Serum S100 calcium-binding protein A4 as a novel predictive marker of acute exacerbation of interstitial pneumonia after surgery for lung cancer

Abstract

Background Acute exacerbation (AE) of interstitial pneumonia (IP) is the most fatal complication after lung resection for lung cancer. To improve the prognosis of lung cancer with IP, the risk factors of AE of IP after lung resection should be assessed. S100 calcium-binding protein A4 (S100A4) is a member of the S100 family of proteins and is a known marker of tissue fibrosis. We examined the usefulness of S100A4 in predicting AE of IP after lung resection for lung cancer. Methods This study included 162 patients with IP findings on preoperative high-resolution computed tomography scan who underwent curative-intent lung resection for primary lung cancer between April 2007 and March 2019. Serum samples were collected preoperatively. Resected lung tissue from 76 patients exhibited usual IP (UIP) pattern in resected lung were performed immunohistochemistry (IHC). Relationship between S100A4 and the incidence of AE of IP and short-term mortality was analyzed. Results The receiver operating characteristic area under the curve for serum S100A4 to predict postoperative AE of IP was 0.871 (95% confidence interval [CI], 0.799–0.943; P < 0.001), with a sensitivity of 93.8% and a specificity of 75.3% at the cutoff value of 17.13 ng/mL. Multivariable analysis revealed that a high serum S100A4 level (> 17.13 ng/mL) was a significant risk factor for AE of IP (odds ratio, 42.28; 95% CI, 3.98–449.29; P = 0.002). A 1-year overall survival (OS) was significantly shorter in patients with high serum levels of S100A4 (75.3%) than in those with low serum levels (92.3%; P = 0.003). IHC staining revealed that fibroblasts, lymphocytes, and macrophages expressed S100A4 in the UIP area, and the stroma and fibrosis in the primary tumor expressed S100A4, whereas tumor cells did not. Conclusions Serum S100A4 had a high predictive value for postoperative AE of IP and short-term mortality after lung resection.

Endothelial-to-mesenchymal transition: a precursor to pulmonary arterial remodelling in patients with idiopathic pulmonary fibrosis

“…causes lung fibrosis by promoting the proliferation and activation of fibroblast (42)(43)(44) and increased S100A4 elevation has been proposed to contribute in the development of IPF (45)(46)(47)(48). The S100A4 expression was significantly higher in intima layer across all arterial sizes however, we didn't find such a significant expression in media and adventitia layers.…”

Usefulness of serum S100A4 and positron‐emission tomography on lung cancer accompanied by interstitial pneumonia

“… 18 There are no studies using cell line or animals that directly compared the serum S100A4 values with the situation in tissues. However, Akiyama et al showed that serum S100A4 is useful in predicting the long‐term prognosis of IP, 19 and our previous study showed its usefulness in predicting AE of IP 8 ; in addition, these studies showed numerous S100A4 expressing cells not present in the normal lung area but are found in the IP area. Although the significance of serum S100A4 as a predictive factor of long‐term survival has been already reported in patients with IP, its significance in predicting long‐term survival in patients with lung cancer with IP after pulmonary resection remains unknown, and we believe that this is a novel point of this article.…”

“…Included patients were divided into three groups based on the serum S100A4 levels and FDG accumulation: low S100A4/FDG (−), high S100A4/FDG (−) or low S100A4/FDG (+), and high S100A4/FDG (+). The cutoff S100A4 (17.13 ng/ml) value determined in the previous study was used 8 …”

“…The S100 calcium‐binding protein A4 (S100A4) is a member of the S100 protein family and is a known marker of tissue fibrosis 7 . Recently, we reported the usefulness of serum S100A4 as a novel predictor of postoperative AE of IP after lung cancer resection 8 . We also showed the usefulness of [18F]‐fluoro‐2‐deoxy‐D‐glucose (FDG) accumulation on positron emission tomography/computed tomography (PET/CT) in predicting AE of IP 9 .…”

“…7 Recently, we reported the usefulness of serum S100A4 as a novel predictor of postoperative AE of IP after lung cancer resection. 8 We also showed the usefulness of [18F]-fluoro-2-deoxy-D-glucose (FDG) accumulation on positron emission tomography/computed tomography (PET/CT) in predicting AE of IP. 9 However, the significance of S100A4 and FDG accumulation in longterm survival after lung resection remains unknown.…”