Evolution and current status of the subclassification of intermediate hepatocellular carcinoma

Table 1 Bolondi criteria

BCLC sub-stage	B1	B2	B3	B4
CPT score	5-7	5-6	7	8-91
Beyond Milan and within Ut-7	In	Out	Out	Any
ECOG (tumor related) PS	0	0	0	0-1
PVT	No	No	No	No
1st option	TACE	TACE or TARE		BSC
Alternative	LT TACE + ablation	SOR	Research trials TACE SOR	LT2

¹With severe/refractory ascites and/or jaundice.

²Only if Up-to-7 IN and PS0. CPT: Child Pugh score; BSC: Best supportive care; LT: Liver transplantation; SOR: Sorafenib; TACE: Transcatheter arterial chemoembolization; TARE: Transarterial radioembolization; PVT: Portal vein thrombosis; Ut-7: Up to-7 criteria.

Table 2 Studies validation and modification of Bolondi criteria

Patients (n)	Treatment	Median follow-up	Ref.	B1	B2	B3	B4	Independent risk factor of survival
80	LR, TACE	28.19 mo	Ciria et al[9]	OS rate: 43.75%; 5-yr survival rate (62.9%)	OS rate: 40%; 5-yr survival rate (28.1%)	OS rate: 11.25%; 5-yr survival rate (28.1%)	OS rate: 5%; 5-yr survival rate (15.1%)	Total bilirubin, subclassification stages B2 and B3-4 vs B1
90	TAE	NR	Scaffaro et al[10]	Mean OS: 33.6 mo	Mean OS: 28.6 mo	Mean OS: 19.0 mo	Mean OS: 13.0 mo	NR
580	TAE	NR	Wang et al[12]	Median OS: 28.8 mo; 1, 3, 5-yr survival rate: 80%, 39.5%, 21.4%	Median OS: 15.6 mo; 1, 3, 5-yr survival rate: 59.2%, 23%, 13.9%	Median OS: 6 mo; 1, 3, 5-yr survival rate: 39.5%, 11.2%, 7.4%	Median OS: 9.6 mo; 1, 3, 5-yr survival rate: 46.2%, 23.1%, 7.7%	AFP level, AST, and substage B2, B3, and B4 vs B1
254	TACE, LR, OLT	15.4 mo	Weinmann et al[13]	Median OS: 31.9 mo; 1, 2-yr survival rate: 82.93%, 60.98%	Median OS: 26.9 mo; 1,2-yr survival rate: 72.9%, 52.44%	Median OS: 13.5 mo; 1, 2-yr survival rate: 65%, 40%	Median OS: 10.9 mo; 1, 2-yr survival rate: 48.98%, 38.35%	Total bilirubin, MELD score, presence of ascites, and the therapies resection and OLT.
269	NR	NR	Giannini et al[11]	Median OS: 25 mo	Median OS: 16 mo	Median OS: 9 mo	Median OS: 5 mo	Subclassification of BCLC B, MELD score, and platelet count.
821	TACE	NR	Kim et al[14]	1, 3, 5-yr survival rate: 95.1%, 66.4%, 41.2%	1, 3, 5-yr survival rate: 78.4%, 33%, 20.3%	1, 3, 5-yr survival rate: 59.3%, 10.5%, 0	1, 3, 5-yr survival rate: 57.4%, 43.7%, 17%	NR

LR: Liver resection; OS: Overall survival; TACE: Transcatheter arterial chemoembolization; OLT: Orthotopic liver transplantation; MELD: Model of end-stage liver disease; NR: Not reported.

Table 3 Yamakado criteria

Substage	B1	B2	B3	B4
Child-Pugh grade	A	A	B	B
4 tumors and 7 cm of maximal diameter	Within	Beyond	Within	Beyond

Table 4 Kinki Criteria

BCLC substage	B1	B2	B3
Child-Pugh score	5-7	5-7	8-9
Beyond Milan and within up-to-7	In	Out	Any
			In	Out
Sub-substage			B3-a	B3-b
Concept of treatment strategy	Curative intent	Non-curative, palliative	Curative intent if within up-to-7	Palliative, no treatment
Treatment option	Resection Ablation Superselective c-TACE	DEB-TACE1 HAIC2 Sorafenib3	Transplantation Ablation Superselective c-TACE	HAIC Selective DEB-TACE
Alternative	DEB-TACE (large, C-P 7) B-TACE4	c-TACE	DEB-TACE B-TACE, HAIC	BSC

¹DEB-TACE is recommended for huge tumors that are > 6 cm;

²HAIC is recommended for multiple tumors > 6;

³Sorafenib is recommended for patients with liver function of Child-Pugh score 5 and 6;

⁴B-TACE is recommended for fewer tumors. TACE: Transcatheter arterial chemoembolization; c-TACE: Conventional subsegmental lipiodol TACE; DEB-TACE: TACE with drug-eluting beads; B-TACE: Balloon occluded TACE; HAIC: Hepatic arterial infusion chemotherapy; BSC: Best supportive care; C-P: Child-Pugh score; BCLC: Barcelona Clinic Liver Cancer.

Table 5 Wang criteria

Bolondi substage	Modified B1	Modified B2	Modified B3
B1a (AFP < 200 ng/mL)	B1a
B1b (AFP > 200 ng/mL)		B1b + B2a
B2a (AFP < 200 ng/mL)
B2b (AFP > 200 ng/mL)			B2b + B3
B3

AFP: Alpha-fetoprotein.

Table 6 Lee criteria

Substage	B1	B2	B3
Tumor size < 5 cm	In	Out	Out
Child-Pugh	Not concerned	A	B

Table 7 Kim criteria

BCLC substage	B1	B2		B3
Child-Pugh	A	A	B	B
Within up to-11	In	Out	In	Out
ECOG performance status (tumor related)	0	0	0	0
Portal vein thrombosis	No	No	No	No

Table 8 Kimura criteria

Substage	B1	B2	B3
Within up to-7 criteria	In	Other than those include in B1 and B3	Out
DCP < 150 mAU/mL	In		Not concerned
AFP > 100 ng/mL	Not concerned		In

AFP: Alpha-fetoprotein; DCP: Des-r-carboxy prothrombin.