Liver Transplantation for Hepatocellular Carcinoma in Young Adults: A United Network for Organ Sharing Study

Abstract

Purpose:

Orthotopic liver transplantation (OLT) is curative for hepatocellular carcinoma (HCC). HCC is typically a disease of older adults (OAs); therefore, characteristics and outcomes of OLT for young adults (YAs) (ages 18–40) are not described. The objective of this study was to assess the characteristics and outcomes of YAs with HCC receiving OLT and compare these to OAs (ages >40 years).

Methods:

YAs with HCC who had OLT from the United Network for Organ Sharing (UNOS) database were included in this study. As a comparison group, OAs with HCC were matched 4:1 to the YA group. Descriptive statistics of demographics, comorbidities, and outcomes were generated. Kaplan–Meier product limit estimates were used to assess patient and graft survival. Conditional logistic regression and Cox proportional hazards frailty models were used to compare the groups.

Results:

A total of 464 YAs received OLT for HCC. The most common underlying liver diseases were hepatitis C virus (21.3%), hepatitis B virus (HBV, 15.5%), and autoimmune/cholestatic disease (12.3%). An increased number of YAs received OLT for HCC after implementation of model for end-stage liver disease scoring. One thousand two hundred eighty OAs served as the comparison group. Post-transplant 5-year survival was 73.1% in YAs with a retransplantation rate of 7.8%. In OAs, survival and retransplantation rates were lower (68.6% p = 0.093; 4.3% p = 0.001).

Conclusion:

Four hundred sixty-four YAs with HCC received OLT in the UNOS database. Compared to the older population, survival and retransplantation rates were higher. HBV, which is vaccine preventable, is a frequent contributor to HCC in YAs.

Introduction

Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality worldwide¹ and the fifth in the United States.¹ In countries with endemic hepatitis B virus (HBV) and without access to vaccination, the rate of HCC is much higher.² Because chronic liver injury resulting in cirrhosis can be a predisposing factor to the development of HCC, it is not surprising that the incidence of HCC increases with age and varies by gender, race/ethnicity, and socioeconomic status. Males have a roughly three times higher rate of HCC than females; Asians and Pacific Islanders have the highest incidence of disease, followed by Hispanics, blacks, American Indians/Alaska Natives, and whites³; and people of all ethnic groups except Hispanics living in lower socioeconomic neighborhoods have a higher incidence.⁴ Incidence rates, thought to be dramatically increasing,⁵ appear to have stabilized recently.³

HCC continues to have a very poor prognosis. Worldwide, the ratio of mortality to incidence is 0.95.⁶ Similar to incidence rates, mortality rates also vary by ethnicity, in the same order as incidence.³ In addition to lower incidence rates of HCC for females compared with males, female sex appears to be protective against mortality, especially in the younger age ranges.⁷ Over recent years, there has been greater increase in the rate of diagnosis of earlier stage disease compared to regional and distant disease, postulated to be due to surveillance programs. Despite earlier diagnosis at earlier stages, there has not been a corresponding increase in use of curative therapies and subsequent improvement in mortality.⁸

Treatment options for HCC continue to be limited to patients with local disease. Historically, curative therapy included only surgical options, including resection and transplantation. In more recent years, radiofrequency ablation has offered a nonsurgical cure.⁹ In patients with intermediate- to advanced-stage disease, only life-prolonging therapy, such as transarterial chemoembolization and sorafenib, rather than curative therapies are typically pursued.

Before the 1990s, HCC was a contraindication for orthotopic liver transplantation (OLT). Following a landmark retrospective study, the Milan Criteria was established, making OLT a treatment option for patients with unresectable HCC for solitary lesions <5 cm in size or up to three lesions each <3 cm.¹⁰ Curative resection is not an option for some patients with HCC, and low model for end-stage liver disease (MELD) scores precluded the qualification for OLT in many patients. Therefore, in 2002, MELD exception points were granted to patients with HCC to increase the availability of OLT for patients with HCC.¹¹ These have been adjusted over the years to optimize the use of transplanted livers.

Because of the relative infrequency of HCC in the young adult (YA) population in the United States, most epidemiologic studies do not report the YA (<40 years) age group separately in large Surveillance, Epidemiology, and End Results program studies. In HBV endemic areas, the outcomes of YAs with HCC have been shown to be worse than in older patients.^12–14 However, these outcomes are thought to be due to the higher stage of disease at diagnosis, and when adjusted for stage, YAs with lower stage disease have been actually shown to have a survival advantage.¹⁵ In studies comparing YA and older patients who underwent partial hepatectomy, disease-free survival and event-free survival were not shown to be statistically different.^16,17 No studies comparing outcomes of YA patients and older adult (OA) patients outside of HBV endemic areas exist to our knowledge.

Given the lack of curative treatment options for patients with HCC and the paucity of data surrounding OLT for YA patients with HCC, understanding the clinical and disease information in the YA population and OLT outcomes for this group is especially important. The objective of this study was to perform a comprehensive analysis of a large national transplantation registry in the United States to assess the characteristics and outcomes of YAs with HCC receiving OLT and compare these to older subjects >40 years with HCC receiving OLT.

Experimental Procedures

Study population

The study population included all YA patients between the ages of 18 and 40 with a diagnosis of HCC, who underwent liver transplantation from a cadaveric donor and had no previous liver transplants from the 1987 to 2012 United Network of Organ Sharing (UNOS) and Organ Procurement and Transplantation Network (OPTN) database. This is a retrospective analysis of de-identified data, and therefore, our local institutional review board was contacted for approval to complete this analysis and approval was granted. Diagnosis of HCC from the database was defined if the primary or secondary diagnosis at time of listing or the diagnosis at time of OLT indicated HCC or if there was an active MELD exception for HCC.

The liver transplant outcomes for the subset of subjects who received their transplantation following the implementation of MELD scoring were assessed. For the case–control analysis, a control group of patients older than 40 with a diagnosis of HCC (OA group) were matched on a basis of 4:1 to the post-MELD YAs with HCC (YA group) based on gender and MELD score (±1) using a greedy algorithm.¹⁸ With the greedy algorithm, the YA subject was selected and matched with four OA control subjects with the closest propensity score based on defined covariates. Once a match was made, it was not reconsidered. All demographic data, laboratory values, MELD scores, and graft and patient survival were obtained from the database.

Statistical analysis

Data are presented as mean ± standard deviation or median [25th, 75th percentiles] for continuous variables and N (%) for categorical factors.

Patient/graft survival and retransplantation rates

Kaplan–Meier product limit estimates and Cox proportional hazards frailty models for clustered data were used to assess patient and graft survival.¹⁹ Retransplantation was evaluated using competing risks analysis for clustered data as death precludes retransplantation. Time of follow-up was defined as months from transplant to event; subjects were censored at time of last visit and follow-up was truncated at 5 years.

Robust sandwich covariance matrix estimates were used to account for intracluster dependence due to matched pairs.

Case–control analysis

The study group (YAs with HCC) was compared to the control group (OAs with HCC) by univariable analysis to assess differences; because the groups were matched, conditional logistic regression and mixed linear regression analyses were used. Binary factors (two level) such as obesity or presence of diabetes were modeled using conditional logistic regression; separate models were built and each factor was modeled as the outcome with age group (YAs vs. OAs) as the independent variable. Similarly, mixed linear regression was used to assess differences in continuous variables such as age and body mass index (BMI). This was done using a natural logarithm transformation for the outcome variable and a variance component correlation matrix to model the intracluster correlation.

All analyses were performed using SAS version 9.4 (The SAS Institute, Cary, NC), and a p-value <0.05 was considered statistically significant.

Results

Patient demographics and secondary diagnoses

A total of 464 YA patients with HCC who received their first cadaveric liver transplant from 1987 to 2012 were found in the UNOS database and included in the analysis. The number of cases undergoing transplant increased dramatically in 2002, following the initiation of MELD-exception points (Fig. 1). Table 1 presents a summary of patient characteristics, including demographics, comorbidities, laboratory findings at the time of transplant, surgical information, and antirejection therapy following transplant. Rates of transplantation increased with increasing age (Fig. 2). The majority of patients were male (64%) and of white race (51.9%), followed by black. The majority of patients were of normal weight (55.2%). Few patients had diabetes (8.6%) or hypertension (6.0%). The most common underlying liver disease was hepatitis C (21.3%), followed by HBV (15.5%), and autoimmune/cholestatic disease (12.3%). The most common causes of autoimmune/cholestatic disease were autoimmune hepatitis (47.4%), primary sclerosing cholangitis (31.6%), primary biliary cirrhosis (12.3%), and secondary biliary cirrhosis (7.0%). Metabolic disease occurred in 2.8% of patients, including glycogen storage disease type 1 (38.5%), alpha-1-antitrypsin disease (30.8%), tyrosinemia (15.4%), primary oxalosis/oxaluria (7.7%), and Wilson's disease (7.7%). Few patients (5.8%) had alcoholic liver disease.

FIG. 1.

Number of liver transplants done in young adults for HCC. Analysis of the United Network for Organ Sharing database 1987–2012. HCC, hepatocellular carcinoma.

FIG. 2.

Age distribution of young adults undergoing liver transplantation for HCC.

Table 1.

Characteristics of Young Adult Liver Transplant Recipients with Hepatocellular Carcinoma: 1987–2012

	Total (N = 464)
Factor	n	Summary
Male	464	297 (64.0)
Age (years)	464	33.3 ± 6.5
Body mass index	460	25.5 ± 5.9
Weight group	460
Normal weight		254 (55.2)
Overweight		124 (27.0)
Obese		68 (14.8)
Severely obese		14 (3.0)
Race	462
White		240 (51.9)
Black		85 (18.4)
Hispanic		54 (11.7)
Other		83 (18.0)
Diabetes	382	33 (8.6)
Hypertension	217	13 (6.0)
Liver disease (nonexclusive)
Alcoholic liver disease	464	27 (5.8)
Acute liver failure	464	22 (4.7)
Autoimmune/cholestatic disease	464	57 (12.3)
Autoimmune cirrhosis	57	27 (47.4)
Primary sclerosing cholangitis	57	18 (31.6)
Primary biliary cirrhosis	57	7 (12.3)
Secondary biliary cirrhosis	57	4 (7.0)
Cholestasis liver disease	57	1 (1.8)
Hepatitis B virus	464	72 (15.5)
Hepatitis C virus	464	99 (21.3)
Metabolic disease	464	13 (2.8)
Glycogen storage disease type 1	13	5 (38.5)
Alpha-1-antitrypsin deficiency	13	4 (30.8)
Tyrosinemia	13	2 (15.4)
Wilson's disease	13	1 (7.7)
Primary oxalosis/oxaluria	13	1 (7.7)
Nonalcoholic steatohepatitis	464	6 (1.3)
Other liver tumors/cancer	464	25 (5.4)
Other liver diseases	464	54 (11.6)

Values presented as mean ± SD, median [P25, P75], or N (column %).

SD, standard deviation.

Comparison of patient characteristics for YAs with HCC who were listed and received transplant and those listed and did not receive transplant

A total of 639 YAs were listed for OLT from 1987 to 2012. Of those 639 patients, 175 (27.4%) did not receive an OLT (Table 2). There was no statistically significant difference in the gender, age, or BMI of the two groups. There was a difference in race, where patients of white and black race were transplanted more frequently than Hispanic or other race (p = 0.005).There was no statistically significant difference in comorbidities, including diabetes and hypertension. Associated liver diseases were similar between the two groups with more cholestatic liver diseases being in the transplanted group. Of the patients who had not been transplanted, 34.3% were still on the waitlist at the time of this data collection, 53.7% were removed from the waitlist, and 12.0% died while listed for transplant.

Table 2.

Characteristics of Young Adults with Hepatocellular Carcinoma Listed for Liver Transplant: 1987–2012

	Not transplanted (N = 175)		Transplanted (N = 464)
Factor	n	Statistics	n	Statistics	p-Value
Male	175	118 (67.4)	464	297 (64.0)	0.42^a
Age (years)	175	33.1 ± 6.2	464	33.3 ± 6.5	0.80^b
BMI	171	28.2 ± 39.4	460	25.5 ± 5.9	0.16^b
Weight group	171		460		0.92^a
Normal weight		97 (56.7)		254 (55.2)
Overweight		43 (25.1)		124 (27.0)
Obese		27 (15.8)		68 (14.8)
Severely obese		4 (2.3)		14 (3.0)
Race	175		462		0.005^a
White		81 (46.3)		240 (51.9)
Black		19 (10.9)		85 (18.4)
Hispanic		25 (14.3)		54 (11.7)
Other		50 (28.6)		83 (18.0)
Diabetes	170	8 (4.7)	382	33 (8.6)	0.10^a
Hypertension	76	4 (5.3)	217	13 (6.0)	0.82^a
Liver disease (nonexclusive)
Alcoholic liver disease	175	9 (5.1)	464	27 (5.8)	0.74^a
Acute liver failure	175	10 (5.7)	464	22 (4.7)	0.62^a
Autoimmune/cholestatic disease	175	9 (5.1)	464	57 (12.3)	0.008^a
Hepatitis B virus	175	30 (17.1)	464	72 (15.5)	0.62^a
Hepatitis C virus	175	30 (17.1)	464	99 (21.3)	0.24^a
Metabolic disease	175	1 (0.57)	464	13 (2.8)	0.086^a
Nonalcoholic steatohepatitis	175	5 (2.9)	464	6 (1.3)	0.18^a
Other liver tumors/cancer	175	0 (0.0)	464	25 (5.4)	0.002^a
Other diagnoses	175	21 (12.0)	464	54 (11.6)	0.90^a
MELD era	175		464		0.92^a
Pre-MELD era		55 (31.4)		144 (31.0)
Post-MELD era		120 (68.6)		320 (69.0)
WL outcome	175		464		—
Transplanted		0 (0.0)		464 (100.0)
Still on WL		60 (34.3)		0 (0.0)
Removed from WL		94 (53.7)		0 (0.0)
Deceased on WL		21 (12.0)		0 (0.0)
Follow-up on WL (months)	175	6.1 [1.7, 15.9]	460	2.7 [0.69, 8.3]	<0.001^c

Statistics presented as mean ± SD, median [P25, P75], or N (column %).

Pearson^'s chi-square test.

Analysis of variance.

Fisher^'s exact test.

BMI, body mass index; MELD, model for end-stage liver disease; WL, waiting list.

Outcomes after first and second OLT for HCC in YAs

The outcomes of liver transplant in YAs with HCC from 1987 to 2012 are described in Table 3. In terms of survival, 58.8% of patients were alive or lost to follow-up without need for another transplant following their first OLT (235 patients alive and 38 lost to follow-up), 9.7% of patients required another transplant, and 31.5% of patients were deceased. The median survival time was 31.4 months. The most common reason for retransplantation was HCC (29.3%). In terms of the patients who died, the most common cause of death was malignancy (45.2%), followed by graft failure (16.4%) and then infection (11.0%).

Table 3.

Outcomes of Liver Transplant in Young Adults with Hepatocellular Carcinoma: 1987–2012

	First LT (N = 464)		Second LT (N = 45)
Factor	n	Summary	n	Summary
Post-OLT length of stay (days)	447	10.0 [7.0, 16.0]	38	18.5 [10.0, 28.0]
OLT outcome	464		41
Alive/lost to FU		273 (58.8)		21 (51.2)
Retransplanted		45 (9.7)		5 (12.2)
Deceased		146 (31.5)		15 (36.6)
Reason for re-OLT	41		5
Acute liver failure		4 (9.8)		1 (20.0)
Autoimmune/cholestatic		4 (9.8)		2 (40.0)
Hepatitis C virus		3 (7.3)		1 (20.0)
Hepatocellular carcinoma		12 (29.3)		1 (20.0)
Other		18 (43.9)		0 (0)
Cause of death	146		15
Operative		2 (1.4)		0 (0)
Graft failure		24 (16.4)		1 (6.7)
Cardiac		1 (0.68)		1 (6.7)
Pulmonary		2 (1.4)		1 (6.7)
Hemorrhage		3 (2.1)		1 (6.7)
Infection		16 (11.0)		3 (20.0)
Malignancy		66 (45.2)		4 (26.7)
Cerebrovascular		3 (2.1)		0 (0)
Renal failure		1 (0.68)		1 (6.7)
Multisystem organ failure		6 (4.1)		1 (6.7)
Other		5 (3.4)		2 (13.3)
Unknown		17 (11.6)		0 (0)
Graft failure	464	191 (41.2)	41	20 (48.8)
Graft survival time (months)	464	31.4 [11.5, 67.5]	41	47.7 [5.9, 83.1]
Patient survival time (months)	464	31.4 [11.5, 67.5]	41	47.7 [5.9, 83.1]

Values presented as mean ± SD, median [P25, P75], or N (column %).

LT, liver transplant; OLT, orthotopic liver transplant; FU, follow-up.

Of the 45 patients requiring second OLT, 51.2% were alive or lost to follow-up (20 patients alive and one lost to follow-up), 12.2% required another OLT, and 36.6% were deceased. The median patient survival time was 47.7 months. The reason for retransplantation for the five patients requiring another OLT was acute liver failure, autoimmune/cholestatic disease, hepatitis C, and HCC. The most common cause of death was again malignancy (26.7%) followed by infection (20.0%).

Comparison of patient characteristics undergoing OLT for HCC between YA and older patients

Three hundred twenty YA patients were transplanted in the post-MELD era (after 2/27/2002). This group of patients was compared to OAs (41+ years). Table 4 presents the comparison of YA and OA characteristics of HCC transplant recipients. Compared to OAs, the YAs had significantly lower BMI (p < 0.001) and less diabetic comorbidity (<0.001). Race was also significantly different, with the older population having a larger white population, with less black and other race (p < 0.001). The underlying liver diseases between the two groups significantly varied. There was a higher frequency of HBV in the YA group (19.1% vs. 5.5%, p < 0.001), as was autoimmune/cholestatic disease (16.3% vs. 3.7%, p < 0.001), metabolic disease (3.4% vs. 1.3%, p = 0.012), and other tumors/cancer (4.4% vs. 1.3%, p = 0.002). The OAs had a higher amount of alcoholic liver disease (6.9% vs. 11.7%, p = 0.012), hepatitis C (23.3% vs. 56.6%, p < 0.001), and nonalcoholic steatohepatitis (NASH, 1.9% vs. 7.8%, p < 0.001).

Table 4.

Characteristics of Hepatocellular Carcinoma Transplant Recipients: Young Adults Compared to Older Adults in the Post-Model for End-Stage Liver Disease Era (2002–2012)

Factor	Young adult (18–40) (N = 320) Summary	Older adult (41+) (N = 1280) Summary	p-Value
Male	220 (68.8)	880 (68.8)	0.99
Age (years)	33.3 ± 6.3	57.9 ± 6.8
BMI (kg/m²)	26.3 ± 6.0	28.5 ± 5.2	<0.001
Obese	70 (21.9)	456 (35.7)	<0.001
Race			<0.001
White	149 (46.6)	864 (67.5)
Black	64 (20.0)	124 (9.7)
Hispanic	42 (13.1)	165 (12.9)
Other	65 (20.3)	127 (9.9)
Diabetes	31 (10.0)	371 (29.6)	<0.001
Underlying liver disease (nonexclusive)
Alcoholic liver disease	22 (6.9)	150 (11.7)	0.012
Acute liver failure	17 (5.3)	55 (4.3)	0.43
Autoimmune/cholestatic disease	52 (16.3)	47 (3.7)	<0.001
HBV	61 (19.1)	71 (5.5)	<0.001
HCV	76 (23.8)	724 (56.6)	<0.001
Metabolic disease	11 (3.4)	17 (1.3)	0.012
NASH	6 (1.9)	100 (7.8)	<0.001
Other liver tumors/cancer	14 (4.4)	16 (1.3)	<0.001
Other diagnoses	47 (14.7)	113 (8.8)	0.002
Ventilator use	5 (1.6)	9 (0.70)	0.15
Serum creatinine at OLT (mg/dL)	0.80 [0.70, 1.00]	0.90 [0.73, 1.1]	<0.001
Total bilirubin at OLT (mg/dL)	1.9 [1.00, 3.7]	1.6 [1.00, 3.0]	0.068
Albumin at OLT (g/dL)	3.2 [2.7, 4.0]	3.1 [2.7, 3.6]	0.021
MELD at OLT	12.5 [9.0, 17.0]	12.5 [9.0, 17.0]	0.99
Days on waiting list	112.0 [29.0, 321.0]	111.5 [35.0, 260.0]	0.99
Total cold ischemic time (hours)	7.0 [5.2, 9.0]	6.5 [5.0, 8.0]	0.004
Partial/split transplant	11 (3.4)	22 (1.7)	0.055
DRI	1.6 ± 0.41	1.6 ± 0.39	0.18
Post-OLT LOS (days)	8.5 [6.0, 13.0]	8.0 [6.0, 13.0]	0.51
Patient survival time (months)	29.4 [11.6, 60.1]	26.0 [11.2, 56.7]	0.46

Values presented as mean ± SD, median [P25, P75], or N (column %).

Conditional logistic regression was used to compare binary factors between the groups. Mixed linear regression was used for the continuous variables using a natural logarithm transformation; a variance component correlation matrix was used to model the intracluster correlation.

HBV, hepatitis B virus; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; DRI, donor risk index; LOS, length of stay.

At the time of transplant, YA patients had lower serum creatinine and higher albumin, with similar total bilirubin. Median patient survival time was similar, 29.4 months in the YA group and 26.0 months in the OA group (p = 0.46).

Comparison of survival and retransplantation outcomes after first OLT for HCC between YA and older patients

Figure 3 presents the 5-year survival and retransplantation cumulative rates comparing the YA and OA groups. Patient survival was higher in the YA group, but this did not reach statistical significance, with the risk of survival being 74.4% in the YA group and 68.6% in OA group (p = 0.093) (Fig. 3A). Graft survival was not different between the two groups, 66.3% in YA group and 65.4% in the OA group (p = 0.79) (Fig. 3B). The rate of retransplantation was significantly higher in the YA population (9.2% vs. 4.3%, p = 0.01) (Fig. 3C).

FIG. 3.

Five-year survival and retransplantation cumulative rates in the post-MELD era (2002–2012). Patient and graft survival values presented are survival estimates (95% CI) and are obtained from Cox proportional hazards frailty models for clustered data. Retransplantation values are cumulative incidence (95% CI) obtained from competing risks analysis for clustered data. (A) Patient survival after undergoing OLT for HCC. YAs with HCC had higher survival rates than OAs (74.4% vs. 68.6%, respectively, p = 0.093). (B) Graft survival after undergoing OLT for HCC. Graft survival was not significantly different between YAs and OAs (66.3 vs. 65.4, respectively, p = 0.79). (C) Retransplantation rates after undergoing initial OLT for HCC. YAs were retransplanted at higher rates than OAs (9.2% vs. 4.3%, respectively, p = 0.001). MELD, model for end-stage liver disease; OLT, orthotopic liver transplant; CI, confidence interval; YA, young adults; OA, older adults.

Discussion

This study is the first to address survival outcomes specifically for YA patients with HCC following therapy with curative intent in the United States. The principle findings of this study are (1) proportionally underlying liver disease leading to HCC is different between the YA and OA populations; (2) YA HCC patients had lower rates of comorbidities, including obesity, diabetes, and hypertension; and (3) survival outcomes were better, although not statistically significant, in the YA population and the rate of retransplantation was higher.

Curative treatment options for patients with HCC are still very limited, but advances in management bridging to transplant have allowed decreased dropout rate during the mandatory waiting period.²⁰ In addition, patients are being diagnosed at an earlier stage, potentially allowing for increased curative therapy.⁸ There is hope that the incidence of HCC will decrease significantly because of improved hepatitis C virus (HCV) therapy.²¹ This therapy is likely to delay the onset of HCC by halting continued inflammation against the virus, but is not projected to stop the progression of fibrosis eventually leading to HCC.²² Although HCV is the most common underlying liver disease leading to HCC, proportionally HCV is less prevalent in the YA population. Because of this, the effect of improved therapies for HCV may have a less effect on transplants in YAs. HBV is more prevalent in the YA population when compared to the OA both in the United States and in HBV endemic countries, while the rate of HBV-associated HCC is much less in the United States than in other countries with endemic HBV. The YAs included in this study during the post-MELD era should have been offered vaccination, as HBV vaccination has been available in the United States since 1981. Therefore, the importance of vaccinating against this cancer-causing virus should be stressed with all families.

Metabolic risk factors such as obesity and diabetes are associated with HCC development, and although not seen in the majority of the patients in this study, the obesity epidemic and increased rates of diabetes in children, adolescents, and YAs will likely impact HCC in this younger population. Prevalence of pediatric nonalcoholic fatty liver disease (NAFLD), a known consequence of metabolic syndrome, has more than doubled over the last 20 years and is expected to continue to rise. NAFLD and NASH can progress to liver cirrhosis and subsequently lead to HCC. The yearly cumulative incidence of HCC in patients with NASH cirrhosis has been estimated at 2.6% per year compared to 4.0% in patients with HCV-induced cirrhosis.²³ With children developing NAFLD and NASH at younger ages, an increase in HCC in these populations can be expected. This is also concerning because NASH has been shown to recur in transplanted livers in YAs, and patients transplanted for NASH have higher retransplantation rates in this age group than other liver diseases requiring transplant.²⁴

Survival outcomes in YA patients with HCC in HBV endemic countries have been thought to be worse than OAs. This has been postulated to be due to advanced stage at diagnosis and in patients with lower stage disease, the outcomes after hepatectomy have been reported as slightly worse or equal to OAs.^15–17 This is the first study to evaluate OLT outcomes of HCC and the first to report better survival outcomes in the YA age group compared to OAs. Because of the younger age and better survival, there are potentially more life-years saved in transplanting a younger patient.

The main strength of the study is the use of a large nationally representative OLT database, which allowed evaluation of the characteristics and outcomes of HCC as an indication for OLT in YA patients and compared this group to OAs. The study has several limitations mainly inherent in the use of large registry database studies. The assignment of HCC as the primary indication for OLT cannot be confirmed by an independent mechanism and errors in coding can occur. In addition, pertinent clinical information, including portal vein invasion, portal hypertension, size and number of tumors, presence of metastatic disease, and tumor histology, is not consistently reported to the database. Also, no data regarding bridging locoregional or systemic therapy are available in this database.

Although HCC is typically a disease of OAs, 464 YAs with HCC received OLT in the UNOS database from 1987 to 2012. Compared to the older population, the YA group had higher survival and retransplantation rates. HBV, a vaccine preventable illness, was more frequently associated with HCC in younger patients. The MELD-exception for HCC has allowed an increased number of YAs with HCC to receive OLT who would have otherwise had little hope for long-term survival.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Siegel

, Miller

, Jemal

. Cancer statistics, 2016. CA Cancer J Clin. 2016; 66(1):7–30.

Zidan

, Scheuerlein

, Schule

, et al. Epidemiological pattern of hepatitis B and hepatitis C as etiological agents for hepatocellular carcinoma in Iran and worldwide. Hepat Mon. 2012; 12(10 HCC):e6894.

Altekruse

, Henley

, Cucinelli

, McGlynn

. Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States. Am J Gastroenterol. 2014; 109(4):542–53.

Shebl

, Capo-Ramos

, Graubard

, et al. Socioeconomic status and hepatocellular carcinoma in the United States. Cancer Epidemiol Biomarkers Prev. 2012; 21(8):1330–5.

Altekruse

, McGlynn

, Reichman

. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009; 27(9):1485–91.

Ferlay

, Soerjomataram

, Dikshit

, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136(5):E359–86.

Yang

, Hanna

, Usher

, et al. Impact of sex on the survival of patients with hepatocellular carcinoma: a surveillance, epidemiology, and end results analysis. Cancer. 2014; 120(23):3707–16.

Ulahannan

, Duffy

, McNeel

, et al. Earlier presentation and application of curative treatments in hepatocellular carcinoma. Hepatology. 2014; 60(5):1637–44.

Fitzmorris

, Shoreibah

, Anand

, Singal

. Management of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2015; 141(5):861–76.

10.

Mazzaferro

, Regalia

, Doci

, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996; 334(11):693–9.

11.

Sharma

, Welch

, Hussain

, et al. Incidence and risk factors of hepatocellular carcinoma recurrence after liver transplantation in the MELD era. Dig Dis Sci. 2012; 57(3):806–12.

12.

Yamazaki

, Kakizaki

, Sohara

, et al. Hepatocellular carcinoma in young adults: the clinical characteristics, prognosis, and findings of a patient survival analysis. Dig Dis Sci. 2007; 52(4):1103–7.

13.

Kim

, Choi

, Lee

, et al. Clinical features and prognosis of hepatocellular carcinoma in young patients from a hepatitis B-endemic area. J Gastroenterol Hepatol. 2006; 21(3):588–94.

14.

Lam

, Chan

, Ho

, et al. Different presentation of hepatitis B-related hepatocellular carcinoma in a cohort of 1863 young and old patients - implications for screening. Aliment Pharmacol Ther. 2004; 19(7):771–7.

15.

Chang

, Ong

, Lui

, Tan

. Is the prognosis of young patients with hepatocellular carcinoma poorer than the prognosis of older patients? A comparative analysis of clinical characteristics, prognostic features, and survival outcome. J Gastroenterol. 2008; 43(11):881–8.

16.

Shimada

, Kamiyama

, Yokoo

, et al. Clinicopathological characteristics and prognostic factors in young patients after hepatectomy for hepatocellular carcinoma. World J Surg Oncol. 2013; 11:52.

17.

Lee

, Kim

, Lee

, et al. The prognosis in cases of hepatocellular carcinoma after hepatectomy: young patients versus older patients. Korean J Hepatobiliary Pancreat Surg. 2015; 19(4):154–60.

18.

Cepeda

, Boston

, Farrar

, Strom

. Optimal matching with a variable number of controls vs. a fixed number of controls for a cohort study. trade-offs. J Clin Epidemiol., 2003; 56(3):230–7.

19.

Kalbfleisch

, Prentice

. The statistical analysis of failure time data, 2nd edn. Hoboken, NJ: John Wiley & Sons, Inc; 2002.

20.

Fujiki

, Aucejo

, Choi

, Kim

. Neo-adjuvant therapy for hepatocellular carcinoma before liver transplantation: where do we stand?. World J Gastroenterol. 2014; 20(18):5308–19.

21.

, Chung

. Impact of hepatitis C virus eradication on hepatocellular carcinogenesis. Cancer. 2015; 121(17):2874–82.

22.

Nagaoki

, Aikata

, Nakano

, et al. Development of hepatocellular carcinoma in patients with hepatitis C virus infection who achieved sustained virological response following interferon therapy: a large-scale, long-term cohort study. J Gastroenterol Hepatol. 2015; 31(5):1009–15.

23.

Ascha

, Hanouneh

, Lopez

, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010; 51(6):1972–8.

24.

Alkhouri

, Hanouneh

, Zein

, et al. Liver transplantation for nonalcoholic steatohepatitis (NASH) in young patients. Transpl Int. 2015; 29(4):418–24.