ICC has poor prognosis because of the aggressivity and heterogeneity of the tumors. As the current AJCC TNM staging system is inadequate for prognostic evaluation of ICC patients who undergo hepatectomy, better tools that can guide clinical decision-making are needed.
Noninvasive markers such as the standard inflammatory indicators NLR, GLR, and AAPR have been used to monitor the progression and predict the outcome of malignant tumors [15–17]. These can easily be calculated by obtaining neutrophil and lymphocyte counts or by measuring γ-glutamyltransferase, serum albumin, and ALP levels. Neutrophil transmigration across the epithelium causes the disruption of epithelial adherens junctions through the release of elastase [29], which can promote tumor progression. Lymphocytes are associated with self-immunity, and patients with malignant tumors are often in a state of immunosuppression that promotes tumor growth, invasion, and metastasis [30, 31]. Immunologic markers are influenced by infection and bone marrow suppression induced by chemotherapy, radiotherapy, or other factors, which reduces their predictive value. As a biochemical marker, FARI is more stable in the circulation and has been used to evaluate long-term prognosis in various cancers including pancreatic ductal adenocarcinoma [32], gastrointestinal stromal tumors [20], and colorectal liver metastases [21]. In this study, we evaluated the prognostic value of FARI for ICC. The optimal cutoff value for FARI in the ROC curve analysis was 0.084, which diverges from the value of 0.076 reported for colorectal liver metastases [20] and the value of 0.08 in gallbladder cancer [22]. The reason for this discrepancy in the cutoff value among tumor types is unclear, but it may be attributable to differences in the biological characteristics of each tumor.
We divided the cohort into FARI-high and -low groups according to the cutoff value of FARI. Patients in the former group had a larger tumor size, elevated serum CA19-9, lymph node metastasis, and elevated TBIL and ALP levels, suggesting that FARI can reflect disease progression and metastasis in ICC. We also found that a high FARI was correlated with inflammatory indicators including high NLR and GLR and low AAPR. Moreover, the survival analysis revealed that RFS was shorter in ICC patients with a high FARI than in those with a low FARI. A nomogram was constructed based on 6 independent prognostic factors that significantly influenced RFS in the univariate and multivariate analyses, including tumor number, TNM stage, lymph node metastasis, cirrhosis, serum CA19-9, and FARI score. In our assessment of nomogram performance in predicting RFS, the C index and AIC were 0.663 and 3081.07, respectively, which were higher than the values for inflammatory indicators. Thus, FARI may be useful for predicting the clinical outcome of patients with ICC undergoing hepatectomy.
Fibrinogen is a large fibrous glycoprotein produced by hepatocytes that has been implicated in cancer growth and metastasis [32]. It is frequently detected in tumors and contributes to the formation of tumor-reactive stroma; moreover, fibrogen can promote tumor angiogenesis by binding several growth factors including fibroblast growth factor 2 (FGF-2) and vascular endothelial growth factor (VEGF), leading to tumor progression [33, 34]. Fibrinogen was shown to promote the malignant transformation of tumors by inducing epithelial-to-mesenchymal transition via the mammalian target of rapamycin (mTOR)/protein kinase B (AKT) signaling pathway [35], and inhibited the cytotoxic activities of natural killer cells in tumors [36]. Thus, fibrinogen is a useful marker for monitoring cancer progression.
Albumin is the most abundant protein in human serum and reflects the biosynthetic function of the liver and as well as the preoperative nutritional status of patients. Malnutrition is frequently observed and is related to outcome in various malignancies. Cancer-related malnutrition is associated with impaired immune function and increased proinflammatory cytokine levels, and some studies have shown that lower preoperative albumin level was associated with poor prognosis [37–39]. All of these factors contribute to low survival in cancer patients [40]. Thus, albumin level is also a useful marker for evaluating clinical outcomes in cancer [41].
There were some limitations to our study. First, the single-center retrospective design may have introduced a bias in our analyses. Second, our sample size was small and there was no external validation of our results. Third, the C index of the nomogram was not ideal, as a high predictive value is not equivalent to clinical applicability; thus, our nomogram needs to be improved by including other clinical variables. Finally, we did not investigate the mechanisms by which fibrinogen and albumin influence ICC recurrence. Further studies using animal models are needed in order to address this point.