Low expression of SerpinB2 is associated with reduced survival in lung adenocarcinomas.

Lung cancer is a leading cause of cancer deaths worldwide and new biomarkers are of utmost importance. Studies have indicated that the anti-plasminogen activators SerpinB2 and Neuroserpin, and the adhesion molecule L1CAM, have a coordinated impact on development of metastasis. Here, we examined whether expression of these markers was associated with clinico-pathologic characteristics and prognosis in resected non-small cell lung cancer (NSCLC). Surgical specimens from 438 NSCLC patients treated at Haukeland University Hospital, Bergen, Norway (1993-2010) were included (median age 68 years; 213 adenocarcinomas, 135 squamous cell carcinomas, 90 others). Representative tumor sections were stained for SerpinB2, Neuroserpin, and L1CAM. Low expression of SerpinB2 was associated with reduced lung cancer specific survival (LCSS) in adenocarcinomas (p = 0.017), also in stage I (p = 0.031). In contrast, high SerpinB2 was associated with reduced LCSS in stage I squamous cell carcinomas (p = 0.022). Although Neuroserpin and L1CAM showed some associations with clinico-pathologic phenotype, there were no associations with survival. In multivariate survival analysis of adenocarcinomas, low SerpinB2 demonstrated independent prognostic value (HR 1.8, p = 0.008). In summary, low expression of SerpinB2 in lung adenocarcinomas was an independent prognostic factor. In contrast to findings by others, we found no impact of L1CAM on survival.

Microvascular proliferation is associated with aggressive tumour features and reduced survival in lung adenocarcinoma.

Despite new treatment options in lung cancer, there is still a need for better biomarkers to assist in therapy decisions. Angiogenesis has been associated with tumour growth and dissemination, and the vascular proliferation index (VPI) is a valuable prognostic marker in other tumours. Nestin, a marker of immature endothelium, was previously applied in combination with Ki67 for proliferating endothelium as a novel marker (Nestin-Ki67) of ongoing angiogenesis. Here, the prevalence and prognostic impact of vascular proliferation on lung cancer-specific survival (LCSS) in lung adenocarcinomas was studied. Selected tumour slides from a cohort of 210 patients treated surgically for adenocarcinoma at Haukeland University Hospital (Norway) from 1993 to 2010 were stained for Nestin-Ki67. VPI, the ratio between the density of proliferating vessels and the overall microvessel density were used, and the cut-off value was set at 4.4% (upper quartile). High VPI was associated with the presence of blood vessel invasion (p = 0.007) and tumour necrosis (p = 0.007). Further, high VPI was significantly associated with reduced LCSS (p = 0.020). By multivariate analysis, VPI remained an independent prognostic factor for reduced LCSS (HR 1.7; 95% CI 1.04-2.68; p = 0.033) when adjusted for other prognostic clinico-pathological features. In conclusion, microvessel proliferation assessed using the VPI was associated with aggressive tumour features such as blood vessel invasion and tumour necrosis and, independently, decreased LCSS. This marker should be further explored in separate cohorts, and in trials of anti-angiogenesis therapy.

Vascular invasion is an adverse prognostic factor in resected non-small-cell lung cancer.

Lung cancer is a leading cause of death, and there is a need for better prognostic factors in treatment decisions. Vascular invasion is a known negative prognosticator, but it is not clear how to evaluate this feature. Here, we studied the prevalence and prognostic impact of blood and lymphatic vascular invasion (BVI, LVI), tumour grade, necrosis, inflammation and pleural invasion on cancer-specific survival (LCSS) and time to recurrence (TTR) in non-small-cell lung cancer (NSCLC). A total of 438 patients surgically treated for NSCLC (1993-2010) were examined, including 213 adenocarcinomas (AC), 135 squamous cell carcinomas (SCC) and 90 other NSCLC. BVI and LVI were found in 25% and 21% of the cases, with reduced LCSS and TTR for both markers in AC and SCC (p < 0.005 for all). BVI and LVI remained independent prognostic factors for LCSS and TTR in separate multivariate models for AC and SCC. Combined BVI/LVI (7%) showed significantly reduced LCSS and TTR (p < 0.001), also by multivariate analysis. Our results support that BVI and LVI are valuable for prognostic staging. Vascular invasion identifies a group of patients at higher risk of recurrence and lung cancer-related death, and this could influence stratification of patients for treatment and follow-up.