Tumor budding as a potential prognostic marker in determining the behavior of primary liver cancers

Table 1 Relationship of tumor budding with clinicopathologic parameters and survival in hepatocellular and cholangiocarcinomas

Ref.	Tumor	No.	Correlations	Prognosis
Kairaluoma et al[75]	HCC	47-R; 212-NR	Not observed; Not observed	OS: TB negative vs TB positive; DSS: TB negative vs TB positive
Wei et al[76]	HCC	423	Tumor subtypes, EMT related marker expression, FOXP3, PD-L1 and CD68 expressions; Frequent mast cell infiltration, p53 mutation (IS-TB type I); CTNNB1 mutation (IS-TB type IV)	DFS: Type II vs Type I + Type IV; Type III vs Type I + Type IV; OS: Type II vs Type I + Type IV; Type III vs Type I + Type IV
Okubo et al[77]	CCC	299	Dif G1/G2vs Dif G3	OS: TB negative vs TB positive
Ogino et al[78]	EHCC-PH; EHCC-DC	195; 115	Grade, T, LI, VI, PN, LNM, RSM; Grade, Higher T, LI, VI, PN, LNM	OS: TB low vs TB ıntermediate vs TB high; OS: TB low vs TB high
Tanaka et al[80]	ICC	107	Stage, Hilar invasion, Grade, VI, LNM, SM	RFS: TB negative vs TB positive; OS: TB negative vs TB positive
	Type 1	49	NP	RFS: Not prognostic; OS: Not prognostic
	Type 2	58	NP	RFS: Not prognostic; OS: TB negative vs TB positive
	EHCC-PH	54	LI	RFS TB negative vs TB positive; OS TB negative vs TB positive
	EHCC-DC	40	VI	RFS: Not prognostic; OS: Not prognostic
Ito et al[81]	EHCC-PH	78	Grade, T, LNM, M
		36 NT	Combined HA/PV Resection, Grade, T, LNM, M	DSS: TB low vs TB high; RFS: TB low vs TB high
		42 WT	Not observed	DSS: TB low vs TB high; RFS: Not prognostic
Agostini-Vulaj et al[83]	EHCC; ICC	58; 54	Gender, Location, Grade, LNI, PNI, RSM; Gender, Location, Grade, LNI, PNI	DSS: TB ıntermediate vs TB high; RFS: TB ıntermediate vs TB high
Budau et al[84]	ICC	89	NP	OS: TB Low vs TB Intermediate vs TB High; RFS TB Low vs TB Intermediate vs TB High ITTB, PTTB, TB
Kosaka et al[85]	ICC	235	Size, Tumor type, Grade, VI, MBI, LNM	DSS: TB Low/Intermediate vs TB High; RFS: TB Low/Intermediate vs TB High
Nakayama et al[82]	EHCC-DC	65	T, LNM, LI, VI, ZEB-1 expression, stage	OS: TB Low vs TB High

CCC: Cholangiocarcinoma; DFS: Disease free survival; DSS: Disease specific survival; Dif: Differentiation; DM: Distant metastasis; EHCC-DC: Extrahepatic cholangiocarcinoma-distal; EHCC-PH: Extrahepatic cholangiocarcinoma-perihilar; EMT: Epithelial to mesenchymal transition; G: Grade; HA/PV: Hepatic artery and portal vein; HCC: Hepatocellular carcinoma; ICC: Intrahepatic cholangiocarcinoma; IS: Immunescore; ITTB: Intratumoral tumor budding; LI: Lymphatic invasion; LNM: Lymph node metastasis; M: Metastasis; MVI: Microvascular invasion; NCR: Noncurative resection; No: Number of cases; NR: Non-resectable; NT: Neoadjuvant therapy OS: Overall Survival; PN: Perineural invasion; PTTB: Peritumoral tumor budding; R: Resectable; RFS: Recurrence free survival; RSM: Residual tumor in surgical margin; T: Tumor invasion; TB: Tumor budding; VI: Type I: ISA-TB_high; Type II: ISB-TB_high; Type III: ISA-TB_low; Type IV: ISB-TB_low; VI: Vascular invasion; MBI: Major biliary invasion; WT: Without neoadjuvant therapy.

Table 2 Criteria applied for tumor budding in previous studies

Ref.	Tumor	Tumor budding criteria
Kairaluoma et al[75]	HCC	Evaluation was performed according to median values; Negative: No buds were found; Positive: At least one bud was present
Wei et al[76]	HCC	Association between TB and clinicopathological parameters; Grade 1 (0-4), Grade 2 (5-9), Grade 3 (≥ 10); For survival analysis; Low grade (0-9), High grade (≥ 10)
Okubo et al[77]	CCC	Negative: < 5 budding focus; Positive: ≥ 5 budding focus
Ogino et al[78]	EHCC-PH, EHCC-DC	Cut-off values of TB obtained by recursive partioning technique; For EHCC-PH; Low grade (0-4), Intermediate grade (5-11), High grade (≥ 12); For EHCC-DC; Low grade (0-4), High grade (≥ 5)
Tanaka et al[80]	ICC, EHCC-PH, EHCC-DC	Low grade (0-4), Intermediate grade (5-9), High grade (≥10)
Ito et al[81]	EHCC-PH	Low TB: < 5 budding focus; High TB: ≥ 5 budding focus
Agostini-Vulaj et al[83]	ICC, EHCC	Grade 1 (0-4), Grade 2 (5-9), Grade 3 (≥ 10)
Budau et al[84]	ICC	Grade 1 (0-4), Grade 2 (5-9), Grade 3 (≥ 10)
Kosaka et al[85]	ICC	Low grade (0-4), Intermediate grade (5-9), High grade (≥ 10)
Nakayama et al[82]	EHCC-DC	Low TB (0-4), High [TB Grade 2 (5-9) and 3 (≥ 10)]

CCC: Cholangiocarcinoma; EHCC-DC: Extrahepatic cholangiocarcinoma-distal; EHCC-PH: Extrahepatic cholangiocarcinoma-perihilar; HCC: Hepatocellular carcinoma; ICC: Intrahepatic cholangiocarcinoma.