Liver transplantation for intermediate hepatocellular carcinoma: An adaptive approach

Table 1 Indications for liver transplantation in patients with hepatocellular carcinoma according to current guidelines

International society	Year	Listing criteria	Downstaging	Ref.
American Association for	2010	Milan criteria	No	[12]
the Study of Liver Diseases (AASLD) for hepatocellular carcinoma
American Association for	2013	Milan criteria	Yes	[13]
the Study of Liver Diseases (AASLD) for liver transplant
European Association for the Study of the Liver (EASL), European Organisation For Research And Treatment Of Cancer (EORTC)	2011	Milan criteria	No	[14]
European Society for Medical Oncology (ESMO), European Society of Digestive Oncology (ESDO)	2012	Milan criteria	No	[15]
Asian Pacific Association for the Study of the Liver (APASL)	2010	Milan criteria	No	[16]
Japan Society of Hepatology (JSH)	2014	Milan criteria	No	[17]
American Hepato-Pancreato-Biliary Association (AHPBA)	2010	Milan criteria	Yes	[18]
International Consensus Conference	2010	Milan criteria	Yes	[19]

Table 2 Preoperative stadiation for patients with hepatocellular carcinoma evaluated for liver transplantation

Diagnostic test	Indications	Comments
Computed tomography (CT) with contrast medium of chest-abdomen-pelvis	Standard test to perform the diagnosis of hepatocellular carcinoma (HCC) in cirrhotic livers to characterize number, size and location of nodules, and exclude macrovascular invasion and extrahepatic spread	Require adherence to established protocols for optimization
Magnetic resonance imaging (MRI) with contrast medium of abdomen	Slightly superior to CT according to recent data	Consider in individual patients
Bone scan	Standard test to exclude bone spread	Cost-effectivity debated
Alpha-fetoprotein (AFP)	Center-specific cut-off for inclusion on the list and drop-out	Surrogate marker of biological aggressiveness
Preoperative biopsy	Proposed to assess tumor grading	Low accuracy
Positron emission tomography (PET)	Proposed predictor of HCC recurrence	Cost-effectivity unclear

Table 3 Eligibility criteria for downstaging of hepatocellular carcinoma before liver transplantation

Protocol	Inclusion criteria	Criteria for successful downstaging	Minimal observation period	Ref.
Bologna “rule of six”	Single HCC ≤ 6 cm	Milan criteria	3 mo	56
	2 HCC ≤ 5 cm
	Less than 6 HCCs ≤ 4 cm and a total tumor diameter ≤ 12 cm
	Absence of vascular or biliary invasion on CT/MRI
	AFP < 400 ng/mL during waiting time
San Francisco (UCSF)	Single HCC ≤ 8 cm	Milan criteria	3 mo	58
	2 or 3 HCC ≤ 5 cm (total tumor diameters ≤ 8 cm)
	4 or 5 HCC ≤ 3 cm (sum of maximal tumor diameters ≤ 8 cm)
	Absence of vascular invasion on CT/MRI

CT: Computed tomography; MRI: Magnetic resonance imaging; HCC: Hepatocellular carcinoma.

Table 4 Liver graft allocation policies for candidates to liver transplantation with and without hepatocellular carcinoma

Principle	Reference outcome	Tools for prioritization		Comments
		Non-HCC	HCC
Urgency	Risk of drop-out from the waiting list	MELD	MELD exception points, adjusted MELD, HCC-MELD equation, deMELD	“Sickest patient first”
Utility	Post-LT patient (graft) survival	DRI, D-MELD	Milan criteria	Donor/recipient matching
Benefit	Post-LT patient benefit	Minimum value of MELD score ≥ 15	HCC-MELD	Feasibility of alternative treatments

LT: Liver transplantation; HCC: Hepatocellular carcinoma; MELD: Model for end-stage liver disease; DRI: Donor risk index; D-MELD: MELD and donor age.