Introduction
Due to the burden of chronic HBV infection, China accounts for over 50% of all newly diagnosed liver cancer cases and deaths in the world, even though the total population in China is only 20% of the world [
1‐
3]. Although the age-standardized incidence rates of liver cancer have declined in China recently [
3‐
5], HCC still ranks as the second most common malignancy, with 360,00 incident cases reported per year, and the second cause of cancer death leading to 350,000 deaths per year in China [
5‐
8]. More importantly, several studies have shown that the overall average medical expenditure and economic burden of HCC management have dramatically increased in China [
9‐
11]. Hence, HCC imposes a significant economic burden on patients’ families and the health system.
Following a diagnosis of liver cancer, one immediate challenge in patient management is the determination of prognosis. Over the last several decades, many traditional clinicopathological prognostic factors and serum biomarkers have been widely applied to determine the prognosis. These score systems or strategies included, but were not limited to, serum alpha-fetoprotein (AFP), Child Turcotte Pugh (CTP), Barcelona Clinic Liver Cancer (BCLC), the Japanese Tumor Node Metastasis staging system, etc. These staging systems have been approved to be useful but are also limited by their complexity and subjectivity. For example, CTP scoring includes ascites and encephalopathy, subject to inter-observer variation [
12], and serum AFP is not sensitive in patients with small tumors. Recently, two simpler prognostic markers: Neutrophil to Lymphocyte Ratio (NLR) and the Albumin Bilirubin (ALBI) grade, are considered emerging prognostic indicators in HCC.
Both systematic and tumor micro-environmental inflammation contribute to cancer development and progression. NLR is one of the generic and straightforward biomarkers to indicate cellular immune response under different disease conditions. Hence, it is not surprising that emerging evidence has shown that NLR could be a useful prognostic index in many liver diseases, including HCC. Several meta-analyses have systematically evaluated the role of NLR as a prognostic biomarker in HCC [
12‐
14]. These works have approved that NLR was a reliable biomarker with prognostic potential for HCC, independent of various treatments. For example, one meta-analysis with 54 studies reported that NLR performed better than the conventional alpha-fetoprotein in predicting HCC survival [
12]. Similar findings have been reported in another meta-analysis encompassing 15 studies and 3094 HCC patients [
13].
ALBI grade is another mathematical model created by Johnson in 2015 based on the data of 1313 Japanese patients [
15], which can evaluate the liver function in patients with HCC. Unlike the CTP score, the ALBI grade only uses two simple objective parameters, enabling a better evaluation [
16]. Since then, the use of ALBI grade in HCC has gained wide attention [
15‐
20]. Gui and his colleagues found that ALBI grade demonstrated clear survival discrimination superior to CTP class in HCC patients with yttrium-90 radioembolization treatment [
17]. Even for patients with early-stage HCC, ALBI grade was strongly associated with recurrence and long-term survival and was sensitive enough to define the outcome [
18]. In a meta-analysis with 95 studies describing the relationship between HCC and ALBI, Bannaga and his colleagues reported that ALBI grade in HCC predicts survival better than alpha-fetoprotein and CTP score [
12].
In the current study, we retrospectively analyzed clinical data and outcomes of 144 HCC patients from our center. We found that the preoperative NLR and ALBI grade had good predictive value for the postoperative prognosis of patients with HCC. However, multivariable analyses only indicated NLR, not ALBI grade, was an independent prognostic factor in our cohort. More importantly, the combination of the NLR-ALBI score confers better prognostic value than using NLR or ALBI grade alone, implicating the effectiveness and feasibility of combining multiple risk factors for postoperative prognosis assessment.
Method
Patient enrollment
Patients with primary hepatocellular carcinoma (HCC) from Jan/2013 to Jan/2017 were recruited from Hepatology Clinic at the first people’s Hospital of Yibin. The inclusion criteria were as follows: (1) diagnosed with primary HCC without metastasis by post-operation pathology; (2) all patients underwent curative hepatectomy; (3) All patients did not receive tumor-related treatments before curative hepatectomy; (4) with complete medical record and follow-up. Patients with hepatic tumors other than HCC, or HCC with metastasis, or died for non-HCC-associated reasons were excluded from the analysis. After screening, 144 patients were identified and recruited using the hospital informatics system.
The study was approved by the Institutional Review Board of the First People’s Hospital of Yibin (IRB 2023003). Because of the retrospective design of our study and only de-identified data was collected, the request of informed consent was waived by the Institutional Review Board. All methods were carried out in accordance with relevant institutional guidelines and regulations.
Data collection and follow-up
Baseline clinical examination and tumor characteristics were collected and assessed retrospectively. The following information was extracted from patients’ medical records for analysis: age, sex, HBsAg positive, liver cirrhosis, blood chemistry, serum AFP level, pathological findings (tumor size, histological grade, number of tumors), and abdominal imaging at the time of HCC diagnosis. The tumor size was determined by either CT or MRI imaging at the diagnosis of HCC. The Albumin Bilirubin (ALBI) grade was calculated using the system described in 2015 by Johnson et al. [
15], and Edmondson and Steiner criteria [
21] were used to evaluate the histological differentiation of HCC. Child Turcotte Pugh (CTP) score was calculated based on the method created by Child CG and Pugh RN [
22].
Patients were followed once every six months after surgery. The last day for the follow-up of the current study was Dec/31/2019, with an average following time of 31.6 ± 1.6 months, ranging from 1 to 69 months. Survival was defined as the time interval between the date of HCC diagnosis and the death or last follow-up examination.
Statistical analysis
The data are presented as means ± standard deviations (SD) or percentages appropriately for the data type. A 2-tailed t-test or Chi-squared test was used to perform univariate analyses as appropriate. Then, these variables with a p-value < 0.05 on univariate analyses were further applied for the multivariate Cox proportional hazard regression analysis to determine hazard ratios and 95% confidence intervals associated with overall survival (OS) using the stepwise backward selection process. The risk levels of OS were defined based on the number of risk factors present, with Kaplan–Meier survival curves constructed for each risk level. Receiver operator characteristic (ROC) curves were used to determine optimal NLR cutoffs, and the cutoff points were selected by maximizing Youden’s index. All statistical analyses were conducted using GraphPad software (Version 5.01, GraphPad, CA, USA).
Discussion
Prognosis plays a critical role in patient management and decision-making, especially in the field of oncology. Determining relevant prognostic factors not only guides treatment planning but also helps us understand the pathogenesis and the natural course of the disease [
23]. In the current work, we evaluated the prognostic value of pre-operative NLR score and ALBI grade in predicting the OS of HCC patients underwent curative hepatectomy from our center. Our work indicated NLR, not ALBI grade, was an independent prognostic factor in our cohort. We also found the combination of the NLR-ALBI score confers better prognostic value than using NLR or ALBI grade alone.
Inflammation plays a vital role in the development and progression of HCC [
24,
25]. NLR, the ratio between neutrophil and lymphocyte counts, can reflect the potential balance between neutrophil-associated pro-tumor inflammation and lymphocyte-dependent anti-tumor immune function. As an indicator reflecting patients’ inflammatory status, NLR has been approved as a reliable index to predict the prognosis of various cancers, including HCC. In line with previous studies addressing the link of NLR with HCC [
12‐
14,
26], our cohort also demonstrated that NLR was associated with tumor size and TNM grade. More importantly, as Fig.
2A shows, the median survival of patients with NLR ≤ 2.6 was 54 months, while it was 27 months for these patients with NLR > 2.60, indicating that patients with higher NLR scores presented worse outcomes.
ALBI is another appealing clinical index to predict HCC treatment response and survival. It uses two simple live function tests: serum Albumin and Bilirubin exam, to calculate scores and category patients [
15]. The utility of ALBI has several advantages. First, it is objective and straightforward. The 2nd, as most HCC cases develop from chronic liver damage, liver functional assessment is of paramount importance in HCC patient management and decision-making. In a systemic review that included 20 studies with 11,365 patients, Geng and his colleagues concluded that higher ALBI was associated with poorer OS [
27]. More importantly, they also found that the correlation between the ALBI grade and poor long-term survival was independent of sample size, patient population, follow-up duration, and quality scores [
27]. Likewise, a similar conclusion has been reached in a most recent systemic review with 95 studies [
9]. In our cohort, however, we identified NLR, not ALBI, as an independent factor in our multivariate model, suggesting that NLR might be superior to ALBI in predicting patient outcomes.
It is clear that multiple clinicopathological factors contribute to and determine the prognostic outcome of HCC patients, such as liver function, pathology grade, treatment plan, etc. Therefore, using a single clinical index to evaluate patients” outcomes is irrelevant. Several index combinations have been reported, such as NLR and platelet-to-lymphocyte [
28], psoas muscle mass index with NLR [
29], and NLR combined with tumor burden score (TBS) [
30]. In this study, NLR combined with ALBI was used for the first time to predict the outcome of HCC. Our work found that these patients with higher NLR-ALBI scores had more extended hospital stays and worse outcomes than those with fewer scores (Table
2; Fig.
2C). Both univariable and multivariable analyses have indicated that the NLR-ALBI score was significantly associated with the OS of HCC patients (Table
3). ROC analysis revealed larger AUC (0.679, 95%CI 0.592–0.767) of NLR- ALBI score than these of NLR alone (0.618, 95%CI 0.526–0.710) and ALBI alone (0.533, 95%CI 0.437–0.629), as shown in Fig.
1. One critical factor reflecting the patient’s per-operative status is systematic inflammation status, which can be assessed by NLR. At the same time, ALBI grade is an index for evaluating the per-operative liver function. Therefore, the combination of NLR and ALBI grade will assess and reflect both patients’ inflammation status and liver function, which will be a better prognostic index for patients with HCC.
In summary, we concluded that NLR is a reliable and inexpensive biomarker and should be incorporated into other predictive models to improve prognostication following HCC treatment. The combination of NLR and ALBI showed a better prognostic performance than using NLR or ALBI alone. These findings may help physicians identify high risk HCC patients with poor outcomes and enable them to consider additional treatment plans and closing monitors of these patients. However, our work was limited in that it was a retrospective study with a relatively small sample size from a single medical center. An internal validation, as exampled by Facciorusso A and his colleagues in their work exploring the factors associated with the recurrence of advanced colorectal adenoma after endoscopic resection [
31], is also needed to unequivocally confirm the new model’s reliability and potential clinical application [
32]. More studies with large sample sizes are warranted to draw definitive conclusions regarding the predictive capabilities of the combination in determining the long-term outcome of HCC patients.
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