Gastroenterol Res

Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access

Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc

Journal website http://www.gastrores.org

Original Article

Volume 12, Number 2, April 2019, pages 78-87

Prognostic Implications of Arginase and Cytokeratin 19 Expression in Hepatocellular Carcinoma After Curative Hepatectomy: Correlation With Recurrence-Free Survival

Figure 1. Expression of arginase-1 and CK19 in HCC. (a) High arginase-1 expression (× 200). (b) Low arginase-1 expression (× 200). (c) Arginase-1 is highly expressed in adjacent benign liver (× 12.5). (d) Positive CK19 expression (× 200). (e) Negative CK19 expression (× 200). (f) CK19 expression in adjacent benign bile duct epithelium (× 200). CK19: cytokeratin 19; HCC: hepatocellular carcinoma.

Figure 2. Prognostic significance of arginase-1 and CK19. Comparisons of recurrence-free survival and overall survival by CK19 (a, b), arginase-1 (c, d), and arginase-1/CK19 (e, f). CK19: cytokeratin 19.

**Table 1.** Associations of Arginase-1/CK19 Expression and Clinicopathologic Parameters in HCC
Variables	n	Arginase-1	CK19
HCC: hepatocellular carcinoma; n: number; HBV: hepatitis B virus; HCV: hepatitis C virus; TNM: tumor-node-metastasis; AFP: alpha-fetoprotein; CK19: cytokeratin 19.
Age				0.617			0.617
≥ 65	57	46	11		11	46
< 65	55	47	8		8	47
Sex				0.16			0.779
Male	81	70	11		13	68
Female	31	23	8		6	25
HBV				0.022			0.103
Present	20	20	0		6	14
Absent	92	73	19		13	79
HCV				1			0.615
Present	61	51	10		9	52
Absent	51	42	9		10	41
AFP				0.217			0.083
Low	62	54	8		7	55
High	50	39	11		12	38
Cirrhosis				0.602			1
Present	72	61	11		12	60
Absent	40	32	8		7	33
Tumor size
≥ 5 cm	29	21	8	0.089	5	24	1
< 5 cm	83	72	11		14	69
Tumor number				0.29			0.598
Solitary	73	63	10		11	62
Multiple	39	30	9		8	31
Grade				0.309			0.077
I-II	68	54	14		8	60
III-IV	44	39	5		11	33
Vascular invasion				0.044			0.273
Present	30	21	9		7	23
Absent	82	72	10		12	70
TNM stage				0.009			1
I-II	95	83	12		16	79
III-IV	17	10	7		3	14

Table 1. Associations of Arginase-1/CK19 Expression and Clinicopathologic Parameters in HCC

Variables

Arginase-1

CK19

High

Low

P value

Positive

Negative

P value

HCC: hepatocellular carcinoma; n: number; HBV: hepatitis B virus; HCV: hepatitis C virus; TNM: tumor-node-metastasis; AFP: alpha-fetoprotein; CK19: cytokeratin 19.

Age

0.617

≥ 65

< 65

Sex

0.16

0.779

Male

Female

HBV

0.022

0.103

Present

Absent

HCV

0.615

Present

Absent

AFP

0.217

0.083

Low

High

Cirrhosis

0.602

Present

Absent

Tumor size

≥ 5 cm

0.089

< 5 cm

Tumor number

0.29

0.598

Solitary

Multiple

Grade

0.309

0.077

I-II

III-IV

Vascular invasion

0.044

0.273

Present

Absent

TNM stage

0.009

I-II

III-IV

**Table 2.** Univariate Predictors for RFS and OS in Patients With HCC
Variables	n	RFS	OS
HCC: hepatocellular carcinoma; OS: overall survival; RFS: recurrence-free survival; HR: hazard ratio; CI: confidence interval; HBV: hepatitis B virus; HCV: hepatitis C virus; VI: vascular invasion; TN: tumor number; TNM: tumor-node-metastasis; AFP: alpha-fetoprotein; Arg-1: arginase-1; CK19: cytokeratin 19.
Age				0.816			0.371
≥ 65	57	1.079	0.786 - 0.57		1.534	0.594 - 3.96
< 65	76	1			1
Sex				0.562			0.517
Male	81	1.244	0.587 - 2.637		1.428	0.47 - 4.34
Female	31	1			1
HBV				0.258			0.905
Yes	20	1.573	0.74 - 3.346		0.928	0.2686 - 3.207
No	92	1			1
HCV				0.065			0.273
Yes	61	0.543	0.283 - 1.043		0.594	0.233 - 1.512
No	51	1			1
AFP				0.004			0.009
High	50	2.639	1.341 - 5.194		3.617	1.288 - 10.15
Low	62	1			1
Cirrhosis				0.052			0.446
Yes	72	0.524	0.275 - 0.999		0.694	0.275 - 1.759
No	40	1			1
Tumor size				0.282			0.200
≥ 5 cm	29	1.471	0.741 - 2.919		1.893	0.733 - 4.339
< 5 cm	83	1			1
TN				0.939			0.884
Multiple	39	1.027	0.974 - 0.523		0.93	0.349 - 2.48
Solitary	73	1			1
VI				0.0001			0.0007
Yes	30	3.675	1.906 - 7.088		5.142	1.987 - 13.31
No	82	1			1
Grade				0.00008			0.0002
I-II	68	1			1
III-IV	44	3.694	1.897 - 7.196		6.538	2.145 - 19.93
TNM stage				0.001			0.01
I-II	95	1			1
III-IV	17	3.547	1.765 - 7.129		3.574	1.378 - 9.265
Arginase				0.185			0.142
High	93	1.904	0.675 - 5.369		3.489	0.464 - 26.23
Low	19	1			1
CK19				0.0002			0.945
Positive	19	4.093	2.059 - 8.136		1.03	0.277 - 3.308
Negative	93	1			1
Arg-1/CK19				0.00008			0.963
High/positive	17	4.71	2.31 - 9.162		1.342	0.298 - 3.56
Others	95	1			1
Arg-1/CK19/TN				0.02			0.884
High/positive/multiple	7	3.556	1.371 - 9.221		0.93	0.349 - 2.479
Others	105	1			1
Arg-1/CK19/TNM stage			0.01			0.242
High/positive/III/IV	7	4.815	0.687 - 13.74		2.706	0.62 - 11.805
Others	105	1			1
Arg-1/CK19/VI		0.00008			0.082
High/positive/present	5	8.061	3.449 - 18.841		3.5	1.033 - 12.36
Others	107	1			1
Arg-1/TNM stage				0.02			0.028
High	93	2.881	0.99 - 8.382		6.091	0.778 - 47.7
Low	19	1			1
Arg-1/stage III-IV				0.03			0.272
High	10	4.394	0.925 - 20.87		2.93	0.343 - 25.167
Low	7	1			1
CK19/stage III-IV				0.338			0.972
Positive	3	1.847	0.55 - 6.191		0.962	0.111 - 8.322
Negative	14	1			1
Arg-1/VI				0.04			0.072
High	21	3.072	0.881 - 10.705		4.659	0.595 - 36.4
Low	9	1			1
CK19/VI				0.007			0.744
Positive	7	4.295	1.591 - 11.594		1.253	0.330 - 4.747
Negative	12	1			1

Table 2. Univariate Predictors for RFS and OS in Patients With HCC

Variables

RFS

95% CI

P value

95% CI

P value

HCC: hepatocellular carcinoma; OS: overall survival; RFS: recurrence-free survival; HR: hazard ratio; CI: confidence interval; HBV: hepatitis B virus; HCV: hepatitis C virus; VI: vascular invasion; TN: tumor number; TNM: tumor-node-metastasis; AFP: alpha-fetoprotein; Arg-1: arginase-1; CK19: cytokeratin 19.

Age

0.816

0.371

≥ 65

1.079

0.786 - 0.57

1.534

0.594 - 3.96

< 65

Sex

0.562

0.517

Male

1.244

0.587 - 2.637

1.428

0.47 - 4.34

Female

HBV

0.258

0.905

Yes

1.573

0.74 - 3.346

0.928

0.2686 - 3.207

HCV

0.065

0.273

Yes

0.543

0.283 - 1.043

0.594

0.233 - 1.512

AFP

0.004

0.009

High

2.639

1.341 - 5.194

3.617

1.288 - 10.15

Low

Cirrhosis

0.052

0.446

Yes

0.524

0.275 - 0.999

0.694

0.275 - 1.759

Tumor size

0.282

0.200

≥ 5 cm

1.471

0.741 - 2.919

1.893

0.733 - 4.339

< 5 cm

0.939

0.884

Multiple

1.027

0.974 - 0.523

0.93

0.349 - 2.48

Solitary

0.0001

0.0007

Yes

3.675

1.906 - 7.088

5.142

1.987 - 13.31

Grade

0.00008

0.0002

I-II

III-IV

3.694

1.897 - 7.196

6.538

2.145 - 19.93

TNM stage

0.001

0.01

I-II

III-IV

3.547

1.765 - 7.129

3.574

1.378 - 9.265

Arginase

0.185

0.142

High

1.904

0.675 - 5.369

3.489

0.464 - 26.23

Low

CK19

0.0002

0.945

Positive

4.093

2.059 - 8.136

1.03

0.277 - 3.308

Negative

Arg-1/CK19

0.00008

0.963

High/positive

4.71

2.31 - 9.162

1.342

0.298 - 3.56

Others

Arg-1/CK19/TN

0.02

0.884

High/positive/multiple

3.556

1.371 - 9.221

0.93

0.349 - 2.479

Others

105

Arg-1/CK19/TNM stage

0.01

0.242

High/positive/III/IV

4.815

0.687 - 13.74

2.706

0.62 - 11.805

Others

105

Arg-1/CK19/VI

0.00008

0.082

High/positive/present

8.061

3.449 - 18.841

3.5

1.033 - 12.36

Others

107

Arg-1/TNM stage

0.02

0.028

High

2.881

0.99 - 8.382

6.091

0.778 - 47.7

Low

Arg-1/stage III-IV

0.03

0.272

High

4.394

0.925 - 20.87

2.93

0.343 - 25.167

Low

CK19/stage III-IV

0.338

0.972

Positive

1.847

0.55 - 6.191

0.962

0.111 - 8.322

Negative

Arg-1/VI

0.04

0.072

High

3.072

0.881 - 10.705

4.659

0.595 - 36.4

Low

CK19/VI

0.007

0.744

Positive

4.295

1.591 - 11.594

1.253

0.330 - 4.747

Negative

**Table 3.** Multivariate Predictors for RFS and OS in Patients With HCC
Variables	RFS	OS
HCC: hepatocellular carcinoma; OS: overall survival; RFS, recurrence-free survival; HR: hazard ratio; CI: confidence interval; TNM: tumor-node-metastasis; AFP: alpha-fetoprotein; CK19: cytokeratin 19. *This P value was obtained from replacement of single variable CK19 to the combined variable in the Cox regression analysis.
AFP	1.629	0.613	0.7506	0.21	2.256	0.677	7.512	0.05856
Tumor grade	2.744	1.2402	6.072	0.01	5.9432	1.7066	20.696	0.00512
Vascular invasion	1.456	0.581	3.646	0.422	1.5537	0.4325	5.582	0.49947
TNM stage III/IV	1.848	0.8172	4.178	0.14	1.495	0.4721	4.734	0.49414
CK19	3.626	1.728	7.608	0.003	0.4419	0.122	1.601	0.21372
Arginase-1/CK19	3.125	1.5149	6.447	0.002*	0.4511	0.1241	1.639	0.22655*

Table 3. Multivariate Predictors for RFS and OS in Patients With HCC

Variables

RFS

95% CI

P value

95% CI

P value

HCC: hepatocellular carcinoma; OS: overall survival; RFS, recurrence-free survival; HR: hazard ratio; CI: confidence interval; TNM: tumor-node-metastasis; AFP: alpha-fetoprotein; CK19: cytokeratin 19. *This P value was obtained from replacement of single variable CK19 to the combined variable in the Cox regression analysis.

AFP

1.629

0.613

0.7506

0.21

2.256

0.677

7.512

0.05856

Tumor grade

2.744

1.2402

6.072

0.01

5.9432

1.7066

20.696

0.00512

Vascular invasion

1.456

0.581

3.646

0.422

1.5537

0.4325

5.582

0.49947

TNM stage III/IV

1.848

0.8172

4.178

0.14

1.495

0.4721

4.734

0.49414

CK19

3.626

1.728

7.608

0.003

0.4419

0.122

1.601

0.21372

Arginase-1/CK19

3.125

1.5149

6.447

0.002*

0.4511

0.1241

1.639

0.22655*