Clinicopathological and prognostic significance of Ki-67 immunohistochemical expression in gastric cancer: a systematic review and meta-analysis

Figures & data

Figure 1 Flow diagram of the meta-analysis process.

Table 1 Characteristics of the included studies

Reference	Country	Case number	Gender (m/f)	Age (y)	Detection method (cutoff)	Increased Ki-67, n (%)	Survival analysis	HR (95% CI)	HR (obtained)
Joo et al (2006)^Citation25	Korea	118	84/35	52/67 (<59 y/≥59 y)	IHC (strong staining)	62 (52.5)	NR	NR	NR
Chen et al (2008)^Citation7	China	86	57/29	Mean 57.6	IHC (>10%)	64 (74.4)	OS	1.62 (1.45–1.81)	Curve
Tsamandas et al (2009)^Citation8	Greece	110	71/39	Mean 66.0	IHC (>5%)	15 (13.6)	OS	2.15 (1.07–4.32)	Direct
Czyzewska et al (2009)^Citation19	Poland	100	67/33	34/65 (<60 y/≥60 y)	IHC (>50%)	37 (37.0)	OS	1.12 (0.86–1.46)	Curve
Lee et al (2010)^Citation20	Korea	245	171/74	202/43 (≤65 y/>65 y)	IHC (>10%)	164 (66.9)	OS	0.56 (0.38–0.83)	Direct
Zhao et al (2010)^Citation26	China	316	NR	Mean 58.1	IHC (score ≥5)	196 (62.0)	NR	NR	NR
Yu et al (2012)^Citation9	China	315	165/150	177/138 (<60 y/≥60 y)	IHC (>50%)	76 (24.1)	OS	1.75 (1.13–2.34)	Direct
Xiao et al (2013)^Citation21	Japan	431	301/130	Mean 66.4	IHC (score ≥1)	362 (84.0)	OS	0.98 (0.82–1.17)	Direct
Kang et al (2013)^Citation22	Korea	184	123/61	Mean 61.0	IHC (>10%)	100 (54.3)	OS	0.18 (0.03–1.06)	Direct
He et al (2013)^Citation22	China	166	113/53	43/38 (<60 y/≥60 y)	IHC (>25%)	94 (56.0)	OS	1.85 (1.30–2.63)	Direct
Ayed et al (2014)^Citation11	Tunisia	54	34/20	21/33 (≤50 y/>50 y)	IHC (>5%)	11 (20.4)	OS	4.17 (1.08–16.1)	Direct
Ezziddin et al (2014)^Citation12	Germany	74	42/32	Mean 62.5	IHC (>10%)	14 (18.9)	OS	3.10 (1.40–6.90)	Direct
Yang et al (2014)^Citation14	China	159	118/41	Mean 58.0	IHC (>30%)	115 (72.3)	OS	1.84 (1.21–2.80)	Curve
Zhou et al (2015)^Citation27	China	40	28/12	18/22 (≤60 y/>60 y)	IHC (>5%)	28 (70.0)	NR	NR	NR
Li et al (2015)^Citation15	China	69	51/18	Mean 55.0	IHC (>50%)	42 (60.9)	OS	1.62 (1.28–2.05)	Curve
Yang et al (2015)^Citation13	China	161	108/53	NR	IHC (>50%)	98 (60.9)	OS	2.50 (1.34–4.65)	Direct
Deng et al (2016)^Citation23	China	62	48/14	Mean 63.4	NR	28 (45.2)	OS	1.56 (0.72–3.38)	Direct
Huang et al (2016)^Citation17	China	693	515/178	Mean 60.3	IHC (>50%)	335 (48.3)	OS	1.46 (1.22–1.75)	Direct
Wang et al (2016)^Citation17	China	173	117/56	NR	IHC (>50%)	114 (65.9)	OS	2.97 (1.94–4.55)	Direct
Zhu et al (2016)^Citation18	China	150	100/50	NR	IHC (>50%)	89 (59.3)	OS	2.93 (1.52–5.65)	Direct
Badary et al (2017)^Citation28	Egypt	42	26/16	Mean 53.0	IHC (>10%)	22 (52.4)	NR	NR	NR
Zhang et al (2017)^Citation24	China	77	44/33	41/36 (≤48 y/>48 y)	IHC (>5%)	48 (62.3)	OS	1.43 (0.67–3.04)	Direct

Note: Age data shown as mean or number of patients per the age ranges specified in parentheses.

Abbreviations: CI, confidence interval; f, female; HR, hazard ratio; IHC, immunohistochemistry; m, male; NR, not reported; OS, overall survival; y, years.

Figure 2 HRs and 95% CIs in studies assessing the relationship between Ki-67 expression and OS.

Abbreviations: CI, confidence interval; HR, hazard ratio; IV, inverse variance; OS, overall survival; SE, standard error.

Figure 3 Forest plot of studies evaluating the association between Ki-67 and clinical parameters (older vs younger age) in gastric cancer with fixed-effects model.

Abbreviations: CI, confidence interval; M–H, Mantel–Haenszel.

Figure 4 Forest plot of studies evaluating the association between Ki-67 and clinical parameters (male vs female gender) in gastric cancer with fixed-effects model.

Abbreviations: CI, confidence interval; M–H, Mantel–Haenszel.

Figure 5 Forest plot of studies evaluating the association between Ki-67 and clinical parameters (N+ vs N− lymph node metastasis) in gastric cancer with fixed-effects model.

Abbreviations: CI, confidence interval; LNM, lymph node metastasis; M–H, Mantel–Haenszel.

Figure 6 Forest plot of studies evaluating the association between Ki-67 and clinical parameters (large vs small tumor size) in gastric cancer with fixed-effects model.

Abbreviations: CI, confidence interval; M–H, Mantel–Haenszel.

Figure 7 Forest plot of studies evaluating the association between Ki-67 and clinical parameters (III+IV vs I+II TNM stage) in gastric cancer with fixed-effects model.

Abbreviations: CI, confidence interval; M–H, Mantel–Haenszel.

Figure 8 Forest plot of studies evaluating the association between Ki-67 and clinical parameters (low vs well/moderate differentiation) in gastric cancer with random-effects model.

Abbreviations: CI, confidence interval; M–H, Mantel–Haenszel.

Table 2 Association of Ki-67 expression and clinicopathological parameters

Clinicopathological parameters	Number of studies	Number of patients	OR (95% CI)	P-value	Heterogeneity
					I^2 (%)	P-value
Age (older vs younger)	8	1,868	1.44 (1.19–1.75)	0.0002	0	0.43
Gender (male vs female)	8	1,578	1.00 (0.76–1.25)	0.98	0	0.54
Lymph node metastasis (N+ vs N−)	9	1,858	1.49 (1.20–1.84)	0.0002	50	0.04
Tumor size (large vs small)	6	1,718	1.37 (1.12–1.68)	0.002	36	0.17
TNM stage (III+IV vs I+II)	7	773	2.28 (1.66–3.12)	<0.00001	46	0.09
Differentiation (low vs well/moderate)	8	735	1.76 (1.02–3.03)	0.04	72	0.0007

Abbreviations: CI, confidence interval; N, node; OR, odds ratio.

Table 3 Subgroup analysis of pooled HR for gastric cancer patients with Ki-67 overexpression

Subgroup	Studies	Pooled HR	95% CI	P-value	Model	Heterogeneity I^2 (%)	P-value
Ethnicity
Asian	14	1.54	1.25–1.89	<0.0001	Random	82	<0.00001
Caucasian	4	2.04	1.08–3.86	0.03	Random	71	0.01
Cutoff of staining
<50%	10	1.52	1.09–2.12	0.01	Random	78	<0.00001
≥50%	7	1.78	1.40–2.27	<0.0001	Random	72	0.002
Number of patients
<100	6	1.64	1.49–1.81	<0.00001	Fixed	0	0.48
≥100	12	1.51	1.15–1.97	0.003	Random	84	<0.00001

Abbreviations: HR, hazard ratio; CI, confidence interval.

Figure 9 Funnel plot and Begg’s and Egger’s tests for evaluation of potential publication bias.

Abbreviations: HR, hazard ratio; SE, standard error.

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