Significance of platelet count and platelet-based models for hepatocellular carcinoma recurrence

Table 1 Scoring of noninvasive models

Index	Formula
CLIP	Sum of:
	Child-Pugh: A = 0, B = 1, C = 2
	Tumor morphology: Uninodular and extension ≤ 50% = 0, multinodular and extension ≤ 50% = 1, massive or extension ≥ 50% = 2
	AFP: < 400 = 0, ≥ 400 = 1
	Portal vein thrombosis: no = 0, yes = 1
Pohl	Positive: AAR > 1 and PLT < 150
AARP	Positive: AAR > 1 or PLT < 150
AAR	AST/ALT
API	Sum of:
	Age (yr): < 30 = 0, 30-39 = 1, 40-49 = 2, 50-59 = 3, 60-69 = 4, ≥ 70 = 5
	PLT: ≥ 225 = 0, 200-224 = 1, 175-199 = 2, 150-174 = 3, 125-149 = 4, < 125 = 5
CDS	Sum of:
	PLT: > 340 = 0, 280–339 = 1, 220-279 = 2, 160-219 = 3, 100-159 = 4, 40-99 = 5, < 40 = 6
	ALT/AST: > 1.7 = 0, 1.2-1.7 = 1, 0.6-1.1 = 2, < 0.6 = 3
	PT: < 1.1 = 0, 1.1-1.4 = 1, > 1.4 = 2
APRI	AST × 100/PLT
FIB-4	Age × AST/PLT × ALT1/2
FibroQ	10 × Age × AST × PT/ALT × PLT
Lok	Lok index = exp (log odds)/[1 - exp (log odds)]
	Log odds = -5.56-0089 × PLT + 1.26 × AAR + 5.27 × PT
GUCI	Normalized AST × PT × 100/PLT
APGA	Log (index) = 1.44 + 0.1490 × log (GGT) + 0.3308 × log (AST) - 0.5846 log × (PLT) + 0.1148 × log (AFP + 1)
PAPAS	Log (index + 1) = 0.025 + 0.0031 × age + 0.1483 × log (ALP) + 0.004 × log (AST) + 0.0908 × log (AFP + 1) - 0.028 × log (PLT)

AAR: Aspartate aminotransferase/alanine aminotransferase ratio; AARP: AAR-platelet count score; AFP: Alpha-fetoprotein; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; APGA: Aspartate aminotransferase/platelet count/γ-glutamyl transpeptidase/alpha-fetoprotein index; API: Age/platelet count index; APRI: Aspartate aminotransferase/platelet count ratio index; AST: Aspartate aminotransferase; CDS: Cirrhosis discriminant score; CLIP: Cancer of the Liver Italian Program; FIB-4: Fibrosis index based on the four factors; FibroQ: Fibro-quotient; GGT: γ-glutamyl transpeptidase; GUCI: Goteburg University Cirrhosis Index; PAPAS: Platelet count/age/ALP/AFP/AST index; PLT: Platelet count; PT: Prothrombin time. AFP (ng/mL); Age (year); ALT (U/L); AST (U/L); GGT (U/L); PLT (10⁹/L); PT (international normalized ratio).

Table 2 Characteristics of patients stratified according to recurrence status

Parameter	Recurrence	No recurrence	P value
	(n = 76)	(n = 96)
Sex, male/female	63/13	76/20	0.537
Age, yr	54.6 ± 10.3	52.7 ± 10.6	0.231
Etiology, yes/no
HBV	51/25	70/26	0.407
Cirrhosis	23/53	36/60	0.321
Ascites	11/65	6/90	0.073
Laboratory results in U/L
ALT	49 (11-1315)	39 (7-1436)	0.291
AST	50 (16-1075)	40 (11-1493)	0.308
ALP	111 (30-732)	89 (36-867)	0.149
GGT	80 (12-623)	62 (14-914)	0.084
PLT as 109/L	136 (41-370)	117 (3-486)	0.055
PT (INR)	1.06 (0.82-1.63)	1.06 (0.73-1.62)	0.697
AFP, ≥ 200/< 200 ng/mL	38/32	36/50	0.122
Tumor
Size, ≥ 5/< 5 cm	57/19	37/59	< 0.001
Type, multiple/single	18/58	14/82	0.128
Vascular invasion, yes/no	8/68	6/90	0.308
Noninvasive model score
CLIP	1 (0-4)	1 (0-4)	0.027
Pohl, negative/positive	47/39	60/36	0.930
AARP, negative/positive	14/62	11/85	0.198
AAR	1.08 (0.13-3.29)	1.02 (0.09-4.85)	0.826
API	7 (1-10)	7 (2-10)	0.319
CDS	6 (2-9)	6 (3-9)	0.286
APRI	0.90 (0.16-19.71)	0.90 (0.17-55.71)	0.658
FIB-4	2.90 (0.51-17.98)	2.94 (0.40-81.57)	0.384
FibroQ	4.68 (0.48-22.82)	4.49 (0.14-108.25)	0.224
Lok index	0.56 ± 0.23	0.58 ± 0.22	0.600
GUCI	1.04 (0.14-19.32)	0.95 (0.17-83.56)	0.624
APGA	22.95 (6.03-89.35)	19.03 (5.81-92.94)	0.136
PAPAS	3.67 (1.52-9.40)	3.02 (1.67-5.75)	0.136
Survival in mo	23 (5-120)	87 (1-117)	0.003
Death, yes/no	69/7	18/78	< 0.001

AAR: Aspartate aminotransferase/alanine aminotransferase ratio; AARP: AAR-platelet count score; AFP: Alpha-fetoprotein; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; APGA: Aspartate aminotransferase/platelet count/γ-glutamyl transpeptidase/AFP index; API: Age/platelet count index; APRI: Aspartate aminotransferase/platelet count ratio index; AST: Aspartate aminotransferase; CDS: Cirrhosis discriminant score; CLIP: Cancer of the Liver Italian Program; FIB-4: Fibrosis index based on the four factors; FibroQ: Fibro-quotient; GGT: γ-glutamyl transpeptidase; GUCI: Goteburg University Cirrhosis Index; HBV: Hepatitis B virus; INR: International normalized ratio; PAPAS: Platelet count/age/ALP/AFP/AST index; PLT: Platelet count; PT: Prothrombin time. Values are expressed as mean ± SD, median (range), or n.

Table 3 Predictors of recurrence stratified according to recurrence time by Log-rank test

Variable	Recurrence, P value
	Overall	Early	Late
Men	0.726	0.768	0.848
Age ≥ 62 yr	0.080	0.006	0.530
HBV	0.143	0.046	0.875
Cirrhosis	0.259	0.134	0.957
Ascites	0.022	0.219	0.028
ALT ≥ 44 U/L	0.086	0.118	0.429
AST ≥ 55 U/L	< 0.001	0.005	0.001
ALP ≥ 116 U/L	< 0.001	0.011	0.001
GGT ≥ 144 U/L	< 0.001	0.004	0.007
PLT ≥ 148 × 109/L	0.021	0.376	0.009
PT (INR) ≥ 1.17	0.398	0.390	0.792
AFP ≥ 96 ng/mL	0.003	0.005	0.246
AFP ≥ 200 ng/mL	0.008	0.011	0.316
Tumor size ≥ 5 cm	< 0.001	< 0.001	0.001
Multiple tumors	0.125	0.169	0.471
Vascular invasion	0.063	0.205	0.150
CLIP ≥ 1	< 0.001	0.001	0.116
CLIP ≥ 2	< 0.001	< 0.001	0.386
Positive Pohl	0.748	0.683	0.993
Positive AARP	0.181	0.120	0.861
AAR ≥ 1.07	0.048	0.491	0.021
API ≥ 6	0.771	0.402	0.575
CDS ≥ 8	0.678	0.972	0.466
APRI ≥ 1.94	0.022	0.053	0.213
APRI ≥ 0.56	0.080	0.054	0.665
FIB-4 ≥ 4.3	0.044	0.130	0.152
FibroQ ≥ 6.36	0.025	0.131	0.084
Lok ≥ 0.33	0.836	0.698	0.870
Lok ≥ 0.70	0.078	0.592	0.026
GUCI ≥ 2.24	0.050	0.318	0.050
GUCI ≥ 0.65	0.125	0.088	0.757
APGA ≥ 26.9	< 0.001	< 0.001	0.333
PAPAS ≥ 2.41	< 0.001	0.002	0.034
PAPAS ≥ 3.62	< 0.001	0.001	0.024

AAR: Aspartate aminotransferase/alanine aminotransferase ratio; AARP: AAR-platelet count score; AFP: Alpha-fetoprotein; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; APGA: Aspartate aminotransferase/platelet count/γ-glutamyl transpeptidase/AFP index; API: Age/platelet count index; APRI: Aspartate aminotransferase/platelet count ratio index; AST: Aspartate aminotransferase; CDS: Cirrhosis discriminant score; CLIP: Cancer of the Liver Italian Program; FIB-4: Fibrosis index based on the four factors; FibroQ: Fibro-quotient; GGT: γ-glutamyl transpeptidase; GUCI: Goteburg University Cirrhosis Index; HBV: Hepatitis B virus; INR: International normalized ratio; PAPAS: Platelet count/age/ALP/AFP/AST index; PLT: Platelet count; PT: Prothrombin time.

Table 4 Comparison of clinicopathologic features

Variable	PLT			APGA			PAPAS
	< 148 × 109/L	≥148 × 109/L	P value	< 26.9	≥26.9	P value	< 2.41	≥2.41	P value
	(n = 111)	(n = 61)		(n = 105)	(n = 51)		(n = 43)	(n = 113)
HBV, yes/no	82/29	39/22	0.172	75/30	38/13	0.686	32/11	81/32	0.732
Sex, male/female	90/21	49/12	0.904	85/20	42/9	0.833	36/7	91/22	0.647
Median age in year	52.6	55.2	0.115	54	52.1	0.263	NA	NA	NA
Ascites, yes/no	8/103	9/52	0.113	12/93	4/47	0.489	5/38	11/102	0.958
Cirrhosis, yes/no	43/68	16/45	0.098	33/72	21/30	0.230	15/28	39/74	0.965
Tumor size, ≥ 5/< 5 cm	55/56	39/22	0.070	51/54	38/13	0.002	14/29	75/38	< 0.001
Tumor type, multiple/single	19/92	13/48	0.499	19/84	11/40	0.606	4/39	26/87	0.052
Vascular invasion, yes/no	11/100	3/58	0.252	7/98	6/45	0.440	2/41	11/102	0.482
Recurrence, yes/no	43/68	33/28	0.052	39/66	31/20	0.005	10/33	60/53	0.001
Median survival in mo	37.5	29.5	0.050	37.3	27.9	0.026	43.4	30.8	0.006

APGA: Aspartate aminotransferase/platelet count/γ-glutamyl transpeptidase/alpha-fetoprotein index; HBV: Hepatitis B virus; NA: Not applicable; PAPAS: Platelet count/age/alkaline phosphatase/alpha-fetoprotein/aspartate aminotransferase index; PLT: Platelet count.