Hepatocellular carcinoma: A comprehensive review

Table 1 Etiology of hepatocellular carcinoma[12]

Risk factors for hepatocellular carcinoma

Chronic hepatitis C infection with advanced fibrosis or cirrhosis

Chronic hepatitis B infection with/without cirrhosis

Alcoholic liver disease with cirrhosis

Hereditary hemochromatosis with cirrhosis

Alpha1-antitrypsin deficiency with cirrhosis

Autoimmune hepatitis with cirrhosis

Porphyrias

Wilson's disease

Non-alcoholic fatty liver disease

Nonalcoholic steatohepatitis with cirrhosis

Primary biliary cirrhosis

Type 1 hereditary tyrosinemia

Type 1 and 2 glycogen storage disease

Hereditary ataxia-telangiectasia

Hypercitrullinemia

Aflatoxin exposure

Other carcinogens

Thorotrast

Polyvinyl choloride

Carbon chloride

Table 2 Criteria for listing for liver transplantation and hepatocellular carcinoma: Various expansion beyond the Milan Criteria

Criteria	Ref.	No. of patients	Selection criteria	Survival rate at 5 yr	Survival rate at 5 yr using MC
MC	Mazzaferro et al[4]	48	Solitary HCC < 5 cm or 3 nodules < 3 cm	75% (4 yr)	-
Up to seven criteria	Mazzaferro et al[86]	283	Sum of the number of tumors and diameter of the largest tumor ≤ 7 cm	71.2%	73.3%
Toronto Criteria	DuBay et al[109]	294	Dominant lesion not poorly differentiated on biopsy, no restriction on tumor size and number	68%	72%
UCSF Criteria	Yao et al[81]	70	Solitary tumor ≤ 6.5 cm or 3 nodules ≤ 4.5 cm in diameter with a total tumor diameter ≤ 8 cm	75.2%	72%
Clinica universitaria de Navarra Criteria	Herrero et al[110]	154	Solitary tumor ≤ 6 cm or ≤ 3 nodules ≤ 5 cm in diameter	68%	66%
Kyoto Criteria	Ito et al[41]	125	≤ 10 nodules all ≤ 5 cm in diameter protein induced by vitamin K absence or antagonist-II ≤ 400 mAU/mL	Overall survival 68.3%	No difference
Asan Criteria	Lee et al[111]	186	≤ 6 nodules with a maximum tumor diameter of ≤ 5 cm	76%	76.3%
Bologna Criteria	Del Gaudio et al[112]	177	Solitary HCC ≤ 6 cm or 2 nodules ≤ 5 cm or	71% (3 yr)	71% (3 yr)
			< 6 nodules ≤ 4 cm and sum diameter ≤ 12 cm
Metroticket Calculator	Mazzaferro et al[86]	> 1000	International Liver Transplant Society meeting in 2005 as a Web-based survey. Predict 5 yr survival based on tumor size	50%-70%	75%-80%
Toso Criteria	Toso et al[113]	288	Total tumor volume ≤ 115 cm3	80%	82%
Silva Criteria	Boin et al[114]	257	≤ 3 nodules with a maximum tumor diameter of ≤ 5 cm and total tumor diameter < 10 cm	69%	62%
Hangzhou Criteria	Fan et al[87]	195	Total tumor diameter < 8 cm with grate I or II tumor on biopsy and AFP < 400 ng/mL	72%	78%

HCC: Hepatocellular carcinoma; MC: Milan Criteria; AFP: Alpha feto protein.

Table 3 Clinical practice guidelines for liver transplantation in hepatocellular carcinoma - European Association for the Study of the Liver and European Organization for Research and Treatment of Cancer

Guideline	Level of evidence	Strength of recommendation
Liver transplantation is considered to be the first-line treatment option for patients with single tumors less than 5 cm or ≤ 3 nodules ≤ 3 cm (Milan criteria) not suitable for resection	2A	1A
Perioperative mortality and one-year mortality are expected to be approximately 3% and ≤ 10%, respectively
Extension of tumor limit criteria for liver transplantation for HCC has not been established. Modest expansion of Milan Criteria applying the “up-to-seven” in patients without microvascular invasion achieves competitive outcomes, and thus this indication requires prospective validation	2B	2B
Neoadjuvant treatment can be considered for loco-regional therapies if the waiting list exceeds six months due to good cost-effectiveness data and tumor response rates, even though impact on long-term outcome is uncertain	2D	2B
Down-staging policies for HCCs exceeding conventional criteria cannot be recommended and should be explored in the context of prospective studies aimed at survival and disease progression end-points	2D	2C
Assessment of downstaging should follow modified RECIST criteria
Living donor liver transplantation is an alternative option in patients with a waiting list exceeding six to seven months, and offers a suitable setting to explore extended indications within research programs	2A	2B

Adapted from the EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012; 56: 908. The level of evidence and strength of recommendation are based on the National Cancer Institute classification and GRADE system, respectively. HCC: Hepatocellular carcinoma; RECIST: Response Evaluation Criteria In Solid Tumors.

Table 4 Organ Procurement and Transplantation Networks classification system for nodules seen on images of cirrhotic livers

OPTN class 0
Incomplete or technically inadequate study	Repeat study required for adequate assessment; automatic priority MELD points cannot be assigned on basis of an imaging study categorized as OPTN class 0
OPTN class 5
Meets radiologic criteria for HCC	May qualify for automatic exception, depending on stage
Class 5A: ≥ 1 cm and < 2 cm measured on late arterial or portal venous phase images	Increased contrast enhancement in late hepatic arterial phase AND washout during later phases of contrast enhancement AND peripheral rim enhancement (capsule or pseudocapsule)
Class 5A-g: Same size as OPTN class 5A HCC	Increased contrast enhancement in late hepatic arterial phase AND growth by 50% or more documented on serial CT or MR images obtained ≤ 6 mo apart
Class 5B: Maximum diameter ≥ 2 cm and ≤ 5 cm	Increased contrast enhancement in late hepatic arterial phase AND either washout during later contrast phases OR peripheral rim enhancement (capsule or pseudocapsule) OR growth by 50% or more documented on serial CT or MR images obtained ≤ 6 mo apart (OPTN class 5B-g)
Class 5T: Prior regional treatment for HCC	Describes any residual lesion or perfusion defect at site of prior UNOS class 5 lesion
Class 5X: Maximum diameter ≥ 5 cm	Increased contrast enhancement in late hepatic arterial phase AND either washout during later contrast phases OR peripheral rim enhancement (capsule or pseudocapsule)

Adpated from Wald et al[30]. HCC: Hepatocellular carcinoma; OPTN: Organ Procurement and Transplantation Networks; MELD: Model for End stage Liver Disease; CT: Computed tomography; MR: Magnetic resonance; UNOS: United Network for Organ Sharing.