The diagnostic and prognostic values of Ki-67/MIB-1 expression in thyroid cancer: a meta-analysis with 6,051 cases

Figures & data

Figure 1 Flow diagram of reviewing and selecting studies.

Figure 2 Risk of bias of studies included in diagnosis with QUADAS-2 tool.

Table 1 Characteristics of studies included in diagnosis

First author	Country	Patients	Type of cancer	Type of control	Antibody	Test method	Threshold, %	TP	FP	FN	TN
Horii et al^Citation29	Japan	50	PTC, FTC, ATC	Adenomatous goiter, FA	Ki-67 monoclonal antibody	IHC	20	276	2	6	15
Huang et al^Citation34	China	160	PTC	FA, goiter	Mouse monoclonal antibody	IHC	5	103	9	0	128
Chou et al^Citation30	Taiwan	46	PTC, FVPTC	NG, normal tissue	Mouse monoclonal antibody anti-Ki-67	IHC	10	16	2	13	15
Nie et al^Citation35	China	26	PTC	TA, NG, toxic goiter	Anti-Ki-67	IHC	25	9	2	5	10
Liang et al^Citation36	China	200	PTC	NG, TA	Ki-67	IHC	25	93	1	7	99
Gan et al^Citation37	China	135	PTC	Adjacent tissue of thyroid carcinoma, normal tissue, NG, FA	Mouse monoclonal antibody	IHC	10	38	26	7	64
Wang et al^Citation38	China	94	PTC, FTC, MTC, ATC	NG, TA	Ki-67	IHC	10	20	0	45	29
Shang et al^Citation39	China	100	PTC, FTC, OCTC	PTA, FTA, OCTA	Anti-Ki-67	IHC	1.50	42	29	8	21
Cui et al^Citation63	China	87	PTC, FTC	TA, normal tissue	Mouse monoclonal antibody	IHC	10	35	3	19	20
Feng et al^Citation40	China	199	PTC, FTC, MTC	NG, FA, adjacent tissue of thyroid carcinoma	Ki-67	IHC	5	58	16	18	107
Jin et al^Citation64	China	79	PTC, FTC, MTC, ATC	TA, normal thyroid gland tissue beside adenoma	Mouse monoclonal antibody	IHC	25	39	3	17	20
Huang et al^Citation42	China	70	PTC	Thyroid hyperplasia, TA	Anti-Ki-67	IHC	10	20	9	10	31
Li and Du^Citation43	China	136	PTC	NG, NG with adenoma hyperplasia, NGWPH	Anti-Ki-67	IHC	10	55	27	0	54
Hao^Citation44	China	236	PTC	NG, TA	Ki-67	IHC	ND	17	2	101	116
Song et al^Citation27	China	592	PTC	NG, nonmaligant follicular adenoma	Mouse monoclonal antibody	IHC	10	179	56	262	95
Tan et al^Citation31	Turkey	39	PTC, FTC	FA	Ki-67	IHC	5	8	10	16	5
Zeng et al^Citation45	China	108	TC	Normal tissue	Mouse monoclonal antibody	IHC	5	46	11	22	29
Qin et al^Citation46	China	120	PTC	NG, normal tissue	Anti-Ki-67	IHC	10	25	78	15	1
Zhao et al^Citation47	China	129	PTC	Multinodular goiters, follicular adenomas, Hashimoto’s thyroiditis	Ki-67	IHC	ND	34	22	9	64
Jiang et al^Citation48	China	63	PTC	TA	Mouse monoclonal antibody	IHC	10	23	2	12	26
Yao et al^Citation49	China	103	PTC, FTC, MTC, ATC	Normal tissue, NG, FA	Mouse monoclonal antibody	IHC	25	60	10	8	25
Yang et al^Citation50	China	55	FTC	FA	Mouse monoclonal antibody	IHC	5	15	6	17	17
Li^Citation51	China	246	PTC	Normal tissue, NG, NGWPH	Mouse monoclonal antibody	IHC	10	68	22	8	68
Shi et al^Citation52	China	130	TC	TA, NG, normal thyroid gland tissue	Rabbit monoclonal antibody	IHC	10	42	10	8	70
Zhang et al^Citation28	China	146	PTC	Multinodular goiter	Ki-67	IHC	1.65	57	9	19	61
Maruta et al^Citation23	Japan	108	FC	FA	Anti-Ki-67	IHC	50	47	35	21	5
Guo et al^Citation53	China	117	PTC, FTC, ATC	TA, normal thyroid tissues	Anti-Ki-67	IHC	10	62	2	87	30
Wang et al^Citation54	China	33	PTC	Hyalinizing trabecular tumor	MIB-1	IHC	10	20	10	0	3
Zhou et al^Citation55	China	120	PTMC	TA, NG, Hashimoto’s thyroiditis	Anti-Ki-67	IHC	25	34	6	46	34
Li et al^Citation56	China	370	PTC	Benign thyroid nodule	Mouse monoclonal antibody	IHC	1.00	112	48	68	142
Xu et al^Citation57	China	62	PTC	Thyroid benign tumor	Ki-67	IHC	5	32	3	14	13
Wang et al^Citation58	China	95	PTC	NGWPH	Ki-67	IHC	10	26	44	19	6
Zhou et al^Citation24	China	158	PTMC	NG, TA, Hashimoto’s thyroiditis	Mouse monoclonal antibody	IHC	25.00	50	7	58	43
Zhu et al^Citation59	China	96	PTC	Thyroid hyperplasia	Anti-Ki-67	IHC	5	40	10	24	22
Li and Pu^Citation60	China	150	PTC	Follicular adenoma, normal tissue	Ki-67	IHC	5	18	9	32	91
Li and Zhang^Citation61	China	120	PTC	TA, NG, normal tissue	Mouse monoclonal antibody	IHC	10	25	8	5	82
Feng and Wang^Citation62	China	60	MTC	Adjacent tissue of thyroid carcinoma	Mouse monoclonal antibody	IHC	1	36	0	6	18

Abbreviations: ATC, anaplastic thyroid cancer; FA, follicular adenoma; FN, false negative; FP, false positive; FTA, follicular thyroid adenoma; FTC, follicular carcinoma; FVPTC, follicular variant of papillary thyroid carcinoma; IHC, immunohistochemistry; MTC, medullary thyroid carcinoma; ND, no data; NG, nodular goiter; NGWPH, nodular goiter with papillary hyperplasia; PTA, papillary thyroid adenoma; OCTA, oxyphilical cell thyroid adenoma; OCTC, oxyphilical cell thyroid carcinoma; PTC, papillary thyroid carcinoma; PTMC, papillary thyroid microcarcinoma; TA, thyroid adenoma; TP, true positive; TN, true negative.

Table 2 The relationships between Ki-67/MIB-1 expression and clinicopathologic parameters

Clinicopathologic parameters	Studies (n)	Test group		Control group		Heterogeneity		Meta-analysis model	OR (95% CI)	P-value
		Events	Total	Events	Total	I^2, %	P-value
Age (45 years)	10	124	303	91	239	0.00	0.806	Fixed-effect analysis	1.71 (1.14–2.57)	0.01
Tumor size (4 cm)	5	35	165	76	730	2.00	0.395	Fixed-effect analysis	1.86 (1.17–2.96)	0.008
Lymph node metastasis	15	233	345	226	509	50.20	0.014	Random-effect analysis	2.49 (1.42–4.39)	0.002
Metastasis status	7	75	133	121	920	59.80	0.021	Random-effect analysis	6.96 (2.46–19.69)	<0.001
TNM stage	7	113	146	103	247	0.00	0.96	Fixed-effect analysis	6.56 (3.80–11.34)	<0.001
Extrathyroid extension	4	64	225	79	413	31.30	0.224	Fixed-effect analysis	1.91 (1.27–2.87)	0.002

Abbreviations: CI, confidence interval; OR, odds ratio; TNM, tumor node metastasis.

Table 3 The features of the studies relating Ki-67/MIB-1 to patients’ prognosis

Type of survival	First author	Country	Year	Patients	Age	Median FU	Test method	Antibody	Threshold, %	HR (95% CI)	P-value
DFS	Kjellman et al^Citation1	Sweden	2003	30	62	146 months	IHC	MIB-1	1.85	4.93 (1.91–12.77)	0.001
	Ito et al^Citation12	Japan	2010	371	49	125 months	IHC	Anti Ki-67 antibody	1	4.13 (2.19–7.75)	<0.001
	Miyauchi et al^Citation22	Japan	2013	390	50.8	88 months	IHC	Anti Ki-67 antibody (clone MIB-1)	>10	15.33 (4.13–56.96)	<0.001
Mortality	Wang et al^Citation33	Sweden	1996	21	53	10.5 years	IHC	Ki-67	5	0.514 (0.086–3.089)	0.467
	Tisell et al^Citation26	Sweden	2003	36	45	20 years	IHC	Anti-Ki67	1	2.12 (0.862–5.233)	0.102
	Ito et al^Citation12	Japan	2010	371	49	125 months	IHC	Anti Ki-67 antibody	3	25.64 (2.49–250)	0.006
	Chen et al^Citation20	USA	2011	9	64.8	32.5 months	IHC	MIB-1	5	0.088 (0.008–1.026)	0.052
	Miyauchi et al^Citation22	Japan	2013	390	50.8	88 months	IHC	Anti Ki-67 antibody (clone MIB-1)	>10	34.08 (3.81–305.16)	0.002
	Gnemmi et al^Citation14	France	2014	82	ND	68 months	IHC	MIB1	4	6.126 (1.662–22.574)	0.007
	Jovanovic et al^Citation32	Macedonia	2015	20	51.2	73 months	IHC	MIB-1	6.50	24.25 (3.63–161.99)	0.001
	Feng and Wang^Citation62	China	2014	42	53.2	7.8 years	IHC	MIB-1	1	2.28 (0.61–8.55)	0.228
DRFS	Gnemmi et al^Citation14	France	2014	82	ND	68 months	IHC	MIB-1	4	7.322 (3.141–17.07)	<0.001

Abbreviations: CI, confidence interval; DFS, disease-free survival; DRFS, distant recurrences-free survival; FU, follow-up; HR, hazard ratio; IHC, immunohistochemistry; ND, no data.

Table 4 Quality assessment of included studies according to NOS

Studies		Selection				Comparability	Outcome			Total
First author	Year	A	B	C	D	E	F	G	H	score
Kjellman et al^Citation1	2003	*	*	*			*	*	*	6
Feng and Wang^Citation62	2015	*	*	*			*	*	*	6
Ito et al^Citation12	2010	*	*	*			*	*	*	6
Jovanovic et al^Citation32	2015	*	*	*			*	*	*	6
Gnemmi et al^Citation14	2014	*	*	*		*	*	*	*	7
Miyauchi et al^Citation22	2013	*	*	*			*	*		5
Chen et al^Citation20	2011	*	*	*			*	*	*	6
Wang et al^Citation33	1996	*	*	*			*	*	*	6
Tisell et al^Citation26	2003	*	*	*			*	*	*	6

Notes: A: representative of the exposed cohort; B: selection of the nonexposed cohort; C: ascertainment of exposure; D: demonstration that outcome of interest was not present at the start of study; E: comparability of cohorts on the basis of the design or analysis; F: assessment of outcome; G: adequacy of follow-up for outcomes to occur (≥2 years or outcomes occurred in all patients); H: adequacy of follow-up of cohorts (follow-up rate ≥75%).

Abbreviation: NOS, Newcastle–Ottawa scale.

Figure 3 Forest plots for the accuracy of Ki-67/MIB-1 for the diagnosis of thyroid cancer.

Notes: (A) Sensitivity; (B) specificity; (C) positive LR (LR+); (D) negative LR (LR−).
Abbreviations: CI, confidence interval; df, degrees of freedom; LR, likelihood ratio.

Figure 4 Forest plot of DOR of Ki-67/MIB-1 for the diagnosis of thyroid cancer.

Note: The pooled DOR of Ki-67/MIB-1 for the diagnosis of thyroid cancer was 8.54 (95% CI: 5.03–14.49).
Abbreviations: CI, confidence interval; df, degrees of freedom; DOR, diagnostic odds ratio; OR, odds ratio.

Figure 5 SROC curve for the accuracy of Ki-67/MIB-1 in the diagnosis of thyroid cancer.

Notes: The area under the SROC curve was 0.804 (SE =0.031). Q* represents the index to judge the accuracy of the diagnostic experiment.
Abbreviations: AUC, area under the curve; SE, standard error; SROC, symmetric receiver operating characteristic.

Figure 6 Forest plots of Ki-67/MIB-1 and clinicopathologic parameters in thyroid cancer patients.

Notes: (A) Age; (B) tumor size; (C) lymph node metastasis; (D) metastasis status; (E) TNM stage; (F) extrathyroid extension. Weights are from random-effects analysis.
Abbreviations: CI, confidence interval; OR, odds ratio; TNM, tumor node metastasis.

Figure 7 Meta-analysis evaluating the association between Ki-67/MIB-1 and DFS (fixed-effect analysis).

Note: The combined fixed-effect HR was 5.19 (95% CI: 3.18–8.46, P<0.001), indicating that high level of Ki-67/MIB-1 was associated with worse DFS.
Abbreviations: CI, confidence interval; DFS, disease-free survival; HR, hazard ratio.

Figure 8 Meta-analysis evaluating the association between Ki-67/MIB-1 and mortality (random-effect analysis).

Notes: The pooled fixed-effect HR was 3.56 (95% CI: 1.17–10.83, P=0.025), indicating that high level of Ki-67/MIB-1 was associated with increased of risk of mortality. Weights are from random-effect analysis.
Abbreviations: CI, confidence interval; HR, hazard ratio.

Figure 9 Assessment of publication bias for clinicopathologic parameters.

Notes: (A) Age; (B) tumor size; (C) lymph node metastasis; (D) metastasis status; (E) TNM stage; (F) extrathyroid extension.
Abbreviations: OR, odds ratio; SE, standard error; TNM, tumor node metastasis.

Figure 10 Assessment of publication bias for DFS and mortality.

Notes: (A) DFS; (B) mortality.
Abbreviations: DFS, disease-free survival; HR, hazard ratio; SE, standard error.

Table S1 Subgroup analysis evaluating the diagnostic value of Ki-67/MIB-1 in thyroid cancer

Groups	No of studies	Pooled sensitivity (95% CI)	Pooled specificity (95% CI)	DOR (95% CI)
Cut-off, %
≤5	12	0.70 (0.67–0.73)	0.80 (0.77–0.83)	7.49 (3.61–15.52)
10	15	0.56 (0.53–0.59)	0.67 (0.63–0.70)	7.73 (2.68–22.30)
>10	8	0.78 (0.75–0.81)	0.79 (0.74–0.84)	15.40 (3.41–69.62)
Types
PTC	21	0.63 (0.60–0.65)	0.74 (0.72–0.76)	8.22 (4.08–16.56)
PTMC	2	0.45 (0.37–0.52)	0.86 (0.77–0.92)	4.76 (2.48–9.17)

Abbreviations: CI, confidence interval; DOR, diagnostic odds ratio; PTC, papillary thyroid carcinoma; PTMC, papillary thyroid microcarcinoma.

Table S2 Subgroup analysis evaluating the prognostic value of Ki-67/MIB-1 for mortality in thyroid cancer

Groups	Pooled HR	95% CI	Heterogeneity test		Statistical method
			I^2, %	P-value
Univariate cut-off, %
≤5	1.98	0.65–6.06	68.80	0.007	Random
>5	28.06	6.68–117.87	0.00	0.818	Random
<10	2.73	0.89–8.38	72.20	0.001	Random
Types
PTC	1.47	2.23–5.18	87.10	<0.001	Random
MTC	0.96	0.24–2.16	65.50	0.035	Random

Abbreviations: CI, confidence interval; HR, hazard ratio; MTC, medullary thyroid carcinoma; PTC, papillary thyroid carcinoma.

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