Expansion of the hepatocellular carcinoma Milan criteria in liver transplantation: Future directions

Table 1 Expanded criteria used for liver transplantation

Criteria	Type of donor	Detailed criteria
UCSF[9,27]	Cadaveric	Solitary tumor ≤ 6.5 cm or ≤ 3 tumors with the largest ≤ 4.5 cm
Up-to-seven[10]	Cadaveric/LDLT	Seven: sum of tumor number and size of the largest tumor without microvascular invasion
Clinica Universidad de Navara (CUN)[12]	Cadaveric	1 tumor ≤ 6 cm or ≤ 3 tumors with the largest ≤ 5 cm
Toso[29]	Cadaveric	Total tumor volume ≤ 115 cm3 and AFP ≤ 400 ng/mL
Hangzhou University[13]	Cadaveric	One of the following: Total tumor diameter ≤ 8 cm Total tumor diameter > 8 cm with histological grade I or II and AFP ≤ 400 ng/mL
Onaca (ITR)[32]	Cadaveric	Solitary tumor, ≤ 6 cm 2-4 tumors, ≤ 5 cm
Tokyo (5-5 rule)[53]	LDLT	Maximum 5 tumors ≤ 5 cm
Kyoto[55]	LDLT	≤ 10 tumors, ≤ 5 cm, DCP§ ≤ 400 mAU/mL
Kyushu University[57]	LDLT	Any number of tumors with diameter ≤ 5 cm or DCP§ ≤ 300 mAU/mL
Asan[58]	LDLT	≤ 6 tumors, diameter ≤ 5 cm
Samsung[59]	LDLT/cadaveric	≤ 7 tumors, diameter ≤ 6 cm, AFP ≤ 1000 ng/mL
BCLC[14]	LDLT	1 tumor, ≤ 7 cm 3 tumors, ≤ 5 cm 5 tumors, ≤ 3 cm Maintained response within Milan criteria during 6 mo after downstaging

AFP: Alpha-fetoprotein; BCLC: Barcelona-Clínic Liver Cancer; DCP: Des-gamma-carboxy prothrombin; LDLT: Living donor liver transplantation; LT: Liver transplantation.

Table 2 Results after liver transplantation with expanded criteria

Ref.	Type	Patients,n (type)	Criteria (findings)	Survival,time (%)	Recurrence,time (%)	Factorsfor survival	Factorsfor recurrence
Yao et al[9], 2001	R	14 (MO)	UCSF (Histol)	5 yr (84.6)	-	pT4, total tumor diameter	-
Yao et al[27], 2007	P	38 (MO)	UCSF (Radiol)		5 yr DFS (93.6)		UCSF Vascular invasion AFP > 1000 ng/mL
Onaca et al[32], 2007	R	129 (MO)	Onaca		5 yr DFS (63.9)		Tumor > 6 cm AFP > 200 ng/mL Tumors > 4
Herrero et al[28], 2008	P	26 (MO)	CUN (Radiol)	5 yr (73) 5 yr I-to-T (68)			Vascular invasion
Zheng et al[13], 2008	R	99 (MI and MO), 26 (MO)	Hangzhou (Histol)	5 yr (70.7)	5 yr DFS (62.4)	Macrovascular invasion Tumor size > 8 cm AFP > 400 ng/mL Histological grading (III)	Macrovascular invasion Tumor size > 8 cm AFP > 400 ng/mL Histological grading (III)
Mazzaferro et al[10], 2009	R	283 (MI and MO)	Up-to-seven (Histol)	5 yr (71.2)	-	Microvascular invasion Tumor grade	-
Toso et al[29], 2015	P	38 (MO)	Toso (Radiol)	4 yr (74.6) 4 yr I-to-T (53.8)	4 yr DFS (68)	-	-
Togashi et al[54], 2016	R	14 (MO)	Tokyo	-	5 yr (8)	-	Tokyo criteria AFP ≥ 400 ng/mL DCP ≥ 200 mAU/mL
Kaido et al[56], 2013	R	42 (MO)	Kyoto	5 yr (80)	5 yr (7)		Kyoto criteria Pretreatment of the HCC
Shirabe et al[57], 2011	R	48 (MI and MO)	Kyushu (Histol)		5 yr DFS (80)		Kyushu criteria
Lee et al[58], 2008	R	174 (MI and MO)	Asan (Histol)	5 yr (81.6)	5 yr (15)	Largest tumor > 5 cm Number > 6 Gross vascular invasion	Largest tumor > 5 cm Number > 6 Gross vascular invasion
Kim et al[59], 2014	R	180 (in the whole study, including Samsung-out)	Samsung (Histol)		5 yr DFS -89.6		Tumors ≤ 7 Diameter ≤ 6 cm AFP ≤ 1000 ng/mL
Llovet et al[14], 2018	P	22	BCLC (Radiol)	5 yr (80.2)	5 yr (23.8)	MI after locoregional therapies

AFP: Alpha-fetoprotein; BCLC: Barcelona-Clínic Liver Cancer; DFS: Disease-free survival; Histol: Histology; I-to-T: Intention-to-treat; LT: Liver transplantation; MI: Milan-in; MO: Milan-out; P: Prospective; R: Retrospective; Radiol: Radiology; UCSF: University of California San Francisco.

Table 3 Prospective studies of downstaging of hepatocellular carcinoma before liver transplantation

Ref.	Criteria	Downstagingsuccess rate (%)	LT rate(%)	Survival,time and rate (%)	HCC recurrence (%)
Roayaie et al[11], 2002	Mount Sinai protocol		53.75	5 yr OS (44) 5 yr DFS (48) 5 yr DFS, tumors < 7 cm (55)
Yao et al[72], 2015	Beyond Milan: single tumor ≤ 8 cm, 2–3 tumors (at least one > 3 and ≤ 5 cm, total diameter ≤ 8 cm), 4–5 tumors each ≤ 3 cm and total diameter ≤ 8 cm	To MC: 65.3	54.2	5 yr OS (77.8) 5 yr I-to-T (56.1)	7.8
Bologna criteria - Ravaioli et al[35], 2008	Beyond Milan: 1 lesion ≤ 6 cm, 2 lesions ≤ 5 cm, 3–5 lesions ≤ 4 cm and total diameter ≤ 12 cm	To MC: 72.9	66.7	3 yr DFS (71) 3 yr I-to-T (56.3)	18.8
Millonig et al[73], 2007	UCSF	RECIST	84.8	5 yr CR (66.6); PR (63.7); NR (25)	25
Graziadei et al[37], 2003	Beyond Milan, no upper limit	Partial response (> 50% of tumor size)	66.6	4 yr OS (41); 5 yr I-to-T (31)	30

CR: Complete response; HCC: Hepatocellular carcinoma; I-to-T: Intention-to-treat; LT: Liver transplantation; NR: No response; PR: Partial response; UCSF: University of California San Francisco.

Table 4 Impact of genetic and molecular factors in post-liver transplantation outcome

Ref.	Criteria	Survival, time and rate (%)	Recurrence, time and rate (%)
Schwartz et al[68], 2008	FAI < 0.27		5 yr (10)
Dvorchick et al[69], 2008	FAI and macrovascular invasion (Pittsburg criteria)	Stage I (FAI ≤ 20% and no macrovascular invasion) - 5 yr DFS (92.8)
Miltiadous et al[67], 2015	Progenitor cell markers (CK19 or S2 signature)	5 yr (67)	5 yr (19)
Sugimachi et al[70], 2015	miR-718 and his target gene HOXB8	5 yr (≈ 80)
Barry et al[71], 2012	67 miRNA
Liese et al[72], 2016	miR-214, miR-3187 and MC	5 yr DFS (≈ 90)

DFS: Disease-free survival; FAI: Fractional allelic imbalance; MC: Milan criteria; miRNA: MicroRNA.