The present study demonstrated that high preoperative plasma Fib levels are significantly associated with poor RFS in patients with primary GIST who underwent radical surgery, and explored its possible cut-off value (3.62g/L) to predict RFS. To the best of our knowledge, This study represents the largest dedicated series published, focusing on the prognostic significance of preoperative plasma Fib levels in patients with primary GIST. Furthermore, we found, for the first time, that high preoperative plasma Fib levels still indicated a poor RFS in patients with mNIH high-risk GIST. In addition, our study showed a positive correlation between the preoperative plasma Fib levels and the well-recognized prognostic factors, including tumour size, mitotic index, and mNIH risk classification.
In our study, the correlation between high preoperative plasma Fib levels with poor prognosis was further verified, which is consistent with the previous studies on GIST [22, 23]. However, the cuff-off value (3.62g/L) is inconsistent with the study by Cai et al (3.24g/L) . Obviously, for the heterogeneity of different populations, it is impossible to determine the ideal threshold for Fib in any small or retrospective study. Although Lu et al first observed the correlation between high preoperative plasma Fib levels with poor prognosis in patients with GIST, their sample size was small (n = 91), the follow-up time was shorter (median follow-up time: 2 years) and no any subgroup analysis was performed . Cai et al recently reported a similar result with a larger sample size (n = 170), but their data bases overlap with Lu et al and the median follow-up time was not given [22, 23]. In addition, our results are also consistent with previous studies in patients with different malignances [15-21]. Moreover, there were some animal studies suggesting that Fib is an important factor of the metastatic potential of tumour cells [25, 26]. And some studies have indicated that, in addition to antithrombotic functions, heparins and derivatives also exert critical antimetastatic effects by interference with P-selectin-mediated cell binding [27, 28]. In the present study, tumour size was not observed to be an independent prognostic factor, which may be due to the limited sample size, the exclusion of patients who received preoperative imatinib treatment or non-radical resection, or the obscurity of prognostic significance by other factors. Since the survival analyses were conducted in overall population, the prognostic benefits of adjuvant imatinib treatment were not observed. However, in our study, the adjuvant imatinib treatment significantly improved the prognosis of patients with mNIH moderate/high-risk GIST (P = 0.015), which is consistent with previous studies [4, 6].
In the mNIH high-risk subgroup analysis, for the first time, preoperative plasma Fib levels were still detected to be a significant prognostic factor, which would be conductive to further grading for high-risk patients, and administrating adjuvant therapy to the appropriate patients. However, correlations were not significant within the very low/low/moderate-risk subgroup analysis, which may be due to the limited number of endpoint events and the shorter follow-up time. Preoperative plasma Fib levels were a significant prognostic factor for GIST at both stomach and non-stomach, which may indicate plasma Fib levels were not significantly associated with the tumour locations. For patients without adjuvant imatinib treatment, high preoperative plasma Fib levels indicated a significantly poor prognosis. However, in subgroup with adjuvant imatinib treatment, correlation was not observed between Fib and RFS, which may be due to the prognostic benefits from imatinib treatment or the limited sample size.
Our study showed a positive correlation between the preoperative plasma Fib levels and several prognostic factors, including tumour size, mitotic index, and mNIH risk classification, which is similar to the study by Cai et al . Furthermore, we even observed a linear correlation between preoperative plasma fibrinogen levels and tumour size, which indirectly indicates Fib’s prognostic significance. In addition, it was found that patients in H-Fib group had lower plasma concentration of Alb, a biomarker of nutritional status, that was a recognized prognostic factor in many kinds of tumours including GIST [29-31]. Previous studies reported that the plasma concentrations of some coagulation factors, such as Fib, increase progressively with age . We also found that patients in H-Fib group were older than patients in L-Fib group, which was in consistent with the previous studies [23, 32]. However, for GIST patients, the correlation between age and the preoperative plasma Fib levels was not strong (Spearman correlation coefficient [r] = 0.198, P = 0.005). Furthermore, in our study, the high preoperative plasma Fib levels were still significantly associated with the poor RFS in patients older than 60 years. Accordingly, the impact from healthy aging could not cover up the possible correlation between the preoperative plasma Fib levels and the malignant degree of GIST.
The reliable molecular mechanisms by which tumour cells interact with the hemostatic system are yet to be clear. Several possible mechanisms were proposed to explain the complex correlation. On the one hand, tumour cells activate the hemostatic system in multiple ways. Tumour cells not only directly activate the coagulation cascade by producing many procoagulant proteins (tissue factor, heparanase, cancer procoagulant, and tissue factor-positive microparticles), but also stimulate the procoagulant properties of the host’s hemostatic cells (endothelial cells, platelets, and leukocytes), thereby increasing plasma Fib levels [33, 34]. We can not also exclude that the pathophysiological mechanism of hypercoagulation may be secondary to tumour-derived systemic inflammatory response and/or intra-abdominal infectious disease [33-36]. Indeed, all of the procoagulant mechanisms elicited by tumour tissues, as well as the patient’s general and clinical thrombotic risk factors, contribute to the occurrence of a hypercoagulation of patients with cancer . On the other hand, Fib could also promote tumour progression in return. In tumour microenvironment, Fib could influence the development of tumours through complex interactions with multiple integrin or non-integrin Fib receptors (e.g., cadherins, αIIbβ3, αVβ3, αXβ2, αMβ2, α5β1, αVβ1, Toll-like receptors) which mediate innate immune cell function, tumour cellular proliferation, migration, and apoptosis [37-43]. For example, Fib has been suggested to be a bridging molecule between tumour cells and vascular endothelial growth factor, which could stimulate angiogenesis and promote tumour proliferation . All of these possible mechanisms promote a positive feedback loop between tumour progression and hypercoagulation.
As a cost-effective biomarker, the Fib is easily detected from conventional coagulation analysis before surgery. Accordingly, the evaluation of Fib levels would be clinically useful for indicating the malignant potential and prognosis in combination with imaging and pathological features.
There are several limitations in the present study. First, a selection bias cannot be excluded due to the nature of a retrospective study in a single institution. The exclusion of patients who did not undergo a radical surgery, as well as the inclusion of patients with adjuvant imatinib treatment, would have an effect on the prognosis of the overall cohort. Second, due to limited follow-up time, the inclusion of patients with adjuvant imatinib treatment and high survival of GIST patients, we did not analyze the OS as the endpoint of this study. Third, genetic mutation analysis was not conducted in most patients because of the high cost, which limits the further studies.