第一部分

肺叶切除术与亚肺叶切除术治疗I期肺浸润性粘液腺癌的远期疗效对比

摘要

背景及目的 

肺浸润性粘液腺癌(lung invasive mucinous adenocarcinoma, LIMA)作为肺腺癌(lung adenocarcinoma, LUAD)的一种特殊亚型，既往曾被称为粘液性细支气管肺泡癌(bronchioloalveolar carcinoma, BAC)。由于发病率低，目前LIMA缺少大规模病例报道研究，尤其是在手术方式对早期LIMA患者预后影响方面。本研究旨在通过收集多中心I期LIMA患者的临床病理学特征，分析预后相关因素，着重探讨手术方式对I期LIMA患者预后的影响。以帮助临床医生了解I期LIMA临床病理特征，为患者提供最佳的治疗方式及随访策略

方法 

纳入2010年8月至2018年12月在国内3家三级甲等医院中，经病理诊断为I期LIMA并行根治性手术的患者资料。明确与无复发生存期(recurrence-free survival, RFS)和总生存期(overall survival, OS)相关的预后因素。比较接受肺叶切除术与亚肺叶切除术患者的累积复发率(cumulative incidence of recurrence, CIR)和累积死亡率(cumulative incidence of death, CID)。分析两组队列中时间与复发及死亡风险曲线。

结果 

在264例纳入的患者中，分别有232例(87.88%)和32例(12.12%)接受肺叶切除术和亚肺叶切除术。肺叶切除组和亚肺叶切除组患者的总复发率分别为7.76%和21.88% (P=0.019)。在肺叶切除组与亚肺叶切除组中术后复发率有显著性差异。肺叶切除组的5年CIR显著低于亚肺叶切除组(6.72% vs. 20.91%, P=0.005)。Cox比例风险单因素回归分析显示，手术方式、VPI是I期LIMA患者RFS的预后因素(P<0.05)。Cox比例风险多因素回归分析显示，VPI(有vs.无：风险比[HR], 2.73; 95%置信区间[CI], 1.23–6.07; P=0.014)和手术方法：(亚肺叶切除术vs.肺叶切除术:风险比[HR], 3.62; 95%[CI], 1.49-8.81; P=0.005)为影响RFS的独立预后因素。

结论 

肺叶切除的I期LIMA患者有着更好的RFS，VPI受累的患者预后更差。LIMA患者术后复发的双峰模式为术后随访策略提出新的挑战。接受亚肺叶切除术并诊断为VPI受累的LIMA患者应当谨慎随访，以及时发现任何潜在的复发情况。

第二部分

肺浸润性粘液腺癌中PD-L1表达与CD8⁺ T细胞浸润的模式探索和预后价值分析

摘要

背景及目的

肺浸润性粘液腺癌(LIMA)作为肺腺癌(LUAD)的一种特殊亚型，其显著特点之一是胞浆内富含粘液物质。这种特性不仅赋予了LIMA独特的病理表现，同时也影响了其对多种治疗方案的反应效果。近年来，免疫疗法的应用为非小细胞肺癌(NSCLC)的治疗领域带来了突破性的进展，但患者之间的治疗效果仍然存在显著的个体差异。PD-L1、CD8⁺ TILs等免疫治疗相关分子在既往研究中已受到广泛关注。然而，目前对于LIMA免疫微环境的研究尚显不足。本研究旨在深入探讨LIMA与免疫系统之间的相互作用机制，从而为制定个体化的癌症治疗策略提供坚实的科学依据。

方法

纳入2016年1月至2021年6月在国内3家三级甲等医院/肿瘤治疗研究中心行根治性手术切除的LIMA患者218例， 根据美国癌症联合委员会第8版TNM分期标准对病理标本重新进行病理TNM分期。对病理标本进行IHC染色、评估PD-L1表达、定量测定CD8⁺ TILs的浸润水平。随后对PD-L1表达、CD8⁺ TILs的浸润水平及密度与RFS及OS进行统计学分析。采用单因素和多因素Cox比例风险模型确定独立预后因素。并构建多因素模型。

结果

PD-L1表达中，以TPS≥1%为诊断标准，TPS评分仅与TNM分期显著相关(P=0.007)。同时，PD-L1表达阳性患者(根据TPS或CPS标准判定)的RFS和OS均未显著延长。CD8⁺ TILs阳性率与密度呈显著线性相关(斯皮尔曼检验，R=0.918, P<0.001)。CD8⁺ TILs阳性率与合并症、肿瘤部位/肺叶、治疗方式、基因检测、N分期(P<0.001)显著相关。CD8⁺ TILs密度与合并症、肿瘤部位/肺叶、治疗方式、基因检测、T分期、N分期、TNM分期(P＜0.05)显著相关。此外，CD8⁺ TILs阳性率(P=0.004)和密度(P<0.001)较高的患者具有较长的RFS，而CD8⁺ TILs浸润水平不能预测OS。PD-L1表达阳性的患者有着较高的CD8⁺ TILs阳性率(P＜0.001)及密度(P＜0.001)。CPS较TPS可更好的评估CD8⁺ TILs阳性率和密度增加与PD-L1表达增加关系(P<0.001和P=0.001)。在4种组合中，CPS评分联合CD8⁺ TILs阳性率的组合能在长期生存方面最好的区分患者。

结论

PD-L1作为LIMA预后生物标志物的效用有限。PD-L1表达和CD8⁺ TILs浸润定量之间呈正相关。较高的CD8⁺ TIL密度和阳性率是LIMA患者RFS的独立有利预后因素。CD8⁺ TIL定量评估可显著改善LIMA的预后模型和免疫治疗策略。

Long-term outcomes of lobectomy versus sublobectomy for stage I lung invasive mucinous adenocarcinoma

Abstract

Background and purpose

Lung invasive mucinous adenocarcinoma (LIMA) is a distinct subtype of lung adenocarcinoma (LUAD), previously called as lung mucinous bronchioloalveolar carcinoma (BAC). Owing to the relatively low incidence of LIMA, there have been limited comprehensive case reports examining the influence of surgical techniques on the prognosis of early-stage patients. The objective of this study is to collect the clinicopathological characteristics of patients diagnosed with stage I LIMA. This study  aims to identify prognostic factors and delve into the influence of surgical techniques on the prognosis of these patients. The ultimate goal is to assist clinicians in comprehending the clinicopathological nuances of stage I LIMA, thereby enabling them to offer optimal treatment and follow-up strategies tailored to the needs of individual patients.

Methods

Patients diagnosed with pathological stage I LIMA of the lung who underwent radical surgery between August 2010 and December 2018 at three tertiary hospitals/cancer treatment research centers in China were enrolled. Prognostic factors for recurrence-free survival (RFS) and overall survival (OS) were identified. The cumulative incidence of recurrence (CIR) and cumulative incidence of death (CID) in patients who underwent lobectomy or sublobectomy were compared. The risk curves for recurrence and tumor-related death over time were analyzed for the two groups.

Results

Among the 264 included patients, 232 (87.88%) and 32 (12.12%) underwent lobectomy and sublobectomy, respectively. The total recurrence rates in patients were 7.76% and 21.88%  in the lobectomy and sublobectomy groups, respectively (P=0.019). There were significant differences in the recurrence rates after lobectomy or sublobectomy. The 5-year CIR in the lobectomy group was significantly lower than that in the sublobectomy group (6.72% vs. 20.91%, P=0.005). Cox proportional risk univariate regression analysis showed that the surgical method, VPI were prognostic factors for RFS in patients with pathological stage I LIMA(P<0.05). Cox proportional risk multivariate regression analysis showed that VPI (Yes vs. No: hazard ratio [HR], 2.73; 95% confidence interval [CI], 1.23–6.07; P=0.014) and surgical method (sublobectomy vs. lobectomy: HR, 3.62; 95% CI, 1.49-8.81; P=0.005) were independent prognostic factors affecting RFS.

Conclusions

Patients with stage I LIMA after lobectomy have better RFS, and patients with VPI have worse prognosis. The bimodal pattern of postoperative recurrence LIMA patients poses a new challenge for postoperative follow-up strategy. Patients with stage I LIMA after sublobectomy and diagnosed with VPI should be followed up with caution to detect any potential recurrence in time.

Patterns and prognostic value of PD-L1 expression and CD8⁺ T cell infiltration in lung invasive mucinous adenocarcinoma

Abstract

Background and purpose

As a distinct subtype of lung adenocarcinoma (LUAD), lung invasive mucinous adenocarcinoma (LIMA) is noted for its abundant mucinous content within the cytoplasm. This unique characteristic confers upon LIMA distinct pathological phenotypes and also influences its responsiveness to various therapeutic approaches. Despite the remarkable advancements in immunotherapy for the treatment of non-small cell lung cancer (NSCLC) in recent years, substantial variations in treatment outcomes among patients persist. Immune-related molecules, such as PD-L1 and CD8⁺ TILs, have garnered significant attention in prior research. Nevertheless, there remains a dearth of studies examining the immune microenvironment of LIMA. The objective of this study is to elucidate the intricacies of the interaction between LIMA and the immune system, ultimately aiming to establish a robust scientific foundation for the development of tailored cancer treatment strategies.

Method

From January 2016 to June 2021, a total of 218 patients with LIMA who underwent radical resection in three tertiary hospitals/cancer treatment research centers in China were enrolled. The pathological TNM staging of pathological specimens was re-evaluated according to the 8th edition TNM staging criteria of the American Joint Committee on Cancer. IHC staining was performed to evaluate PD-L1 expression and quantitative determination of CD8 TILs infiltration in pathological specimens. Then the PD-L1 expression, CD8 TILs infiltration level and density and RFS and OS were statistically analyzed. Univariate and multivariate Cox proportional hazards models were used to determine the independent prognostic factors. A multivariate model was constructed.

Results

In terms of PD-L1 expression, TPS score was only significantly correlated with TNM stage (P=0.007) when TPS≥1% was used as the diagnostic criterion. At the same time, the RFS and OS of patients with PD-L1 positive (according to TPS or CPS criteria) were not significantly prolonged. There was a significant linear correlation between the positive rate of CD8⁺ TILs and the density (Spearman test, R=0.918, P<0.001). The positive rate of CD8⁺ TILs was significantly correlated with comorbidities, tumor location/lobe, treatment method, genetic testing, and N stage (P<0.001). The density of CD8⁺ TILs was significantly correlated with comorbidities, treatment methods, tumor location/lobe, genetic testing, T stage, N stage, and TNM stage (P<0.05). In addition, patients with higher CD8⁺ TILs positive rate (P=0.004) and density (P<0.001) had longer RFS, while CD8⁺ TILs infiltration level did not predict OS. Patients with PD-L1 expression had a higher positive rate (P<0.001) and density of CD8⁺ TILs (P<0.001). CPS was better than TPS in evaluating the relationship between the increased positive rate and density of CD8⁺ TILs and the increased expression of PD-L1 (P<0.001 and P=0.001). Among the four combinations, the combination of CPS score and CD8⁺ TILs positive rate best differentiated patients in terms of long-term survival.

Conclusions

PD-L1 has limited utility as a prognostic biomarker in LIMA. positive correlation between PD-L1 expression and quantification of CD8⁺ TILs infiltration. Higher CD8⁺ TIL density and positive rate were independent favorable prognostic factors for RFS in LIMA patients. Quantitative assessment of CD8⁺ TIL can significantly improve the prognostic model and immunotherapy strategy of LIMA.