Paulsen Erna-Elise, Andersen Sigve, Rakaee Mehrdad, Pedersen Mona Irene, Lombardi Ana Paola, Pøhl Mette, Kilvaer Thomas, Busund Lill-Tove, Pezzella Francesco, Donnem Tom
Department of Pulmonology, University Hospital of North Norway, Tromso, Norway.
Department of Oncology, University Hospital of North Norway, Tromso, Norway.
Front Oncol. 2023 Apr 26;13:1157461. doi: 10.3389/fonc.2023.1157461. eCollection 2023.
Non-small cell lung carcinomas (NSCLC) exhibit different microvessel patterns (MVPs). Basal (BA), diffuse (DA) and papillary (PA) patterns show signs of angiogenesis (new blood vessels), while an alveolar pattern indicates that tumors are co-opting existing normal vessels (non-angiogenic alveolar, NAA). NAA tumor growth is known to exist in NSCLC, but little is known about its prognostic impact in different histological subgroups, and about associations between MVPs and immune cell infiltration.
Detailed patterns of angiogenic and non-angiogenic tumor growth were evaluated by CD34 immunohistochemistry in whole tissue slides from 553 surgically treated patients with NSCLC stage I-IIIB disease. Associations with clinicopathological variables and markers related to tumor immunology-, angiogenesis- and hypoxia/metabolism were explored, and disease-specific survival (DSS) was analyzed according to histological subtypes.
The predominant MVP was angiogenic in 82% of tumors: BA 40%, DA 34%, PA 8%, while a NAA pattern dominated in 18%. A contribution of the NAA pattern >5% (NAA+), i.e., either dominant or minority, was observed in 40.1% of tumors and was associated with poor disease-specific survival (DSS) (=0.015). When stratified by histology, a significantly decreased DSS for NAA+ was found for adenocarcinomas (LUAD) only (< 0.003). In multivariate analyses, LUAD NAA+ pattern was a significant independent prognostic factor; HR 2.37 (CI 95%, 1.50-3.73, < 0.001). The immune cell density (CD3, CD4, CD8, CD45RO, CD204, PD1) added prognostic value in squamous cell carcinoma (LUSC) and LUAD with 0-5% NAA (NAA-), but not in LUAD NAA+. In correlation analyses, there were several significant associations between markers related to tumor metabolism (MCT1, MCT4, GLUT1) and different MVPs.
The NAA+ pattern is an independent poor prognostic factor in LUAD. In NAA+ tumors, several immunological markers add prognostic impact in LUSC but not in LUAD.
非小细胞肺癌（NSCLC）呈现出不同的微血管模式（MVP）。基底型（BA）、弥漫型（DA）和乳头型（PA）模式显示出血管生成（新血管）的迹象，而肺泡型表明肿瘤正在利用现有的正常血管（非血管生成性肺泡，NAA）。已知NAA肿瘤生长存在于NSCLC中，但关于其在不同组织学亚组中的预后影响以及MVP与免疫细胞浸润之间的关联知之甚少。
通过CD34免疫组织化学对553例接受手术治疗的I-IIIB期NSCLC患者的全组织切片中血管生成性和非血管生成性肿瘤生长的详细模式进行评估。探讨与临床病理变量以及与肿瘤免疫学、血管生成和缺氧/代谢相关的标志物之间的关联，并根据组织学亚型分析疾病特异性生存（DSS）情况。
82%的肿瘤中主要的MVP是血管生成性的：BA占40%，DA占34%，PA占8%，而18%的肿瘤以NAA模式为主。在40.1%的肿瘤中观察到NAA模式占比>5%（NAA+），即无论是占主导还是少数，且与较差的疾病特异性生存（DSS）相关（=0.015）。按组织学分层时，仅在腺癌（LUAD）中发现NAA+的DSS显著降低（<0.003）。在多变量分析中，LUAD的NAA+模式是一个显著的独立预后因素；风险比2.37（95%置信区间，1.50 - 3.73，<0.001）。免疫细胞密度（CD3、CD4、CD8、CD45RO、CD204、PD1）在鳞状细胞癌（LUSC）和NAA占比0 - 5%（NAA-）的LUAD中增加了预后价值，但在LUAD NAA+中没有。在相关性分析中，与肿瘤代谢相关的标志物（MCT1、MCT4、GLUT1）与不同的MVP之间存在若干显著关联。
NAA+模式是LUAD中一个独立的不良预后因素。在NAA+肿瘤中，几种免疫标志物在LUSC中增加了预后影响，但在LUAD中没有。
