0.01). Among the intermediate grade by the predominant subtype based classification, cases classified as grade 3 by the new classification had higher number of CD204+TAMs (P < 0.01) and PDPN+CAFs (P = 0.02) than those classified as grade 2.

结果：无复发生存期（RFS）曲线显示，3级生存期明显短于1级（P < 0.01）和2级（P = 0.03）。RFS的多因素分析显示，侵袭性成分大小、淋巴渗透和3级（P < 0.01）是独立的不良预后因素。3级CD 204 + TAM和PDPN+ CAF的数量明显高于1级或2级（均P < 0.01）。在按主要亚型分类的中等级别中，按新分类为3级的病例的CD 204 + TIM（P < 0.01）和PDPN+ CAF（P = 0.02）数量高于分类为2级的病例。

CONCLUSION: The IASLC grading system correlated with the outcomes of EGFR-mutated lung adenocarcinoma. Grade 3 was found to have the TME that most contributes to tumor progression, which probably explained their poor prognosis.

结论：IASLC分级系统与EGFR突变肺腺癌的结局相关。本研究表明3级患者的TME对肿瘤进展有显著影响，这可能解释了此类人群预后不良的原因。

目录

1. INTRODUCTION

2. METHODS

    2.1 Patients (Supplementary Figure 1A)

    2.2 Histological evaluation and analyses of EGFR mutations (Supplementary Figure 1B)

    2.3 Immunohistochemical staining and immunohistochemical score (Supplementary Table 1-2)(Supplementary Figure 2)

    2.4 Statistical Analysis

3. Results

    3.1 Patient characteristics (Table 1)

    3.2 Survival curve analysis (Figure 1)

    3.3 Univariate and multivariate analyses for RFS (Table 2)

    Immunochemical staining scores of cancer cells and immune cells according to each grading system.(Fgiure 2)(Supplementary Figure 3-4)(Figure 3)

    Relationship between the predominant subtype-based classification and the IASLC grading system-based classification. (Fgiure 4)

4. Discussion

— 图表汇总—

2. METHODS

    2.1 Patients

Supplementary Figure 1A. Flowchart of the patient selection process and representative hematoxylin and eosin (HE) stained images of the tumor for each grade classification.

    2.2 Histological evaluation and analyses of EGFR mutations Supplementary Figure 1B. Representative hematoxylin and eosin (HE) stained images of the tumor for each grade classification.

    2.3 Immunohistochemical staining and immunohistochemical score

Supplementary Table 1. Clinicopathological factors for each randomly selected IASLC grading system.

Supplementary Table 2. Antibodies for immunohistochemical staining.

Supplementary Figure 2. Representative immunohistochemical staining of HALO analyze.

(A) CD8, (B) CD20, (C) Foxp3, (D) CD138, (E) CD204, (F) PDPN, and (G) E-cadherin.

    2.4 Statistical Analysis

3. Results

    3.1 Patient characteristics

Table 1. Clinicopathological factors of each IASLC grading system.

    3.2 Survival curve analysis

Fig. 1. Recurrence-free survival and overall survival curves of lung adenocarcinoma classified according to the IASLC grading system.

(A) RFS for stage ⅠA cohort, (B) RFS for stage ⅠB cohort, (C) RFS for all cohort, (D) OS for stage ⅠA cohort, (E) OS for stage ⅠB cohort, and (F) OS for all cohort.

The black line shows grade 1, the red line shows grade 2, and the green line shows grade 3. For OS in the stage IB cohort, grade 1 and grade 2 hazard ratios could not be estimated, since no event occurred.

    3.3 Univariate and multivariate analyses for RFS

Table 2. Univariate and multivariate analyses for recurrence-free survival.

Fig. 2. Immunohistochemical scores of lung adenocarcinoma classified according to the IASLC grading system.

(A) CD8-positive lymphocyte, (B) CD20-positive lymphocyte, (C) FoxP3-positive lymphocyte, (D) CD138-positive lymphocyte, (E) CD204-positive macrophage, (F) the percentage of podoplanin-positive cancer-associated fibroblasts (PDPN+CAFs) area, and (G) E-cadherin immunostaining score in cancer cells. The X- and Y-axes represent the IASLC grading system and immunohistochemical score, respectively.

Supplementary Figure 3. Detailed immunostaining results for each individual.

(A) CD8, (B) CD20, (C) Foxp3, (D) CD138, (E)CD204, (F) PDPN, and (G) E-cadherin expression

The X and Y axes represent patient number and immunostaining results, respectively.

Supplementary Figure 4. Comparison of the frequency of PDPN expression in CAFs in grades 1–3.

Fig. 3. Representative images of immunostaining. 

(A) Foxp3 of grade 1 case, (B) Foxp3 of grade 2 case, (C) Foxp3 of grade 3 case, (D) CD204 of grade 1 case, (E) CD204 of grade 2 case, (F) CD204 of grade 3 case, (G) PDPN of grade 1 case, (H) PDPN of grade 2 case, and (I) PDPN of grade 3 case.

Fig. 4. Comparison of the IASLC grading system with the predominant subtype-based classification.

(A) Immunostained cases were reclassified from predominant subtype-based classification to IASLC grading system-based classification.

(B) Comparison of the immunostaining results between Group-1 and Group-2. The Y axis represents the IASLC grading system and the immunohistochemical score.

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