As soft tissue tumors have various subgroups and histological variants, pathological diagnosis is a critical tool for making objective decisions on treatment strategies. Occasionally, pathological diagnosis and differentiation between benign tumors or STS is complicated. To screen carcinoma, blood tests for CEA (carcinoembryonic antigen), SCC (squamous cell carcinoma) antigen, alpha-fetoprotein, or CA-125 are useful[6]. However, blood examinations to screen for STS have not been established. Notably, the intimate relationship between coagulation and fibrinolysis in malignant tumors is a well-known phenomenon. Increased DD in plasma is associated with poor prognosis in cancer patients such as breast cancer, renal cell carcinoma, gastric cancer, lung cancer, bladder cancers, colorectal cancers, gynecological tumors and lymphoma5,[5, 7–11]. Among coagulation and fibrinolysis factors, DD is one of the most reported factors analyzed as a prognostic marker. However, coagulation and fibrinolysis factors are rarely reported for distinguishing between benign and malignant tumors. Previously, we reported that fibrinogen levels were an effective marker for diagnosing the differentiation of benign tumors and STS[12]. Currently, few markers are available for estimating the state of coagulation and fibrinolysis. In this study, we evaluated whether fibrinolysis markers (DD and PIC) and coagulation markers (SF and TAT) could be used to differentiate benign tumors and STS.
DD is the most well-known fibrinolysis marker and has been reported as a marker capable of differentiating between benign and malignant ovarian tumors[13, 14]. In musculoskeletal tumors, DD levels showed a potential to discriminate between well-differentiated liposarcoma and lipoma[15]. Furthermore, PIC has been used for detecting breast cancer[16], and TAT was reported to distinguish between benign and malignant breast and ovarian tumors[14, 16]. Given these reports, coagulation and fibrinolysis markers may be more generally useful for distinguishing between benign and malignant tumors. However, there have been no reports investigating the accuracy of coagulation and fibrinolysis markers in detecting STS. Thus, the current study compares the accuracy of coagulation and fibrinolysis markers for detecting STS.
A comparison of plasma levels of DD, PIC, SF and TAT in benign tumors and STS indicated that DD, PIC and SF levels were significantly higher in STS. However, logistic analysis using continuous variables indicated that PIC showed a significant difference, while the other factors did not. This indicates that increased PIC levels correspond to increased risk of STS. In contrast, univariate analysis of threshold values indicated that DD (≥ 0.37), PIC (≥ 0.80), SF (≥ 0.90) and TAT (≥ 0.82) showed significant differences. In comparison, multivariate analysis demonstrated significant differences for PIC (≥ 0.80) and SF (≥ 0.90). This indicates that populations with PIC and SF levels over 0.80 and 0.90, respectively, include many STS patients. Additionally, among the markers evaluated, PIC had a higher positive predictive value and a higher accuracy than the others. We previously reported that the AUC of fibrinogen for identifying STS was 0.805[12]. Here, only PIC (0.784) exhibited an AUC that was roughly equivalent to fibrinogen. Thus, in order to detect STS, the PIC values over 0.80 represent the most effective marker of the four coagulation and fibrinolysis markers examined.
In the patient population of this study, the STS group contained many elderly patients. Epidemiological studies indicate that the incidence STS increases with age[17] and an age of 52.7 years was delimited with 73.8% sensitivity and 52.3% specificity (AUC: 0.64, 95%CI 0.56–0.72) for distinguishing benign tumors and STS[18]. In this study, an age of 55 years was delimited with 58.8% sensitivity and 71.6% specificity (AUC: 0.737, 95%PI 0.653–0.821). Thus, age could be one of the references for the distinction of STS. Additionally, DD, PIC, SF and TAT exhibited higher values in patients over 60 years of age. It was thought that there is some association between age and DD, PIC, SF and TAT. In contrast, tumor size is a critical factor in predicting a patient's prognosis in STS. The thresholds for staging STS are 5, 10 or 15 cm, according to the 8th AJCC system. In distinguishing benign soft tissue tumors and STS, a threshold of 5 cm is a weak predictor of malignancy (AUC: 0.663, sensitivity 68.8%, specificity 50.3%)[18]. In this study, a size of 9.5 cm was delimited with 58.8% sensitivity and 71.6% specificity (AUC: 0.72, 95%CI 0.636–0.805). Additionally, DD, PIC and SF showed higher values in patients with tumor sizes ≥ 10 cm. Some association between tumor size and DD, PIC and SF was considered as well as age. However, the results of the multivariate logistic analysis revealed that age and size were not significant indicators, and they did not contribute to detecting STS along with PIC or SF.