Pretreatment neutrophil–lymphocyte ratio: useful prognostic biomarker in hepatocellular carcinoma

Figures & data

Table 1 Prognostic value of pretreatment NLR in HCC patients treated with LT

First author	Year	Center location	n	LT type	Within MC, n (%)	Within UCSF criteria, n (%)	NLR cutoff	HR (Analysis method) (CI, p-value)	5-Year survival rate, high versus low NLR, (%, p-value)	Follow- up time (months) mean/median (range)	Proposed prognostic score using NLR	Comments
Agopyan et al^Citation32	2015	Los Angeles, USA	865	DDLT	717 (84)	789 (92)	Continuous variable	RFS (M) – 1.89 (1.15–3.10, 0.002)	−	30 (9–73)	Risk score (R). Monogram includes: nuclear grade, vascular invasion, downstaging, tumor size, AFP, NLR, cholesterol	Among pretransplant variables, only NLR, AFP, and Milan status were independent predictors of RFS. The risk score (R) used all clinicopathologic variables to predict RFS (C statistic 0.85)
Bertuzzo et al^Citation33	2011	Bologna, Italy	219	DDLT	138 (74)	−	5	OS (M) – 4.87 (2.47–9.58, <0.0001) RFS (M) – 19.14 (6.95–52.71, <0.0001)	RFS – (8 vs 93, <0.0001)	40 (1–146)	−	Only NLR and MVI were significantly predictive of OS and RFS on multivariate analysis. Ninety percent of patients with high NLR had MVI
Halazun et al^Citation34	2009	New York, USA	150	DDLT	104 (70)	126 (84)	5	OS (M) – 6.10 (2.29–16.29, <0.0001) RFS (M) – 19.99 (2.48–161.24, 0.005)	OS – (28 vs 64, 0.001) RFS – (25 vs 75, <0.0001)	37 (3–83)	Preoperative recurrence score: NLR and tumor size	On multivariate analysis, preop AFP level >400 and NLR were predictive for OS, and tumor size >3 cm and NLR were predictive for RFS. Preop recurrence score C statistic 0.74
Lai et al^Citation35	2013	Brussels, Belgium	146	DDLT	114 (78)	124 (85)	5.4	−	ITTS – (48 vs 65, 0.02)	50 (IQR: 22–100)	−	NLR was the best predictor of dropout from transplant waiting list but did not predict OS or RFS, while PLR best predicted RFS
Limaye et al^Citation36	2013	Florida, USA	160	DDLT	134 (84)	−	5	OS (M) – 2.22 (1.1–14, 0.021) RFS (M) – 67 (11–413, 0.001)	OS – (38 vs 68, 0.005) RFS – (27 vs 79, 0.01)	38 (1–116)	−	On multivariate analysis, preop AFP level >400, MVI, and NLR were predictive for OS, while only NLR was predictive for RFS
Motomura et al^Citation31	2012	Fukuoka, Japan	158	LDLT	94 (59)	−	4	RFS (M) – 6.24 (2.52–15, 0.0002)	OS – (57 vs 84, 0.002) RFS –(30 vs 89, <0.0001)	40	−	1, 3, and 5 years OS rates were higher in the low NLR group. NLR and MC were predictive of recurrence and RFS
Na et al^Citation37	2014	Seoul, South Korea	224	LDLT	133 (59)	−	6	OS (M) – 2.90 (1.40–6.00, 0.004) RFS (M) – 2.512 (0.987–6.391, 0.053)	−	68 (6–139)	NPF: NLR and CRP	Patients outside MC. Only NLR was predictive for OS. NLR was associated with RFS by univariate analysis only. On multivariate analysis, preop AFP level >100 and tumor size >5 cm were predictors of RFS. Preop CRP and NLR as well as the “NPF” were predictive of OS and RFS in patients outside MC
Parisi et al^Citation38	2014	London, UK	150	DDLT	150 (100)	−	5	−	−	28 (0–116)	−	NLR did not predict HCC recurrence or OS. The absence of neoadjuvant therapy and nonfulfillment of MC on explant histology were the only predictors of recurrence
Shindoh et al^Citation39	2014	Tokyo, Japan	124	LDLT	80 (65)	87 (69)	2.4	RFS (M) – 1.26 (1.06–1.62, 0.011)	−	102 (4–165)	Prognostic score: Tokyo criteria, AFP, and DCP	Beyond Tokyo criteria, MVI, AFP, DCP, and NLR were preop predictors of recurrence. Max AFP and DCP were better prognostic markers than NLR (higher sensitivity and specificity)
Wang et al^Citation40	2011	Guangdong, China	101	DDLT	65 (64)	56 (55)	3	OS (M) – 2.654 (1.419–4.964, <0.001) RFS (M) – 3.665 (1.799–7.466, <0.001)	OS – (20 vs 62, 0.001) RFS – (29 vs 65, 0.001)	34 (5–74)	Preoperative prognostic score model: HBV, MVI, and NLR	HBV-associated HCC, MVI, tumor number, and high NLR were independent prognostic factors of RFS and OS
Wang et al^Citation41	2015	Zhejiang, China	248	DDLT/LDLT	97 (39)	−	4	OS (M) – 1.097 (1.04–1.15, <0.001) RFS (M) – 1.088 (1.029–1.151, 0.003)	RFS – (49 vs 32, 0.015)	26 (0.2–134)	Model_OS=1000×TN+0.090×MD+0.528×AFP+0.487×VI+0.092×NLR Model_TFS=1.0 94×TN+0.094×MD+0.754×AF P+0.085×NLR – 0.024×Age	Tumor number and size, AFP, and NLR predict RFS. Tumor number and size, AFP, NLR, and MVI predict OS. All patients were male. Model_OS, AUC=0.806 Model_TFS, AUC=0.820
Xiao et al^Citation42	2013	Sichuan, China	280	DDLT/LDLT	−	−	4	RFS (M) – 1.758 (1.22–2.530, 0.002)	OS – (62 vs 30, <0.001) RFS – (61 vs 30, <0.001)	32 (13–144)	−	HBV-associated HCC, NLR, tumor size, and MVI were associated with RFS and OS. However, NLR only predicted RFS and not OS
Yoshizumi et al^Citation43	2013	Fukuoka, Japan	104	LDLT	52 (100)	−	4	RFS (M) – 4.02 (1.38–11.6, 0.011)	RFS – (42 vs 86, 0.0002)	58 (IQR: 24–96)	−	Cohort composed only of patients with recurrent HCC after resection or locoregional therapy. Nodule size + number >8 and NLR were predictive of RFS

Abbreviations: AFP, alpha fetoprotein; AUC, area under the curve; CRP, C-reactive protein; DCP, des-gamma-carboxyprothrombin; DDLT, deceased donor liver transplantation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HR, hazard ratio; IQR, interquartile range; ITTS, intention to treat survival; LDLT, living donor liver transplantation; LT, liver transplantation; M, multivariate analysis; MC, Milan criteria; MVI, microvascular invasion; NLR, neutrophil–lymphocyte ratio; NPF, new prognostic factor; OS, overall survival; PLR, platelet to lymphocyte ratio; RFS, recurrence-free survival; TFS, tumor-free survival; U, univariate analysis; UCSF, University of California, San Francisco.

Table 2 Prognostic value of pretreatment NLR in HCC patients treated with curative-intent resection

First author	Year	Center location	n	NLR cutoff	HR (Analysis method) (CI, p-value)	5-year survival rate, high vs low NLR (%, p-value)	Follow-up time (months) mean/median (range)	Proposed prognostic score using NLR	Comments
Chan et al^Citation46	2015	Hong Kong	324	5	−	−	44.6 (0.1–160)	−	All BCLC Stage 0/A. PNI was a predictor of OS and RFS; however, neither NLR nor PLR has any prognostic significance for RFS or OS
Fu et al^Citation47,*	2016	Shanghai	772	Preop NLR: 1.65 Postop NLR: 3.65	“IBS” (Preop NLR and postop NLR) OS (M) – 4.247 (2.786–6.473, <0.001) RFS – 2.111 (1.696–2.626, <0.001)	“IBS” (Preop NLR and postop NLR) OS – (69 vs 93) RFS – (39 vs 66)	39 (2–60)	IBS: Preop NLR and postop NLR	Preop NLR results were not reported separately, preop NLR was combined in IBS with postop NLR. Elevated IBS (persistently elevated NLR pre- and postop) predicted both OS and RFS
Fu et al^Citation48	2013	Guangdong	282	2	OS (M) – 1.434 (1.044–1.970, 0.023) RFS (M) – 1.362 (1.025–1.811, 0.033)	OS – (29 vs 50), <0.001 RFS – (20 vs 32), <0.001	29 (2–83)	−	HBV-associated HCC. NLR predicts OS and RFS along with tumor size, tumor number, MVI, and Child score
Goh et al^Citation49	2016	Singapore	166	4	−	−	23 (0–170)	−	Large HCC tumors (>10 cm). NLR was associated with OS, not RFS and only on univariate analysis. AFP and tumor rupture predicted OS whereas MVI and AFP predicted RFS
Gomez et al^Citation50	2008	Leeds	96	5	OS (M) – 1.031 (1.002–1.060, 0.033) RFS (M) – 2.59 (1.15–5.84, 0.02)	Median RFS – (8 vs 18 months), <0.01	30 (6–152)	−	On univariate analysis, MVI, NLR, and R1 resection were associated with but did not predict OS. NLR and R1 resection predicted RFS
Huang et al^Citation51	2015	Wenzhou	1659	Stratified into quartiles			−	−	Stratified NLR predicted OS along with tumor number, PVT, MVI, and Child-Pugh score
Huang et al^Citation52	2014	Guangdong	349	3			39	J	NLR was associated with OS only on univariate analysis but not on multivariate. Combined GPS and CLIP scores had the best prognostic value (C-index=0.705)
Ji et al^Citation53	2016	Guangzhou	321	2	OS (M) – 1.473 (1.083–2.004, 0.014) RFS (M) – 1.405 (1.076–1.833, 0.012)	OS – (30 vs 50), <0.001 RFS – (21 vs 35), <0.001	–	NLR combined with APRI	Preoperative NLR and APRI are independent predictors of RFS and OS, their combination provided the highest prognostic value for OS
Li et al^Citation54	2015	Chengdu	236	2.3	−	−	37 (±20)	X0	HBV–HCC only. NLR has no prognostic significance for RFS or OS. Postop NLR–PLR score predicted OS and RFS
Liao et al^Citation55	2014	Guilin	256	2.31	OS (M) – 1.639 (1.212–2.218, 0.001) RFS (M) – 1.690 (1.247–2.291, 0.001)	OS – (38 vs 76, <0.001) RFS – (30 vs 70, <0.001)	–	“RS” stratifies OS and RFS 0 to 5, 1 point given for: 1) NLR>2.3, 2) Tumor size >5 cm, 3) TNM Stage 3 4) AST level >40 (µ/L)	Preop NLR, tumor size, TNM stage, and AST level were independent predictors of RFS and OS
Liao et al^Citation56	2015	Chongqing	222	2.1	OS – 3.013 (1.633–5.561, <0.001) RFS – 1.619 (1.057–2.478, 0.027)		42	−	Single nodule small HCC. Preop NLR, postop TACE, and MVI predicted RFS, whereas only preop NLR and postop TACE predicted OS. AFP level not correlated with outcomes (however, high AFP group >400 had small sample size of 53)
Liao et al^Citation57,*	2016	Chongqing	387	NMLR 1.2	“NMLR” OS (M) – 4.247 (2.786–6.473, <0.001) OS – 19.307 (8.804–42.341, <0.001) RFS – 4.457 (2.254–8.812, <0.001)	−	44 (1.5–84)	NMLR	NLR was not a predictor of OS and RFS; however, an integrated NMLR was. Other predictors of OS were platelet count, MVI, tumor number and size, TNM staging, and intratumoral CD16/CD8; while other predictors of RFS were HBs Ag status, AFP, BCLC stage, and intratumoral CD16/CD8
Lu et al^Citation58	2016	Guangxi	963	2.81	OS (M) – 1.296 (1.074–1.563, 0.007) RFS (M) – 1.32 (1.06–1.65, 0.014)	OS – (31 vs 46, <0.001)	−	−	NLR was a predictor of OS and RFS in BCLC 0/A and B HCC, not in advanced BCLC C cases. Predictors of OS were preop NLR, tumor number and size, macrovascular invasion, presence of tumor capsule, and ALT. Predictors of RFS were NLR, AFP, macrovascular invasion, and tumor size
Mano et al^Citation59	2013	Kyushu	958	2.81	OS (M) – 3.745 (1.027–1.088, 0.0002) RFS (M) – 2.096 (1.002–1.060, 0.0361)	OS – (52 vs 73,<0.001)	−	−	Preop NLR was a predictor of both OS and RFS after HCC resection. Other predictors of OS were tumor stage, number and size, PVT, and serum albumin, whereas AFP, sum albumin, ICGR 15, and PVT also predicted RFS.
Okamura et al^Citation60	2016	Shizuoka	375	2.8	OS (M) – 2.69 (1.57–4.59, <0.001)	OS – (45 vs 76, <0.001)	41 (6–120)	−	TNM stage 1 only. NLR was the strongest independent prognostic risk factor for OS. Other factors included: Age, AFP, and DCP. However NLR did not predict OS in TNM stages 2 and 3
Peng et al^Citation61,*	2014	Sichuan	189	Increased versus decreased	Change in NLR (preop to postop). OS (M) -. 2.637 (1.356–5.128, 0.004) RFS (M) – 2.372 (1.563–3.601, <0.001)	OS – (53 vs 76, 0.003) RFS – (22 vs 54, <0.001)	33 (5–75)	−	Increased NLR, but not high preoperative NLR or postoperative NLR, helps to predict worse OS and RFS in patients with small HCC who underwent curative resection
Wang^Citation62	2015	New York	234	2.5	OS (M) – 4.9 (1.8–13.2, 0.002) RFS (M) – 2.2 (1.3–3.8, 0.005)	−	−	−	HBV–HCC. NLR predicted OS and RFS in the absence of liver fibrosis; however, it did not in the patients with fibrosis. PLR and PNI did not independently predict OS or RFS.
Yamamura^Citation63	2014	Nagoya	113	3.1	RFS (M) – 2.58 (1.43–4.58, 0.002)	−	30 (1–124)		NLR was the only inflammatory marker independently associated with RFS. PLR, PI, PNI, and GPS were not predictive of RFS

Note:

* Indicates variation from NLR score.

Abbreviations: AFP, alpha fetoprotein; ALT, alanine aminotransferase; APRI, aminotransferase/platelet count ratio index; AST, aspartate aminotransferase; BCLC, Barcelona clinic liver cancer; CLIP, Cancer of the Liver Italian Program; DCP, des-γ-carboxy prothrombin; GPS, Glasgow prognostic score; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HR, hazard ratio; IBS, inflammation-based score; ICGR, indocyanine green retention rate; M, multivariate analysis; MVI, microvascular invasion; NLR, neutrophil to lymphocyte ratio; NMLR, neutrophil and monocyte to lymphocyte ration; OS, overall survival; PI, prognostic index; PLR, platelet to lymphocyte ratio; PNI, prognostic nutritional index; PVT, portal vein thrombosis; RFS, recurrence-free survival; RS, risk score; TACE, transarterial chemoembolization; U, univariate analysis.

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