論文の公開元へSerum S100 calcium-binding protein A4 as a novel predictive marker of acute exacerbation of interstitial pneumonia after surgery for lung cancer
概要
(2021) 21:186
Kagimoto et al. BMC Pulm Med
https://doi.org/10.1186/s12890-021-01554-y
Open Access
RESEARCH
Serum S100 calcium‑binding protein
A4 as a novel predictive marker of acute
exacerbation of interstitial pneumonia
after surgery for lung cancer
Atsushi Kagimoto1, Yasuhiro Tsutani1, Kei Kushitani2, Takahiro Kambara2, Takahiro Mimae1, Yoshihiro Miyata1,
Yukio Takeshima2 and Morihito Okada1*
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.
Keywords: Interstitial pneumonia, Acute exacerbation, S100A4, Lung cancer, Lung resection
*Correspondence: morihito@hiroshima-u.ac.jp
1
Department of Surgical Oncology, Hiroshima University, 1‑2‑3, Kasumi,
Hiroshima 734‑8551, Japan
Full list of author information is available at the end of the article
Background
Interstitial pneumonia (IP), mostly idiopathic pulmonary fibrosis (IPF), is associated with an increasing risk
of lung cancer [1, 2]. Approximately 4–6% of resected
specimens of lung cancer showed some types of interstitial lung disease (ILD) [3]. The short-term mortality rate
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Kagimoto et al. BMC Pulm Med
(2021) 21:186
after lung resection for lung cancer has been improved;
however, the major cause of death is acute exacerbation
(AE) of IP, and the reported incidence and rate of mortality among patients with non-small cell lung cancer
and AE with IP range from 0 to 32% and from 0 to 42%,
respectively [4–6]. Among deaths of patients with IP and
lung cancer, lung cancer is responsible for approximately
50%; the remaining deaths result from other causes, such
as respiratory failure [3, 5]. 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 [7]. Reportedly, S100A4 promotes lung
fibrosis via proliferation and activation of fibroblasts
[8]. By inducing expression of α-smooth muscle actin
(αSMA) and type 1 collagen, S100A4 also promotes the
transition of fibroblasts to myofibroblasts [7]. Li et al.
reported that a deficiency of S100A4 weakened pulmonary fibrosis; conversely, adoptive transfer of S100A4positive macrophages induced lung injury/fibrosis in
S100A4−/− mice [9]. Based on these findings, S100A4 is
assumed to play an important role in the pathogenesis
of IPF. Recently, Akiyama et al. showed that high serum
level of S100A4 was a significant predictive factor of IPF
[10]. However, the significance of serum S100A4 level
on the AE of IP after lung resection remained unknown.
Therefore, we examined the relationship between S100A4
and AE of IP after lung resection for lung cancer.
Methods
Patients
This study was approved by the Ethics Committee of
Hiroshima University Hospital (approval numbers Gen38 and E-2098). Patient consent was obtained by using
informed consent documents with an opt-out process.
The study was carried out in accordance to institutional
guidelines which is established based on the Declaration of Helsinki. Patients in whom IP had been diagnosed
on preoperative high-resolution computed tomography
(HRCT) and had undergone lung resection for primary
lung cancer between April 2010 and March 2019 were
included in this study. Twenty patients for whom preoperative serum samples were unavailable were excluded
from this study. Among included patients, patients with
UIP pattern in resected specimen was underwent immunohistochemistry (IHC). Flowchart of patient selection
was shown in Additional file 1: Fig. S1. Chest HRCT,
whole body [18F]-fluoro-2-deoxy-D-glucose positron
emission tomography/CT, brain magnetic resonance
imaging, and pulmonary function tests were conducted
preoperatively to determine the indications for surgery,
the appropriate surgical procedure, and clinical stage
Page 2 of 9
according to the eighth edition of the TNM Classification
for Lung Cancer [11].
HRCT
A 16-row multidetector CT was used to obtain chest
images. We used the following parameters for high-resolution images of the lungs: 120 kVp, 200 mA, 1–2 mm
section thickness, 512 × 512 pixel resolution, 0.5–1.0 s
scanning time, a high-spatial reconstruction algorithm
with a 20 cm field of view, and mediastinal (level, 40 HU;
width, 400 HU) and lung (level, 600 HU; width, 1600 HU)
window settings. ILD was defined radiologically according to the American Thoracic Society (ATS), European
Respiratory Society (ERS), Japanese Respiratory Society
(JRS), and Latin American Thoracic Association classifications (ALAT) and the patterns were classified as usual
IP (UIP), possible UIP pattern, and inconsistent with UIP
(Additional file 5: Table S1) [12]. Example images of each
pattern are shown in Additional file 2: Fig. S2.
Serum S100A4 level measurement
Serum samples were obtained 1 day before surgery. The
samples were stored at − 80 °C until measurement of
S100A4. To measure S100A4, we used a commercially
available enzyme-linked immunosorbent assay kit (CircuLex S100A4 ELISA Kit Ver.2; MBL Co., Ltd., Nagoya,
Japan).
Surgical procedure and evaluation of complications
Hybrid video-assisted thoracic surgery was conducted
as an approach method [13]. Postoperative complications were evaluated according to the Clavien–Dindo
classification [14]; complications of grade IIIa or worse
were considered severe. The respiratory complications
were AE of IP, bacterial pneumonia, bronchopleural fistula, pulmonary fistula that lasted more than 7 days or
performed pleurodesis. Pleural effusion after chest tube
removal was also included. AE of IP was defined by the
following clinical characteristics within 30 days from surgery: (1) appearance or worsening of dyspnea, (2) deterioration of the interstitial shadow on CT, (3) decrease of
SpO2 or PaO2 that was more severe than before surgery,
and (4) no evidence of other cause of these findings [12].
Pathological diagnosis and IHC
The pathological stage of lung cancer is based on the
eighth edition of the TNM Classification of Lung Cancer [11]. Because the area of IP is not always resected
due to the tumor location, among patients who measured serum S100A4, only patients who detected the
UIP pattern in resected specimen were performed
IHC. UIP pattern in resected specimen was diagnosed
with following features according to the statement
Kagimoto et al. BMC Pulm Med
(2021) 21:186
about IP from ATS/ERS/JRS/ALAT [12]: (1) evidence
of marked fibrosis/architectural distortion and honeycombing in a predominantly subpleural/paraseptal
distribution; (2) the presence of patchy involvement
of lung parenchyma by fibrosis; (3) the presence of
fibroblast foci; and (4) the absence of features that
suggested an alternative diagnosis. The representative
image of UIP pattern in resected specimen is shown in
Additional file 3: Fig. S3. ...
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