Hepatocellular carcinoma (HCC) represents about 90% of primary liver cancers, and also, it is the 5th most common cancer in the world and the 3rd cause of cancer-related mortality as estimated by the World Health Organization [14].
As regards surgical treatment for HCC, initially it started with resection but soon grew to include liver transplantation (LT) which is potentially curative and has become increasingly more common and successful [7].
Although the Milan criteria lower the risk of HCC recurrence and improve the survival of those patients, still 15–20% experience recurrence after transplantation. So the outcome of liver transplantation depends on the recurrence of HCC as well as its progression post-LT [15].
The histopathological examination of the explant pathology to assess the microvascular invasion and the grade of differentiation was used to predict HCC recurrence as tumor biology is an important risk factor for recurrence [1].
So assessing tumor biology for the risk of recurrence noninvasively by biomarkers is essential. The measurement of inflammatory markers represents a significant tool to assess the risk of HCC recurrence post-LT as the proinflammatory effects of a systemic inflammatory response (SIR) have been linked with HCC [16].
Among the inflammatory indices, the NLR, the PLR, and CRP have been widely investigated as prognostic values for determining post-therapeutic HCC recurrence and survival [7].
In our study, regarding the etiology of the studied cases, 98 (98%) are HCV-positive. In fact, there are controversial reports on the influence of hepatitis C on the risk of HCC recurrence after LT.
However, Vasavada and Chan [17] reported an association of viral infection with lower 5-year recurrence-free survival (RFS) in the subgroup of hepatitis C patients as a result of rapid development of liver fibrosis after living-donor LT.
In the present study, the explant pathology of our studied cases post-LT revealed that microvascular invasion MVI was found in 7 (7%) of them; besides, HCC grade I was found in 52 (52%) while the rest showed HCC grade II.
These results agree with Mehta et al. [18] who conducted their study on 911 HCC patients and concluded that MVI was found in the explant pathology of 10 (10%) of patients, and also, 40% of their patients had HCC grade I and 45% had HCC grade II.
In our study, after 10 years of the follow-up period, we found out that the total number of patients with HCC recurrence was 11 (11%) out of 100 cases. In concordance with our results, Nissen et al. [19] who reported that 13 (11%) out of 122 HCC patients developed HCC recurrence post-LT during the 8 years of follow-up.
Therefore, it is necessary to identify different risk factors for tumor recurrence TR to refine the patient selection. Also, it is important to define recipients who need closer follow-up and to identify modifiable factors that may reduce the incidence of TR [20].
Concerning the correlation between different parameters and HCC recurrence, firstly the demographic data of the studied patients showed that there was significant relation regarding the age of the cases with mean (47.27 ± 4.92) years and HCC recurrence (P value = 0.01).
This is against the results reported by Chan et al. [21] who conducted their study on 126 patients and concluded that that age was not a significant predictor for HCC recurrence post-LT.
This may be attributed to that usually HCC patients aged > 60–70 years are not considered as potential candidates for LT because of the increased comorbidity in elderly patients, so most of the studied candidates are younger than that age as our study [21].
Regarding pre-transplantation data of the studied cases showed that there was a significant relation regarding AFP (ng/dl) with median (66 ± 50) and HCC recurrence (P value > 0.01) while no significant relation with NLR, PLR, and CRP.
This partially agrees with Citores et al. [22] who summarized 9 studies and found that elevated pre-LT AFP level is an independent risk factor for HCC recurrence in 8 out of 9 studies.
Regarding the systemic inflammatory markers, they reported that NLR was found to be associated with HCC recurrence in 6 out of 9 studies and CRP in 1 out of 2 studies, while PLR was not shown as an independent risk factor in any of the 4 studies in which it was analyzed [22].
So, the authors concluded that the utility of systemic inflammatory markers as prognostic markers for patient selection for LT is limited and they cannot be universally applied in all patients, and most of the data are based on very few retrospective studies, with most having small sample sizes [22].
On the contrary, Halazun et al. [23] were the first to demonstrate the link between NLR and liver malignancies in patients who underwent surgery for colorectal liver metastasis. After that, many studies identified NLR as an independent risk factor for HCC recurrence, along with microvascular invasion and/or tumor size and number in some studies, but not in others [24, 25] which disagree with our results.
Also, the prognostic significance of PLR for HCC recurrence after LT has been less extensively studied than that of NLR, but in a recent systematic review and meta-analysis including 899 patients from five studies, high PLR was associated with a significant increase of HCC recurrence after LT [26].
Moreover, Pinato et al. [27], Lai et al. [28], and Xia et al. [10] evaluated PLR as a post-therapeutic HCC prognostic marker.
In addition, a meta-analysis of 24 studies by Zheng et al. [29] comprising 6318 patients with HCC, confirmed that the NLR and PLR can be used as prognostic markers for predicting post-therapeutic HCC recurrence.
As regards post-transplantation data of our studied patients, it showed that there was a significant relation regarding those who had microvascular invasion in the explant pathology and HCC recurrence (P value >0.01). The previous data goes with Chan et al. [21] who studied 17 out of 126 patients with HCC recurrence following LT and concluded that the presence of microvascular invasion was an independent prognostic factor for HCC recurrence.
Therefore, pre-LT elevated alpha-fetoprotein (AFP) and the presence of microvascular invasion (MVI) have been identified as the most commonly independent predictors of overall survival OS and recurrence-free survival RFS in HCC patients post-LT [25] that goes with our results.
Moreover, in our study, the ROC curve of the predictive ability of AFP for detection of HCC recurrence post-LT showed that it can predict HCC recurrence with the best cutoff value of > 17.8 ng/ml with a sensitivity of 82% and specificity of 70%.
Interestingly, the 9 studies analyzing pre-LT AFP level, except for one [30], found AFP to be an independent risk factor for HCC recurrence [22] which supports our results.
Our results also were near to Berry and Ioannou [31] who reported that HCC recipients with serum AFP level > 15 ng/ml at transplant time had worse post-transplant mortality and shorter recurrence-free survival.
Also, Lai et al. [26] found that AFP > 200 ng/mL was the best prognostic factor with an area under the receiver operating characteristic curve (AUC) of 70.6.
Regarding the ROC curve of predictive ability of post-transplantation CRP in our study showed that it can predict HCC recurrence with the best cutoff value of > 0.85 (mg/dl) with a sensitivity of 73% and specificity of 71%.
This agrees with Kornberg et al. [32] who concluded that elevated CRP level > 3.5 mg/dl in post-transplant patients with HCC was an independent predictor of poor recurrence-free survival.
Also, several studies have reported that the elevated CRP level independently predicts poor outcomes in HCC patients undergoing living donor LT [33].
Moreover, it was found out that that elevated serum CRP was associated with more aggressive tumor behavior and spread pre- and post-LT [34]. Moreover, Na et al. [35], Mori et al. [36], and Kim et al. [37] reported the usefulness of using preoperative CRP for prognosis of HCC recurrence post-LT.
Regarding the relation between HCC recurrence and outcome post-LT in our study, it showed that HCC recurrence significantly affects the outcome of patients undergoing LT (p < 0.001).
This is in concordance with Chan et al. [21] who found that the prognosis of 17 (13.5%) out of 126 patients with HCC recurrence following LT patients was very poor (p < 0.001).
Finally, regarding the survival analysis according to the presence or absence of HCC recurrence in our study, it is concluded that the mean time to death (survival time) of the studied patients without HCC recurrence 89 (89%) after liver transplantation was 9 years with 95% confidence interval 8–10 years, while those with HCC recurrence 11 (11%) was 2.5 years with 95% confidence interval 1–4 years.
The previous data are near to Meischl et al. [38] who reported the median overall survival OS of the total study population post-LT was 11 years, while those with HCC recurrence had a significantly shorter survival with a median overall survival OS of 3.5 years with 95% CI.
Moreover, they concluded that the mean time to HCC recurrence post-LT was 2 years [38], which agrees with our results and the study conducted by Clavien et al. [39] who reported that HCC recurrence usually occurs in 8–20% of recipients and is usually seen during the first 2 years after LT.
The limitation of the current study is that it was a retrospective trial with a limited sample size, although the pro-inflammatory markers did not significantly affect the HCC recurrence, yet more retrospective studies with a larger number of patients are needed to reach the final decision on their role in the HCC recurrence.