Cancer is characterized by neoplastic cells that are closely related to chronic inflammatory infiltrates. In fact, there is increasing evidence showing that systemic inflammation is responsible for tumor-promoting activities and neoangiogenesis in several tumors [17].
Humoral response has an impact on carcinogenesis, exerting pro-tumoral action [18]. Recent studies have shown that the molecular environment created by humoral response (mediated by the production of enzymes such as metalloproteinases, vascular growth factors, and cytokines) favors conjunctive matrix degradation, the activation of neoangiogenesis, the recruitment and activation of cell profiles favoring tissue invasion, and metastasis. Therefore, an increase in humoral inflammatory response can lead to worse oncological outcomes [18]. Conversely, lymphocytic cellular response (mediated by T lymphocytes CD4+, CD8+, and NK cells) inhibits carcinogenesis, leading to better oncological prognosis [17].
Recent studies have shown the interaction between platelets and tumoral microenviroment [19]. The main platelet-associated mechanisms are based on signaling pathways that orchestrate tumor growth, activation of angiogenesis, and metastatic dissemination [20]. In fact, platelets play a pivotal role in tumor neoangiogenesis from the early to advanced stages [21]. Activated circulating platelets have metabolic pathways diverted to synthesize vascular growth factors such as vascular endothelial growing factor and platelet-derived growing factor, which leads to changes in vascular permeability and in the underlying smooth musculature [21]. Activated platelets also take part in the metastatization process through the activation of the epithelium-mesenchymal transition, an initial phenomenon in metastasis development [22]. Additionally, activated circulating platelets bind to tumor cells, acting as a mechanical protection against immune cytotoxic cells, especially NK cells [23].
The prognostic impact of systemic inflammatory response has been studied in several gastrointestinal tumors, such as pancreatic, colorectal, and gastric cancers [24, 25]. The main advantages of inflammatory markers include calculation using routine laboratory tests, low cost, and access to results before therapeutic intervention [26].
The NLR is the most studied inflammatory index. A large metanalysis, comprising more than 40,000 patients showed an association of high NLR with lower survival rate in patients with several solid tumors [27]. Recently, a study from our institution conducted by Szor et al [7]. showed that the NLR had an impact on OS (HR=1.50; 95%CI 1.27-4.21; P=0.048) and refines the TNM staging in patients with gastric adenocarcinoma who underwent curative intent gastrectomy. In a systematic review, Malietzis et al. [28] showed that a high NLR had a negative impact on OS and DFS in patients with colorectal cancer undergoing resection. Likewise, Yshibashi et al. [29] studied patients undergoing curative intent esophagectomy for cancer and showed a close correlation between the NLR and OS.
However, the prognostic impact of inflammatory markers in patients with HCC who undergo resection remains controversial. Most studies that assessed these prognostic markers came from eastern centers, where HCC presents distinct clinical and epidemiological features [30]. The present study is one of the first from a western center to evaluate the association between main inflammatory markers (NLR, PLR, and MLR) and long-term outcomes after liver resection for HCC. In our study, the mean age was 62 ± 11 years, similar to those in other western centers but higher than those in eastern centers (52 ± 9 years) [31]. Regarding chronic liver disease etiology, hepatitis C (60%) was the most frequent, followed by hepatitis B (20%) and NASH (11%). In contrast, in eastern centers, the prevalence of hepatitis B infection is higher than 50% [32]. Our data showed that 84% of patients had chronic liver disease and 94.8% were classified as Child-Pugh A. Beard et al. [33] compared surgical outcomes after HCC resection in cirrhotic and non-cirrhotic North American patients and found a cirrhosis prevalence of 73%. In the eastern centers, the prevalence of cirrhosis/chronic liver disease is lower than 54% [9].
In our study, the median alpha-fetoprotein value was 19 ng/mL (4.7-172.7), while in eastern studies, it was 46.55 ng/mL (15.01-369.47) [9]. Several studies have demonstrated the correlation between alpha-fetoprotein levels and tumor volume or the presence of satellite lesions [34]. In fact, eastern studies showed larger tumors and a higher frequency of satellite nodules [35]; thus, the lower median AFP values in our study were probably due to a lower tumor burden.
The preoperative NLR is the most studied biomarker in patients with HCC. Although several studies have suggested that high NLR may correlate with a poor prognosis [9, 10], others failed to detect this association [12]. Another issue is that the reported cut-off values of NLR were different across the studies, which could not provide a consistent standard for comparison among different populations. Additionally, some studies have used the same cut-off for OS and DFS [36].
OS and DFS represent different aspects of disease evolution and treatment; therefore, different cut-offs for each outcome are advisable. The present study showed that a high NLR (> 1.715) was a predictor of short OS in patients undergoing hepatectomy for HCC. The 5-year OS was 56% in the low NLR group and 40% in the high NLR group (P=0.018). Similarly, NLR > 2.745 was also a predictor of short DFS (p=0.047). A systematic review including 100 studies (40,559 patients) showed that a high NLR was associated with adverse outcomes in several solid neoplasms, including HCC [27]. Similarly, in a recent meta-analysis conducted by Xingshun et al. [37] including 20,475 patients with HCC, it was found that patients with low NLR (< 2.0) presented better OS when compared to patients with high NLR (> 4.0) (HR=1.80; 95%CI 1.59-2.04; P < 0.00001).
However, in the multivariate analysis, the NLR was not an independent factor associated with OS or DFS in our study, which was also observed in other studies, especially from western centers. In a study conducted by Sullivan et al. [12], evaluating patients with HCC showed that the NLR was not a predictor for OS after surgical or locoregional treatment (HR=1.09; 95%CI 0.95-1.24; P=0.23). Another study from the United Kingdom showed that the NLR was a predictor of DFS (HR=4.67; 95%CI 1.88-11.64; P=0.001) but was not a good predictor of OS in cirrhotic patients undergoing HCC resection. Interestingly, no relationship was found between NLR and prognosis in non-cirrhotic patients [38]. Thus, the presence of cirrhosis may impact the predictive value of NLR, justifying the heterogeneous results between the available studies.
Few studies have addressed the prognostic impact of other inflammatory markers in HCC patients [39]. In our study, we observed that high PLR (> 100.25) was an independent factor of DFS, which is consistent with recent studies [40]. Kaida et al. [41] evaluated patients with early-stage HCC who underwent resection and compared five inflammatory marker scores, showing that preoperative PLR was an independent predictor of recurrence. Similarly, Qing et al. [40] showed that increased preoperative platelet levels were associated with a higher recurrence rate following HCC resection. Thus, there is a potential association between platelet-derived markers and the prognosis of patients with HCC who underwent liver resection.
To date, few studies have evaluated the prognostic impact of MLR in HCC patients [42]. An interesting finding of our study was the prognostic impact of MLR on OS in patients with early-stage HCC (< 5 cm). This finding can be justified by the fact that activation of monocytes and macrophages usually occurs at earlier stages of tumor growth. Otherwise, in patients with larger lesions, other cells such as neutrophils and platelets play a predominant role in local invasion and metastatic dissemination [43].
Another independent factor associated with short OS in the present study was the presence of portal hypertension, which is in accordance with other studies [44]. In a meta-analysis comprising 2,285 HCC patients who underwent resection, the group of patients with portal hypertension presented short OS than the group without portal hypertension (HR=1.48; 95%CI 1.11-1.98; P=0.007) [45]. An AST level > 50 U/dL was an independent factor related to both OS and DFS. The exact mechanism underlying this finding is poorly understood; however, it might be explained by the fact that AST is exclusively present in hepatocytes and released into the circulation during liver inflammatory insults. Additionally, the reduced clearance in progressive chronic hepatic disease can lead to an increase in AST levels [46]. In our study, microvascular invasion was also an independent prognostic factor for recurrence. In fact, vascular invasion is frequently associated with higher recurrence rates due to aggressive biological behavior, represented by a greater volume of micrometastatic disease and a higher frequency of mural invasion [47].
This study is one of the first studies from a western center to evaluate the impact of the main inflammatory markers on the long-term outcomes after HCC resection, as well as in subgroups stratified by tumor size. Based on our findings, all the studied inflammatory markers are useful tools to predict long-term outcomes after liver resection in western patients. High NLR was able to stratify subgroups of patients with short OS and DFS, and increased PLR was a marker of short DFS, while high MLR was associated with short OS in patients with early HCC. In fact, these markers were able to identify subgroups of patients with poor clinical features, such as higher bilirubin levels, larger tumors, and a higher frequency of vascular invasion. Therefore, inflammatory indexes are promising tools for preoperative selection of patients who require strict postoperative follow-up or even potential candidates for new adjuvant strategy protocols.
However, our findings should be viewed with caution due to some limitations. The first was the retrospective nature of this study, which increases the risk of selection, confusion, and measurement biases. Another limitation was the small number of patients enrolled, which may impair statistical power, especially in the subgroup analysis. Thus, the insights provided herein should be confirmed by larger prospective studies.
In conclusion, our study suggested that a high preoperative NLR is associated with short OS and DFS, whereas a high PLR is an independent factor associated with short DFS. In the subset of patients with HCC < 5 cm, a high MLR is a predictor of short OS.