Hepatic resection in adolescent and young adult patients with hepatocellular carcinoma

Abstract

BACKGROUND

In Japan, primary hepatocellular carcinoma (HCC) often develops in the setting of chronic hepatitis, such as persistent hepatitis B virus (HBV) or hepatitis C virus infection. Patients with HCC are commonly in their 50s or 60s, and the occurrence of HCC in individuals in their 40s or younger is extremely rare. The adolescent and young adult (AYA) population refers to individuals aged 15-39 years. Patients with cancer in the AYA population may present distinct clinical features and biological characteristics.

AIM

To evaluate the outcomes of hepatic resection for AYA patients with HCC at our institution.

METHODS

We retrospectively analyzed 885 patients who underwent hepatectomy at our institution between 1994 and 2024. Patients were categorized into two groups: the AYA group and the non-AYA group. Patient demographics, operative details, perioperative outcomes, pathological features, clinicopathological findings, overall survival (OS), and recurrence-free survival (RFS) were compared between the groups.

RESULTS

Nine patients (5 males and 4 females) were younger than 40 years. The incidence of AYA HCC was 1.0%. Six patients had a history of hepatitis B. The percentage of HBV-positive patients was significantly greater in the AYA group than in the non-AYA group, and the tumor diameter was significantly greater in the AYA group. There were no significant differences in tumor marker levels, vascular invasion, differentiation, OS rate, or RFS rate between the AYA and non-AYA groups.

CONCLUSION

The outcomes of hepatic resection for AYA patients with HCC are favorable. Early detection of AYA HCC and timely hepatectomy are recommended.

Key Words: Hepatocellular carcinoma; Hepatectomy; Adolescent and young adult; Lung metastasis; Overall survival

Core Tip: This study evaluated the outcomes of hepatic resection in adolescent and young adult (AYA; age 15-39 years) patients with hepatocellular carcinoma (HCC). Among 885 patients who underwent hepatectomy, 9 (1.0%) were classified as AYAs, with hepatitis B virus infection significantly more common and tumors larger in the AYA group than in the non-AYA group. However, tumor marker levels, vascular invasion, differentiation, overall survival, and recurrence-free survival did not differ between the groups. Although rare, AYA HCC showed favorable surgical outcomes, highlighting the importance of early detection and timely hepatectomy.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related mortality[1]. More than 815000 new cases of HCC are diagnosed globally each year, and approximately 40% of patients present with advanced-stage disease at the time of diagnosis. Despite advances in treatment, HCC accounts for approximately 700000 deaths annually. The mortality rate of liver cancer is consistently higher in men than in women[2].

In Japan, primary HCC often develops against a background of chronic liver disease, particularly persistent hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients with HCC are most commonly diagnosed in their 50s or 60s, and the occurrence of HCC in individuals in their 40s or younger is extremely rare[3]. In Japan, such cases reportedly account for only 0.23% of all HCC cases. The adolescent and young adult (AYA) population refers to individuals aged 15-39 years[4]. Patients with cancer in the AYA population may exhibit distinct clinical features and biological characteristics[4]. In this study, we evaluated the outcomes of hepatic resection in AYA patients with HCC treated at our institution.

MATERIALS AND METHODS

Study design

We retrospectively analyzed 885 patients who underwent hepatectomy at our institution between 1994 and 2024. Patients were categorized into two groups: The AYA group and the non-AYA group. Patient demographics, operative details, perioperative outcomes, pathological features, clinicopathological findings, overall survival (OS), and recurrence-free survival (RFS) were compared between the groups. The median follow-up durations for the AYA group and the non-AYA group were 1221 days and 979 days, respectively.

Ethics

This was a retrospective study. Ethical approval was obtained from the accredited Ethics Committee of Nippon Medical School Hospital (Approval No. B-2023-795), and written informed consent was obtained from all participants before enrolment. Data collection and analysis were performed in accordance with the institutional guidelines and the ethical standards of the Declaration of Helsinki. Consent for publication was obtained from all participants. The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request. The authors declare no competing interests. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Statistical analysis

Statistical analysis was performed using the SPSS statistical software (IBM Corp., Armonk, NY, United States). Categorical variables were compared using the χ² test or Fisher’s exact test, as appropriate. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test and Cox proportional hazards regression analysis. A P value less than 0.05 was considered statistically significant.

RESULTS

AYA population

The clinical characteristics of the study participants are summarized in Table 1. Nine patients (5 male and 4 female) were younger than 40 years, representing 1.0% of the HCC cases. A detailed summary of these nine patients is provided in Table 2. Among the AYA patients, six had a history of HBV infection, and five had a history of liver cirrhosis. Two patients experienced recurrent HCC, and one patient died 18 months after surgery.

Table 1 Clinicopathological characteristics of the study participants.

Clinical features	Data
Age (year)	69.6
Sex (male/female)	684/201
BMI (kg/m2)	26.8
HBV	120 (13.6)
HCV	367 (41.5)
LC	341 (38.5)
AFP (ng/mL)	4273
PIVKA-II (mAU/mL)	6482
Child-Pugh class (A/B/C/NA)	752/96/0/37
Partial hepatectomy	367 (41.5)
Laparoscopic hepatectomy	304 (34.4)
Vascular invasion (+)	269 (30.4)
Single tumor	640 (72.3)
Tumor diameter (mm)	42.4
pStage (I/II/III/IV/NA)	143/337/243/100/62
Operative time (min)	313
Intraoperative blood loss (mL)	745
Positive surgical margin	82 (9.27)
Blood transfusion	112 (12.7)
Postoperative hospital stays (days)	15.7
Morbidity	106

Data are presented as n (%), n, or mean, unless otherwise indicated. AFP: Alpha-fetoprotein; BMI: Body mass index; HBV: Hepatitis B virus; HCV: Hepatitis C virus; LC: Liver cirrhosis; NA: Not available; PIVKA-II: Protein induced by vitamin K absence or antagonist-II; pStage: Pathological stage defined according to the Union for International Cancer Control (8^th edition).

Table 2 Summary of hepatectomy for hepatocellular carcinoma in the adolescent and young adult group.

Date	Age (year)	Sex	HBV	Child-Pugh class	LC	Hepatectomy	pStage	Cur	Recurrence	Outcome	OS (day)
September 22, 2023	24	M	-	A (5)	-	Lap-subsectionectomy (S8)	II	A2	-	Alive	65
March 4, 2022	26	F	+	A (5)	-	Central bisectionectomy	III	B	-	Alive	177
March 29, 2024	30	F	-	A (6)	+	Lap-partial hepatectomy (S2)	III	C	+	Alive	102
June 25, 2008	34	M	+	A (6)	+	Rt. hepatectomy	III	B	+	Dead	525
December 9, 2015	35	F	+	A (5)	+	Lap-partial hepatectomy (S6)	II	A2	-	Alive	2691
April 10, 2015	37	M	+	A (5)	-	Lap-partial hepatectomy (S8)	I	A1	-	Alive	2983
October 13, 2011	38	M	+	A (6)	+	Rt. hepatectomy	III	B	-	Alive	3842
August 15, 2016	38	F	-	A (5)	+	Partial hepatectomy (S6)	II	A2	+	Alive	2565
August 15, 2008	38	M	+	B (7)	-	Posterior sectionectomy	IV A	B	-	Alive	22

Cur: Surgical curability classification; F: Female; HBV: Hepatitis B virus; LC: Liver cirrhosis; M: Male; OS: Overall survival; pStage: Pathological stage according to the Union for International Cancer Control (8^th edition); S: Couinaud segment.

The percentage of HBV-positive patients was significantly greater in the AYA group than in the non-AYA group, and the tumor diameter was significantly larger in the AYA group (Table 3). There were no significant differences in tumor marker expression, vascular invasion, differentiation, OS rate, or RFS rate between the groups (Table 3 and Figure 1). A total of 382 deaths and 453 recurrences were recorded during the study period.

Figure 1 Survival curves of the adolescent and young adult (AYA) and non-AYA groups. A: Overall survival curve for patients in the adolescent and young adult (AYA) and non-AYA groups; B: Recurrence-free survival curve for patients in the AYA and non-AYA groups. AYA: Adolescent and young adult; HCC: Hepatocellular carcinoma.

Table 3 Clinicopathological findings in the adolescent and young adult and non-adolescent and young adult groups.

Variable	AYA group (n = 9)	Non-AYA group (n = 885)	P value
Age (year)	33.3	70.0	0.001
Sex (male/female)	5/4	679/197	0.125
BMI	21.6	26.9	0.875
HBV	6/3	114/733	0.001
HCV	0/9	367/483	0.006
LC	2	370	0.353
AFP in ng/mL	7971	4236	0.795
PIVKA-II in mAU/mL	6489	6483	0.999
Child-Pugh class: A/B/C	8/1/0	744/95/0	0.820
Partial hepatectomy: +/-	4/5	363/522	0.554
Laparoscopic hepatectomy: +/-	4/5	300/585	0.375
Vascular invasion: +/-	5/4	264/550	0.134
Tumor number as single/multiple	8/1	632/151	0.460
Tumor diameter in mm	79.3	44.3	0.002
pStage: I/II/III/IV	1/3/4/1	142/334/239/99	0.866
Operate time (min)	263	313	0.269
Operate bleeding (mL)	642	745	0.803
Surgical margin: +/-	0/9	82/686	0.456
Blood transfusion: +/-	¾	109/429	0.156
Postoperative hospital stays (days)	10.0	15.8	0.335
Morbidity: +/-	0/9	106/449	0.349

Data are shown as n (%), n, or mean, unless otherwise indicated. AFP: Alpha-fetoprotein; AYA: Adolescent and young adult; BMI: Body mass index; HBV: Hepatitis B virus; HCV: Hepatitis C virus; LC: Liver cirrhosis; PIVKA-II: Protein induced by vitamin K absence or antagonist-II; pStage: Pathological stage according to the Union for International Cancer Control (8^th edition).

Single case presentation

Here, we present the case of a 38-year-old woman who was admitted to our hospital with an abdominal tumor. Serological testing showed no evidence of hepatitis virus infection; however, serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels were elevated. Abdominal computed tomography revealed a 10-cm tumor in segment 6 of the liver. A slightly strong uptake of the contrast agent was observed in the hepatic arterial phase, followed by isodensity in the portal venous, hepatic venous, and equilibrium phases (Figure 2).

Figure 2 Abdominal computed tomography images demonstrating a 10-cm tumor in segment 6 of the liver. A slightly strong uptake of the contrast agent was observed in the hepatic arterial phase, and the lesion became isodense during the portal venous, hepatic venous, and equilibrium phases (arrows).

Based on these findings, the patient was diagnosed with clinical stage IB HCC (cT1bN0M0) according to the Union for International Cancer Control (UICC) 8^th edition. A partial hepatectomy of segment 6 was performed. Postoperative examination of the resected specimen revealed a 100-mm × 80-mm tumor with expansive growth (Figure 3A). Histopathological examination revealed moderately differentiated HCC without vascular invasion, corresponding to pathological stage IB (pT1bN0M0; UICC, 8^th edition; Figure 3B).

Figure 3 Pathological findings of the resected tumor. A: Gross specimen showing a 100-mm × 80-mm lesion with expansive growth; B: Histological examination revealing moderately differentiated hepatocellular carcinoma without vascular invasion (pT1bN0M0, pathological stage IB; Union for International Cancer Control, 8^th edition).

One year after surgery, the patient’s AFP and PIVKA-II levels were again elevated. Positron emission tomography revealed lung metastasis without evidence of intrahepatic recurrence (Figure 4). Partial resection of the left lung was subsequently performed. Histopathological examination confirmed metastatic HCC (Figure 5). At the time of writing this report, the patient has remained alive for more than 7 years since the initial hepatectomy.

Figure 4 Positron emission tomography findings demonstrating pulmonary metastasis (arrow). A: Plane computed tomography (CT) image; B: Positron emission tomography (PET)-CT axial image; C: Coronal PET-CT image.

Figure 5 Pathological findings of the pulmonary lesion. A: Resected lung specimen; B: Histopathological examination confirming pulmonary metastasis from hepatocellular carcinoma.

DISCUSSION

In this study, we focused on HCC in the AYA population. Although individuals in this age group are generally in a period of peak health, approximately 1 million new cases of cancer are diagnosed worldwide each year among AYA individuals[5]. In Western countries, patients with HBV-associated HCC in East Asia and Africa are generally younger than those with HCV-associated HCC[6]. Mechanistically, HBV DNA integration into the host genome and the oncogenic effects of HBV X (HBx) protein have been implicated in hepatocarcinogenesis in young patients[7,8].

Approximately 50%-80% of HCC cases worldwide are caused by HBV infection[9]; however, in Japan, HBV-related HCC represents only 13.8% of cases[10]. Zhang et al[11] reported that most AYA patients with HCC had a history of HBV infection and good liver function. In contrast, the occurrence of non-HBV and non-HCV-related HCC in AYA individuals with normal liver parenchyma is extremely rare[12].

Several studies have revealed that AYA patients with HCC are usually diagnosed at an advanced stage[13-15] and tend to present with larger tumors[14]. Consistent with these findings, the tumor size was significantly larger in AYA patients than in non-AYA patients. According to the Barcelona Clinic Liver Cancer staging system, 5%-10% of patients in Western countries are diagnosed at stage 0, while in Japan, almost 30% are diagnosed at this stage, largely owing to the widespread implementation of surveillance programs[16]. In our study, AYA patients were also diagnosed at a non-advanced stage, reflecting the effectiveness of surveillance strategies in Japan.

Liver resection in AYA patients with HCC is associated with a lower complication rate, with only 1.1% of patients experiencing severe postoperative complications. This favorable outcome is largely attributed to the generally good preoperative physical condition and preserved organ function of young patients[3]. However, despite favorable surgical outcomes, AYA survivors of cancer remain at increased risk of mental health challenges, including anxiety, depression, and other mood disorders[17]. AYA oncology patients also face unique psychosocial issues[3]. When diagnosed with cancer, these patients might experience disruptions in their social life, potential loss of reproductive capacity, and concerns about their long-term health. Additionally, many AYAs are the main economic contributors to their households and are responsible for supporting their parents or raising their children. Consequently, the potential loss of social roles and work capacity can lead to significant financial strain. Therefore, multidisciplinary efforts are needed to improve the social function and quality of life of AYA patients in the long term.

The prognosis of HCC in the AYA population is controversial. Several reports have revealed that the poorer outcomes in AYA patients are largely attributable to the advanced stage of the disease at diagnosis[18]. In contrast, other studies have demonstrated comparable disease-free survival and OS between AYA patients and older patients[11,19]. In our study, no significant differences were observed in the OS or RFS between the AYA and non-AYA groups. However, further studies with larger sample sizes are warranted to better clarify the prognosis of HCC in AYAs.

This study had several limitations. First, its retrospective design limited causal inference, and the characteristics of the AYA patients in this single-center cohort cannot be generalized to patients in other regions. Second, the number of AYA patients with HCC was small, reflecting the rarity of the disease in this age group. Third, the study period spanned several decades, during which the indications for hepatectomy, chemotherapy protocols, and surveillance strategies evolved, potentially introducing temporal bias. Future studies involving larger cohorts and multicenter collaborations are needed to validate these findings and better characterize the clinical features and outcomes of AYA HCC.

CONCLUSION

Outcomes following hepatic resection for AYA HCC were favorable in the present patient. Early detection of AYA HCC and prompt hepatectomy are strongly recommended to optimize clinical outcomes.