Globally, HCC is reported to be the second most common cause of cancer-related death. Chronic HCV remains on the top of the etiologic factors, considered as a strong promoter of inflammation and hence hepatocarcinogenesis [18]. In recent years, despite the revolution in HCV treatment by the direct-acting antiviral agents (DAAs) with achievement of high rates of sustained virologic response (SVR), the risk of HCV-related HCC could not be fully eradicated, particularly in those with advanced liver disease [19]. Consequently, diagnosis of HCC at early stages seems crucial giving an optimum chance for successful curative treatment, but frequently a challenge due to the scarcity of symptoms until discovered at late stage. Besides, current screening strategies comprising ultrasound for high-risk patients (mainly those with cirrhosis) consume substantial amounts of resources, and sensitivity is often suboptimal [20].
For years, serum AFP has been used as the most useful serum marker for diagnosis of HCC. However, serum AFP is not always elevated to a diagnostic level in all patients, particularly in small HCC, and considerable numbers of patients with more advanced stages would be missed unless another diagnostic tool is used [21]. Thus, it seems implausibly demanding to require a biomarker that helps in diagnosis and follow-up of HCC after locoregional treatment.
Recent studies have raised the significance of the tumor microenvironment in the development, metastasis, and recurrence of HCC. Tumor-associated macrophages (TAMs) are copious in the tumor microenvironment and vital in tumor development and metastasis [22]. Upon activation of the resident liver macrophages (Kupffer cells) by various stimuli including hepatocyte death, it releases a variety of interleukins, cytokines, and reactive oxygen species which modulate hepatocellular growth. Soluble CD163 was shown to reflect macrophage activity in serum and can be regarded as a marker for activated macrophages. Thus, soluble CD163 has shown a promising capacity as a biomarker of the severity and outcome of various liver diseases, including HCC [23].
In this study, we aimed at evaluating the diagnostic value of serum level of sCD163 as a tumor marker for HCC and studying its prognostic performance before and after locoregional therapies.
Sixty subjects were included in the present study, classified into 2 groups: group I (HCC group) including 40 randomly selected patients with HCV-related liver cirrhosis and HCC (excluding BCLC class D) who underwent either RFA or TACE, and group II (LC group) including 20 age- and sex-matched patients with HCV-related liver cirrhosis only. Among the randomly selected HCC patients, 4 were excluded due to portal vein thrombosis; thus, 36 patients were subjected to locoregional treatment according to the selective criteria for intervention.
Among HCC patients, males were predominantly affected (28 males (70%) vs. 12 females (30%)); a result that is in accordance with a recent single-center Egyptian study that aimed at identifying the trend, possible risk factors, and any pattern change of HCC over a decade, [24] showing a significant increase in male proportion from 82.5 to 87.6% (p = 0.009), M/F from 5:1 to 7:1 in periods I (1993–1997) and II (1998–2002), respectively. This finding might be explained in part by exposure to risk factors and sex hormones. It has been speculated that estrogens, androgens, degree of iron deposition, and difference in ethnicity could modulate hepatocarcinogenesis and explain the higher incidence of HCC in men [25].
For HCC diagnosis, the present study did not demonstrate any significant difference in serum sCD163 levels between patients with HCC and LC patients (p =0.079), yet AFP showed a significant difference between the 2 groups with a median value much higher in HCC group (p < 0.001). These results might be explained by the fact that sCD163 expression is significantly increased in liver tissues of chronic HCV patients, correlated well with the degree of hepatic fibrosis and cirrhosis, which is in line with another recent publication confirming sCD163 as a fibrosis predictor [26]. Moreover, an anecdotal study reported elevated levels of plasma sCD163 in patients with acute and chronic viral hepatitis [27]. Taken together, all these findings could explain the poor diagnostic value of sCD163 in differentiating HCC from mere liver cirrhosis. That is why the difference in sCD163 level was insignificant between the 2 groups in our study.
Moreover, sCD163 shows an inferior sensitivity, specificity, and overall accuracy to that of AFP in discriminating HCC from LC groups. The AUC of sCD163 was lower than that of AFP (0.767 vs. 0.880), indicating that AFP had a better diagnosing accuracy.
Interestingly, in the present study, sCD163 was significantly higher among patients with portal vein invasion (p < 0.001). That result agreed with those made by Ling-Qun et al. [28] who stated that soluble CD163 was significantly higher among patients with microvascular invasion (p= 0.037). Most notably, sCD163 is a specific marker for the M2 macrophage which produces a variety of matrix metalloproteinase and chemokines such as MMP-2, CCL18, and CCL22 that facilitate cancer microvascular invasion [29].
Contradictory to our results, Konstantin et al. [30] stated that there was no association between sCD163 and vascular invasion.
On comparing the values of sCD163 and AFP before and after locoregional intervention, of notice, sCD163 showed a marked decline after intervention (3.1 ± 2.5 post-intervention vs. 6.5 ± 1.5 pre-intervention; p< 0.001), while AFP showed insignificant decline after intervention (p = 0.66). As observed in previous studies, sCD163 activity in HCC patients had a significant decrease after 1 month of intervention with TACE or RFA. Besides, its activity decreased close to the normal level, showing that serum CD163 activity appeared to be correlated with curative effect, thus might have an important value in post-treatment monitoring of HCC patients [30, 31].
Currently, there is a clinical need for monitoring the outcome of HCC prior to locoregional therapy to assess susceptibility and predict tumor response to locoregional therapies, and thus, an exploration of effective predictive indicators is of great significance and of great value in adopting timely treatment strategies to avoid recurrence and improve outcomes of HCC patients [32, 33]. To our knowledge, there is still limited number of studies that have investigated whether sCD163 could predict the prognosis of HCC patients treated with TACE or RFA. In the present work, sCD163 showed a good predictive value in comparing patients who were successfully eradicated and those who had failed locoregional treatment. At baseline, sCD163 had higher values in patients who had HCC recurrence after intervention as compared to eradicated cases (8.4 ± 0.4 vs. 6.1 ± 1.4 mg/L; p < 0.001). Also, during follow-up after intervention, there was a notable decline in sCD163 in eradicated cases from 6.1 ± 1.4 to 2.3 ± 1.4 mg/L (p < 0.001), while those who had HCC recurrence showed a significant increase from 8.4 ± 0.4 to 10.3 ± 1.6 mg/L (p = 0.022).
The diagnostic accuracy of both AFP and sCD163 was assessed for discriminating between patients with recurrent HCC and those with eradicated HCC. AUC of AFP was low both before and after intervention 0.528 (95% CI 0.311–0.744) and 0.642 (95% CI 0.374–0.910), respectively (p > 0.05), while sCD163 showed a significantly higher AUC, 0.986 (95% CI 0.000–1.000) and 0.994 (95% CI 0.000–1.000), respectively (p < 0.001). At baseline, the best cutoff of sCD163 to predict HCC recurrence was 7.8 mg/L, and post-intervention, it was 5 mg/L. Thus, this study highlights the importance of sCD163 as a prognostic predictor in ablative therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features. These findings agreed with Konstantin et al. [30] who found that patients with high level of basal soluble CD163 with cutoff ≥8.0 mg/L had shorter progression-free survival. Also, these results were supported by Shabo and Svanvik [34] who reported that soluble CD163 is not only a parameter of macrophage activation but also an indicator of the M2 polarization of tumor-associated macrophage which support tumor progression. Consistently, recent studies introduced by Mark et al. [35] reported that increased plasma concentration of the soluble form of CD163 “a marker of alternatively activated M2” has been associated with poor survival in HCC patients indicating that M2 macrophage may be a potential target for HCC immunotherapy.
Some limitations should be considered in the present work. The number of studied populations was relatively small; CD163 levels were not assessed at different stages of HCC as regards tumor size and number; the follow-up period had to be extended to a more prolonged time.
