In the present study, 6 (.9%) patients were diagnosed with carcinoma in situ, 221 (33.9%) on stage IA, 125 (19.1%) on stage IB, 107 (16.4%) on stage IIA, 45 (6.9%) on stage IIB, 114 (17.5%) on stage IIIA,10 (1.6%) on stage IIIB and 24 (3.7%) on stage IV, and the medians of Fbg were 256.1 mg/dL, 292.6 mg/dL, 316.6 mg/dL, 314.6 mg/dL, 318.9 mg/dL, 327.4 mg/dL, 428.3 mg/dL, and 304.4 mg/dL, respectively. CS and Fbg were corresponded to a linear unary correlation (P = .001) and the later the CS stages were, the higher the Fbg levels were (Fig. 1). Similarly, as shown in Figures 2 and 3 , the later the N stages (P = .002) and M stages (P = .002) were, the higher the Fbg levels were. Nevertheless, we did not observe a linear correlation between T stages (P = .217) and Fbg levels.
3.3 Relationship between Fbg and tumor markers
The study researched pretreatment tumor markers related with NSCLC, including SCCA (P = .001), CYFRA21–1 (P = .092), CA125 (P = .041), NSE (P < .001), and CEA (P = .571). In conclusion, Fbg levels were correlated to SCC, CA125, NSE, and they were linearly related and positively correlated (Figs. 4–6). However, Fbg levels were not correlated to CYFRA21–1 and CEA. And there is not a linear correlation between Fbg and D-dimer (P = .918).
Hyperfibrinogenemia can exist in many patients with malignant tumors including NSCLC and SCLC, which suggests a poor prognosis.[4,5,7,10,19] Fbg, synthesized by liver, is the highest content of coagulation proteins in plasma and can be converted to fiber polymer (insoluble fibrin) by activated thrombin. It plays a vital role in blood coagulation, fibrinolysis, inflammatory response, wound healing, and tumorigenesis. Moreover, the crosslink of Fbg and various blood cells can form blood clots and protect circulating cancer cells from the killing effect of immune cells, thereby increasing the potential of cancer metastasis. Fbg may promote stable adhesion among tumor cells, platelets, and endothelial cells,[3,7,20,21] thereby further protecting the tumor cells from the impact of the immune system, enhancing the ability of cell establishment, deep infiltration, and metastasis.[4,22] Therefore, in our research and early studies, we found the later the N, M, and CS were, the higher the average levels of plasma Fbg were.
Studies by Tas et al have also shown that male patients have higher Fbg levels than the females, probably because the coagulation cascades of males are easier to be activated than that of females. This is consistent with our findings.
The expression of coagulation factors may vary with the pathological type of lung cancer, and the level of anti-thrombin in patients with SCC is significantly lower than that in adenocarcinoma patients. Tas et al have found that D-dimer levels in patients with SCC are higher than those in other pathological types. Li and other studies have also shown that SCC has significantly higher Fbg levels than adenocarcinoma, and Fbg and platelet count levels are higher in stage III and IV than in stage I-II.[3,25] In our study, we observed that patients with SCC have higher levels of Fbg than patients with adenocarcinoma, but the mechanism is still unclear.
SCCA is a member of the serine protease inhibitor family of endogenous serine protease inhibitors. Multiple studies have shown that high levels of SCCA are usually associated with poorly differentiated and advanced metastatic SCC.[26,27] Fbg levels are also associated with advanced tumor metastasis.[18,22,28–30] The relationship between SCCA and Fbg was accorded with ULR in our study, and the higher the SCCA concentration was, the higher the Fbg levels were.
NSE is a type of tumor markers of SCLC, and related studies have shown that plasma Fbg often increases obviously in SCLC patients.[7,24] The mechanisms activating coagulation and fibrinolysis in SCLC patients and NSCLC patients are different. In SCLC, tumor cells can release tissue factor to activate coagulation system directly, whereas in NSCLC, host macrophages release factors that activate the fibrinolytic system. NSE levels are reported to be elevated in SCLC patients and are significantly higher in patients with advanced stages.[33,34] This is consistent with the positive correlation between Fbg and NSE in our study.
CA125 is a kind of tumor markers of adenocarcinoma. Wang et al revealed that breast cancer patients with distant metastases have higher plasma CA125 than those do not. Also, Jiang et al's study suggested that renal cancer patients with elevated plasma CA125 are often in a hypercoagulable state. Xie et al's study showed that elevated levels of CA125 lead to hypercoagulation. In our study, we found that Fbg level also increased with elevating CA125.
Up to now, there was a great deal of studies on Fbg and NSCLC, but the results were not consistent and the mechanism was still unclear. We observed positive correlation among Fbg concentration and sex, N stages, M stages, CS, SCCA, NSE, and CA125 in our research, supported by the results of Tas, Li, Xie et al.
Many studies have found that cancer patients with higher Fbg have lower resectability and poorer prognosis. Fbg is an independent prognostic factor for cancer patients, which suggests active anticoagulation therapy can improve the prognosis of them.[15,18] Patients with significantly increased tumor markers also have poor prognosis. In our study, the change of several tumor markers (SCCA, CA125, and NSE) was consistent with that of plasma Fbg. Now we suspect that the elevated tumor markers may be associated with poor prognosis in patients with high Fbg levels.
Cancer constitutes an enormous burden on families and the society in more and less economically developed countries alike.[1,38] As an independent prognostic factor, Fbg can help doctors reasonably choose palliative treatment in combination with other indicators in order to reduce unnecessary pain and improve the quality of life. Further studies are needed to focus on the mechanism and the relationship between Fbg and survival, including overall survival and progression-free survival.
Data curation: Nannan Bian, Xin Hu, Yang Ge.
Methodology: Nannan Bian, Xinyu Shi, Guangyu An, Guosheng Feng.
Writing – original draft: Nannan Bian, Xinyu Shi, Hongyu Qi.
Writing – review and editing: Guosheng Feng.
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Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
clinicopathological stages; fibrinogen; non-small cell lung cancer; tumor makers