Neutrophil to lymphocyte ratio and albumin bilirubin grade in hepatocellular carcinoma: A systematic review

Table 1 studies describing the relation between hepatocellular carcinoma and Neutrophil to Lymphocyte Ratio in the last 5 years

Ref.	Type	Patients/Studies (n)	Summary of main clinical points
Kong et al[67]	Retrospective	292 patients	Combined preoperative fibrinogen with NLR was an independent predictor OS and DFS in patients with surgically resectable HCC
Hong et al[68]	Retrospective	441 patients	NLR was found to be predictive factor of long-term survival and able to identify patients with resectable HCC who benefit from neoadjuvant TACE
Cruz et al[69]	Retrospective	190 patients	Elevated baseline NLR was associated with higher rates of HCC tumour progression at two month follow-up imaging after TACE
Uchinaka et al[70]	Retrospective	176 patients	Combination of platelet count and neutrophil-lymphocyte ratio (COP-NLR) was an independent predictor for prognosis of HCC patients after hepatic resection
McVey et al[71]	Retrospective	422 patients	The objective of this retrospective study was to characterize the NLR on the transplantation waitlist and determine its prognostic utility in LT for HCC. NLR demonstrated a positive correlation with MELD-Na at LT (P < 0.001). However, NLR lost its statistical significance when MELD-Na was added to the Cox regression model (OS: HR = 1.46, P = 0.098) (recurrence: HR = 1.40, P = 0.115). NLR was a volatile marker on the waitlist that demonstrated a significant correlation and collinearity with MELD-Na temporally and at the time of LT. These characteristics of NLR bring into question its utility as a predictive marker in HCC patients
Sun et al[72]	Retrospective	47 patients	Pre-treatment NLR ≥ 3.09 is related to poor prognosis of young HCC patients implemented minimally invasive treatment (TACE/RFA). However, it is not an independent indicator for prognosis
Kabir et al[73]	Retrospective	132 patients	The preoperative NLR in combination with platelet to lymphocyte ratio was predictive of both OS and recurrence free survival in patients with HCC undergoing curative liver resection
Wong et al[74]	Retrospective	789 patients	Elevated NLR is associated with advanced cancer stage and aggressive tumour characteristics, such as large size, rupture, and invasion. NLR ≥ 3 was associated with early and overall recurrence after resection but varied with aetiology
Chon et al[75]	Retrospective	1697 patients	The tumour size, tumour number, AFP level, vascular invasion, CTP score, objective response after TACE, and NLR were selected as predictors of OS via multivariate Cox's regression model, incorporated into a 14-point risk prediction model called SNAVCORN score. The prognostic performance of the SNAVCORN score including NLR in patients with HCC treated with TACE was remarkable, much better than those of the conventional scores
Hong et al[76]	Retrospective	82 patients	A change in NLR after sorafenib therapy was associated with a better prognosis in patients with advanced HCC
Hu et al[77]	Retrospective	565 patients	NLR correlated with the BCLC stages, CTP score and tumour size. However, it was not correlated with Edmondson-Steiner histological grades for HCC
Shiraki et al[78]	Retrospective	478 patients	An elevated NLR (>  3.2) is predictive of a poor survival in patients with primary HCC showing normal AFP levels
Uchinaka et al[79]	Retrospective	135 patients	NLR was an independent predictor for OS in hepatectomy treated HCC
Hu et al[80]	Retrospective	545 patients	AFP and NLR offers better diagnostic performance than either marker alone for differentiating HCC from liver disease
Wu et al[81]	Retrospective	344 patients	HCC patients who receive radical liver resection, postoperative NLR ≥ 2.29 implicates poor prognosis. Moreover, postoperative NLR ≥ 2.41 suggests early recurrence, while NLR ≥ 2.15 suggests late recurrence
Wang et al[82]	Meta-analysis	17 studies	Elevated preoperative NLR had a close relationship with the OS, RFS and DFS of HCC. Additionally, preoperative NLR was associated with vascular invasion and tumour size
Gauln et al[83]	Retrospective	109 patients	Prognostic value of NLR was confirmed in noncirrhotic HCC patients who underwent curative-intent liver surgery. In HCC patients with cirrhosis, the prognostic role of NLR was not confirmed
Qi et al[84]	Meta-analysis	20475 patients; 90 studies	Low baseline NLR was significantly associated with better OS, RFS and DFS. Low post treatment NLR was significantly associated with better OS. Decreased NLR was significantly associated with OS, RFS and DFS
Tan et al[85]	Retrospective	402	Pre-ablation NLR was a valuable predictor in locally advanced HCC patients treated with RFA. NLR ≥ 2.2 indicated a poor prognosis
Najjar et al[86]	Systematic review	7902 patients with liver resection; 2929 patients with liver transplantation	Pretransplant NLR was most often predictive of HCC recurrence, RFS and OS. NLR was, however, more variably and less clearly associated with worse outcomes following liver surgical resection
Xu et al[87]	Meta-analysis	13 studies 1936 patients	Elevated pretransplant NLR had a close association with the OS, RFS DFS of patients undergoing liver transplantation for HCC, respectively. In addition, elevated NLR was associated with the presence of vascular invasion and Milan criteria
Chen et al[88]	Retrospective	287 patients	The combination of the NLR and the PLR, for predicting the survival time of patients with HCC who had received RFA was associated with developing distant intrahepatic recurrence, extrahepatic metastasis, shorter OS and RFS
Lué et al[89]	Retrospective	154 patients	NLR was found to be an independent prognostic indicator for OS in HCC patients treated with sorafenib
Liu et al[90]	Retrospective	760 patients	Combination of the NLR to the aspartate aminotransferase-to-alanine aminotransferase ratio was found to be an independent marker of poor prognosis in patients with HCC receiving TACE
Margetts et al[91]	Retrospective	1168 patients	Neutrophils alone, rather than lymphocytes, were independently associated with outcome
Min et al[92]	Meta-analysis	12979 patients	Elevated NLR had a close relationship with OS and DFS of liver cancer. It was also associated with tumour vascular invasion, multiple tumours, AFP ≥ 400 ng/ML, presence of HBV S Ag and cirrhosis
Liu et al[93]	Retrospective	793 patients	NLR plus prognostic nutritional index score had superior discriminative abilities, compared with either the NLR or PNI alone in predicting the outcomes of patients with unresectable HCC after TACE
Hung et al[94]	Retrospective	672 patients	In patients who had curative liver resection for HCC, NLR > 2.5 had larger tumour size, higher histology grade, and higher rates of tumour multiplicity and vascular invasion. After a median follow up of 76.3 mo, 437 (65.0%) patients had tumour recurrence. When patients had tumour recurrence, 5-year post-recurrent survival was best in the patients staying with NLR ≤ 2.5
Li et al[95]	Retrospective	724 patients	In HCC patients undergoing curative resection a prognostic index model, NγLR = [neutrophil count (109/L) × γ-glutamyl transpeptidase (U/L)]/[(lymphocyte count) (109/L) × U/L], was selected. Elevated NγLR predicted a worse OS and progression-free survival (PFS) for HCC patients
Jin et al[96]	Retrospective	556 patients	Platelet times neutrophil to lymphocyte ratio in hepatitis B related HCC within BCLC stage A was found to be a prognostic indicator of poor outcomes
Zhang et al[97]	Retrospective	756 patients	Investigated the outcome of synchronous hepatectomy and splenectomy in HCC. Splenectomy and NLR were found to be significant independent prognostic factors
Li et al[98]	Retrospective	81 patients	The preoperative NLR is a prognostic predictor after hepatectomy for HCC patients with portal/hepatic vein tumour thrombosis. NLR > 2.9 indicated poorer OS and DFS
Liu et al[99]	Prospective	160 patients	Elevated NLR is associated with the pathogenesis and progression of HBV related HCC. The study also identified that there was also reduced thymic output and hyperactivation of T lymphocytes which may contribute to the decrease of T lymphocytes, which could be also related to the pathogenesis of HBV related HCC
Son et al[100]	Retrospective	56 patients	Low NLR was significantly associated with better PFS and OS in patients with locally advanced HCC treated with radiotherapy
Taussig et al[101]	Prospective	86 patients	In 86 HCC treatment-naïve patients who had chemoembolization or radioembolization, NLR was found to be associated with early progressive disease after intra-arterial therapy of HCC
Yang et al[102]	Retrospective	1020 patients	NLR found to be independent prognostic factor for DFS in HCC patients undergoing hepatectomy
Personeni et al[103]	Prospective	98 patients	A study that randomized HCC patients to tivantinib or placebo. High NLR was associated with hazard ratio for overall survival (OS) of 1.58 [95% confidence interval (CI) 1.01; 2.47; P < 0.046], corresponding to median OS of 5.1 months vs 7.8 mo in patients with low NLR (P = 0.044). In contrast, time to progression was not significantly affected by NLR (P = 0.20). Multivariable model confirmed that both NLR > 3 (P = 0.03) and presence of vascular invasion (P = 0.017) were negatively associated with OS. After adjustment for vascular invasion, NLR independently predicted survival in both the placebo and the tivantinib cohort
Fu et al[104]	Retrospective	130 patients	Combination of preoperative Fibrinogen and NLR enlarges the prognostic accuracy of testing in HCC patients who underwent liver transplantation
Ji et al[105]	Retrospective	303 patients	Combining the preoperative aspartate aminotransferase to neutrophil ratio index and NLR increases the prognostic accuracy of testing in patients who underwent curative resection for HCC
Yang et al[106]	Retrospective	526 patients	Preoperative NLR ≥ 2.81 is an indicator of poor DFS and OS in patients with HCC undergoing surgery
D'Emic et al[107]	Retrospective	339 patients	Study evaluated the association between NLR and clinical outcomes in patients receiving SIRT. The results confirm that pre- and/or post-treatment NLR is predictive of clinical outcomes
Arai et al[108]	Retrospective	42 patients	Elevated preoperative NLR is an independent predictive risk factor for patients undergoing two-stage treatment combining reductive surgery and percutaneous isolated hepatic perfusion for multiple HCC with portal vein tumour thrombus. The median survival of patients with a preoperative NLR > 2.3 was 14.9 mo, whereas that of patients with a preoperative NLR ≤ 2.3 was 26.1 mo
Hu et al[109]	Retrospective	213 patients	Elevated preoperative NLR was found to be a reliable biomarker for assessing early recurrence of HCC after the initial hepatectomy
Lu et al[110]	Retrospective	963 patients	NLR is an independent predictor of OS and tumour recurrence after potentially curative resection in HCC patients of BCLC stages 0/A or B
Sun et al[111]	Meta-analysis	1687 patients 10 studies	Elevated NLR was significantly associated with poorer OS and poorer DFS in HCC patients treated with LT. In addition, poor prognosis was not altered by cut off values of NLR or types of LT
Tajiri et al[112]	Retrospective	163 patients	Pre RFA treatment NLR >  2.5 was significantly associated with recurrence in HBV-HCC
Huang et al[113]	Retrospective	1659 patients	NLR measurements were associated with worse OS from HCC patients who had liver resection with curative intent
Wang et al[114]	Retrospective	248 patients	NLR > 4 was associated with early tumour recurrence in HCC patients treated with LT
Xiao et al[115]	Retrospective	305 patients	NLR > 4 showed recurrence-free survival rates when compared to NLR ≤ 4 in HCC patients treated with LT
Liao et al[116]	Retrospective	222 patients	Preoperative NLR is a prognostic marker in HCC after curative resection
Li et al[117]	Retrospective	263 patients	The postoperative NLR predicted outcomes of hepatitis B virus-related HCC patients within Milan criteria after liver resection
Sukato et al[118]	Retrospective	176 patients	HCC patients with a normal NLR were found to have longer survival than individuals with a high NLR. HCC patients with BCLC stage C disease with elevated NLR may not derive benefit from yttrium-90 radioembolization
Gao et al[119]	Retrospective	825 patients	NLR ≥ 2.7 was a significant predictor of poor OS, and the survival period of patients with an NLR ≥ 2.7 decreased with more advanced BCLC and tumour node metastasis stage
Fan et al[120]	Retrospective	132 patients	High NLR and was associated with poor prognosis and metastasis in recurrent HCC patients treated with TACE
Okamura et al[121]	Retrospective	256 patients	NLR was an independent prognostic factor for overall, and recurrence-free survival in patients who undergo hepatectomy for HCC with curative intent

NLR: Neutrophil to lymphocyte ration; OS: Overall survival; DFS: Disease free survival; HCC: Hepatocellular carcinoma; TACE: Transarterial chemoembolization; LT: Liver transplantation; MELD-Na: Model for end-stage liver disease-Na; RFA: Radiofrequency ablation; PLR: Platelet to lymphocyte ratio; RFS: Recurrence free survival ; CTP: Child Turcotte Pugh score ; BCLC: Barcelona clinic liver cancer staging system; AFP: Alpha fetoprotein; HBV: Hepatitis B virus; SIRT: Selective internal radiation therapy.