Tumor cell invasion of the external elastic lamina designates visceral pleural invasion and predicts poorer patient outcomes in pulmonary non-mucinous invasive adenocarcinoma
Yi-Chen Yeh, MD, PhD,a,b Chi-Hung Chiang, MD,c Po-Kuei Hsu, MD, PhD,d,e Lei-Chi Wang, MD, PhD,a,b Wei-Chin Chang, MD, PhD,f Hsuan-Tung Lee, MD,f Chen-Yuan Chiang, MD, DrPhilos, MPH,g,h Yu-Chung Wu, MD,c,i Teh-Ying Chou, MD, PhDf,j*
JTO, 06 Aug, 2025
Introduction: Visceral pleural invasion (VPI) of lung cancer is defined as involvement by tumor cells into the elastic laminae of visceral pleura. In both AJCC staging system and CAP cancer protocol, VPI is classified as below: PL-0 for tumors that do not invade the elastic lamina; PL-1 for tumors that invade the elastic lamina but not up to the pleural surface; PL-2 for tumors that invade up to the pleural surface without involvement of adjacent anatomic structures; and PL-3 for tumors that invade the parietal pleura; staging of tumors smaller than 3 cm in size will be upgraded from T1 to T2 if VPI (PL-1 or PL-2) is present. Currently, it is recommended that tumor cells invading the outmost (external/outer) elastic lamina, rather than the internal/inner elastic lamina, serves as the criterion for diagnosing VPI. Nevertheless, there is scarce evidence supporting this widely adopted recommendation. Real world experiences are needed to further validate the clinical significance of lung cancer invading external versus internal elastic lamina of visceral pleura.
方法：回顾性分析了2011年至2016年1217例经手术切除的非黏液性浸润性腺癌肺癌患者的临床病理特征。采用双层弹性膜的分类方法，将VPI分为PL- n（无胸膜侵犯，肿瘤侵犯至内弹性膜下）、PL- i（肿瘤侵犯至内弹性膜或超出内弹性膜且侵犯至外弹性膜下）、PL- e（肿瘤侵犯至外弹性膜或超出外弹性膜但未到达壁层胸膜）和PL- p（肿瘤侵犯至弹性膜并到达壁层胸膜）。分析了VPI各类型与预后的关系，并结合其他相关临床和组织病理学参数。
Results: The 5-year overall survival rates were 89.7% for patients with PL-n, 89.5% for PL-i, 71.3% for PL-e, and 53.3% for PL-p, while 5-year recurrence-free survival rates were 88.1%, 85.8%, 55.8%, and 48.6%, respectively. PL-e showed significant differences in univariate analyses in overall survival analysis whereas in disease-free survival analysis, PL-e showed significant differences in both univariate and multivariate analyses.
结果：PL- n 型、PL- i 型、PL- e 型和 PL- p型患者的 5 年总生存率分别为 89.7% 、89.5%、71.3% 和 53.3% ；5 年无复发生存率分别为 88.1%、85.8%、55.8% 和 48.6%。在总生存率的单因素分析中， PL- e 型患者存在显著差异；在无病生存率的单因素和多因素分析中，PL- e 型患者均存在显著差异。
Conclusions: Tumor cells invading external elastic lamina (PL-e) was a significant prognostic factor for recurrence and associated with worse overall survival for pulmonary non-mucinous invasive adenocarcinoma, compared to tumor cells invading beneath external elastic lamina (PL-i). This study provides evidence supporting the use of the outmost external elastic lamina involvement as the landmark of visceral pleural invasion in current clinical practice.
结论：肿瘤细胞侵袭外弹性膜（PL- e）是复发的重要预后因素，且与肺非黏液性浸润性腺癌的总生存期较差（与肿瘤细胞侵袭至外弹性膜下（PL- i）相比）。本研究为在当前临床实践中使用最外层外弹性膜受累作为脏层胸膜侵犯的标志提供了证据。
1.首先该研究主要关注胸膜侵犯这个组织病理学分期相关的描述因子。VPI的病理评估目前尚存在争议，传统意义上将肿瘤突破脏层胸膜的外弹力层作为VPI阳性的标准。但是更精细化和深入的评估仍然缺乏循证医学相关的数据。
2.上细节（区分事实，畅谈观点）：
首先这篇单中心回顾性大样本研究对肺癌患者不同胸膜浸润的程度进行了研究。在这一个与分期密切相关的话题上，该研究进行了更深入的病理分层分析。研究结果肿瘤侵犯外部弹力层（PL-e）是肺腺癌复发和生存的独立不良预后因素，而仅侵犯内部弹力层（PL-i）不影响预后。
其次有趣的是该研究没有捧臭脚，没有按照目前IASLC Grade进行分级数据呈现及进一步校正哪种Grade中VPI的分布和对预后的影响。亚组分析中（I期且肿瘤≤3cm）PL-e的5年RFS（71.5%）显著低于PL-n（93.7%）和PL-i（91.4%）。PL-e仍是独立复发风险因素（多因素分析p<0.05）。这一结果也强调了PL-e对于预后的指导意义。
最后需要注意的是该研究仅对比了VPI不同程度与脉管瘤栓的预后影响。VPI、STAS、神经侵犯都尚未纳入到R分期中，目前也不得而知这些高危因素与在早期肺癌中对预后的影响孰轻孰重。同时也缺乏驱动基因突变情况的数据。PL-e/Pl-p患者的胸水灌洗液脱落细胞学与预后的关系也需要进一步研究。
3. 这篇文章也给早期肺癌中伴有高危因素患者的诊疗提了个醒，需要更加注重合并高危因素患者的综合诊疗。对于VPI患者是否有必要进行热灌注或其他干预性治疗，仍然需要更多的临床证据。
10.1016/j.jtcvs.2023.02.025
目录
1. INTRODUCTION (Figure 1)
2. Methods
2.1 Patients and study design
2.2 Pathological review (Figures 1a & 1b)
2.3 Statistical analysis (Table 1)
3. Result
3.1 Patient and Treatment Characteristics (Table 1)
3.2 PCI Effects on Clinical Outcomes (Figure 1) (Supplementary Table 1)(Table 2)(Figure 2)
3.3 Validation of PCI Effects in the Matched Cohort (Supplementary Table 2)(Supplementary Figure S2-4)
3.4 Outcomes After Isolated BM (Table 3)(Supplementary Figure S5)(Supplementary Table 3)(Figure 3)
4. CONCLUSION
— 图表汇总—
Figure 1: Schematic illustration of the histology and histopathology in different depths of pleural invasion.
(1a) Categories of pleural invasion based on elastic lamina involvement include PL-n: no pleural invasion; tumor involvement beneath internal elastic lamina, PL-i: tumor invading into or beyond internal elastic lamina and beneath external elastic lamina, PL-e: tumor invading into or beyond external elastic lamina but not reaching parietal pleura, and PL-p: tumor invading through elastic laminae and reaching parietal pleura; the corresponding classification scheme defined by the ninth edition of TNM staging is shown as PL-0, PL-1, PL-2, and PL-3.
(1b): Representative pathological images of different depths of pleural invasion.
(A) PL-n: tumors that demonstrate no invasion of the internal elastic lamina (hollow arrow). The external elastic lamina is indicated by solid arrow.
(B) PL-i: tumors that demonstrate invasion into and beyond the internal elastic lamina (hollow arrow) but do not penetrate the external elastic lamina (solid arrow).
(C) PL-e in PL-1: tumors that demonstrate invasion through the external elastic lamina (solid arrow) but not up to the visceral pleural surface.
(D) PL-e in PL-2: tumors that demonstrate invasion through the external elastic lamina (solid arrow) and up to the visceral pleural surface (arrowhead).
3.1 Patient and Treatment Characteristics
Table 1
3.2 PCI Effects on Clinical Outcomes
Figure 1: Schematic illustration of the histology and histopathology in different depths of pleural invasion.
(1a) Categories of pleural invasion based on elastic lamina involvement include PL-n: no pleural invasion; tumor involvement beneath internal elastic lamina, PL-i: tumor invading into or beyond internal elastic lamina and beneath external elastic lamina, PL-e: tumor invading into or beyond external elastic lamina but not reaching parietal pleura, and PL-p: tumor invading through elastic laminae and reaching parietal pleura; the corresponding classification scheme defined by the ninth edition of TNM staging is shown as PL-0, PL-1, PL-2, and PL-3.
(1b): Representative pathological images of different depths of pleural invasion.
(A) PL-n: tumors that demonstrate no invasion of the internal elastic lamina (hollow arrow). The external elastic lamina is indicated by solid arrow.
(B) PL-i: tumors that demonstrate invasion into and beyond the internal elastic lamina (hollow arrow) but do not penetrate the external elastic lamina (solid arrow).
(C) PL-e in PL-1: tumors that demonstrate invasion through the external elastic lamina (solid arrow) but not up to the visceral pleural surface.
(D) PL-e in PL-2: tumors that demonstrate invasion through the external elastic lamina (solid arrow) and up to the visceral pleural surface (arrowhead).