Juvenile Hepatocellular Carcinoma in a Healthy Liver.

Primary hepatocellular carcinoma (HCC) in patients <30 years old is extremely rare. In younger patients, HCC develops against a background of persistent hepatitis B virus infection. We herein report a 23-year-old woman with HCC with all-negative hepatitis virus markers developing in an apparently healthy liver. Imaging studies showed a 50-mm hypervascular mass in segment 4 of the left liver lobe, compatible with HCC. The patient underwent surgical resection. A histological examination showed the presence of poorly differentiated HCC. The patient was diagnosed with HCC developing in a healthy liver. This is an extremely rare case of non-B non-C HCC.

Introduction

In Japan, primary hepatocellular carcinoma (HCC) often develops against a background of chronic hepatitis, resulting from persistent infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Individuals over 50 years old are considered the most susceptible. However, the onset of primary HCC at a younger age is often associated with persistent HBV infection (1).

We herein report a 23-year-old woman with primary HCC who showed no findings of chronic hepatitis and for whom all hepatitis-related markers remained consistently negative.

Case Report

A 23-year-old healthy Japanese woman had normal vaginal delivery at 21 years old. One year before this presentation, she noticed an abdominal mass, visited a local doctor, and underwent a follow-up examination. On admission because of dysuria, a tumor was detected by abdominal ultrasonography (US) in her upper abdomen, and she was referred to our hospital for a further examination of the mass. She had no family history of HCC or any other malignancy. Furthermore, she was a non-smoker and non-drinker, with no history of medications including pills or supplements. The patient also had no history of blood transfusion or trauma, such as hepatic trauma. She did not have any metabolic abnormalities, including her thyroid function based on the findings obtained either at the clinic of her own obstetrician at the time of her first child's birth or at our hospital.

On visiting our hospital, her physical characteristics were as follows: height, 159 cm; weight, 35 kg; and body mass index (BMI), 13.8 kg/m2. She had a soft abdomen with no palpable liver or spleen, no abdominal distension, no tenderness, and no edema. Blood test results showed normal results for liver function tests (Table 1). However, some tumor markers were elevated: alpha fetoprotein, 941.8 ng/mL; protein induced by vitamin K absence-II, 1,170 mAU/mL. These findings suggested HCC (Table 1). All HBV markers, including HBsAg, HBsAb, and HBcAb, were negative (Table 1). Results for anti-HCV antibody were also negative. Serum concentrations of IgG, IgM, copper, and ferritin were all normal (Table 1). The laboratory findings for the patient were negative for antinuclear antibody and anti-mitochondrial antibody (Table 1). The albumin level, total bilirubin level, prothrombin time, and indocyanine green (ICG) R15 value were within normal ranges, suggesting a good hepatic reserve (Table 1).

Table 1.

Results of Laboratory Blood Examination on Admission.

TP	7.8	g/dL	AFP	941.8	ng/mL
Albumin	4.8	g/dL	AFP-L3	1.80	%
BUN	11	mg/dL	PIVKA-II	1,170	mAU/mL
Cre	0.49	mg/dL	CEA	0.5	ng/mL
AST	18	U/L	CA19-9	13.2	U/mL
ALT	12	U/L	HBsAg	(-)
γ-GTP	16	U/L	HBsAb	(-)
ALP	216	U/L	HBcAb	(-)
T-bil	0.6	mg/dL	HCVAb	(-)
LDH	161	U/L	IgG	1,179	mg/dL
Na	140	mmol/L	IgM	294	mg/dL
K	3.8	mmol/L	ANA	<40
Cl	106	mmol/L	AMA	<20
ChE	263	U/L
HbA1c	5.3	%	Fe	35.8	ng/mL
WBC	9,320	/μL	Cu	107	μg/dL
RBC	498×104	/μL	TC	204	mg/dL
Hb	13.8	g/dL	TG	55	mg/dL
Plt	26.4×104	/μL
PT-INR	1.06	%
APTT	42.2	s

TP: total protein, BUN: blood urea nitrogen, Cre: creatinine, AST: aspartate aminotransferase, ALT: alanine aminotransferase, γ-GTP: γ-glutamyl transferase, ALP: alkaline phosphatase, T-bil: total bilirubin, LDH: lactate dehydrogenase, ChE: cholinesterase, WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Plt: platelet, PT-INR: prothrombin time-international normalized ratio, APTT: activated partial thromboplastin time, AFP: alpha-fetoprotein, PIVKA-II: protein induced by vitamin K absence or antagonist II, HBsAg: hepatitis B surface antigen, HBsAb: hepatitis B surface antibody, HBcAb: hepatitis B core antibody, HCVAb: hepatitis C virus antibody, ANA: antinuclear antibody, AMA: anti-mitochondrial antibody, TC: total cholesterol, TG: triglyceride

Abdominal US showed a solitary hypoechoic tumor with clear boundaries in segment 4 of the left liver lobe. Abdominal computed tomography (CT) showed a 5-cm tumor in S4 of the liver (Fig. 1a). Multiphase CT showed a strong uptake of the contrast agent in the hepatic arterial phase (Fig. 1b), followed by washout in the portal venous phase (Fig. 1c) and the equilibrium phase (Fig. 1d). However, CT showed no findings of a central scar. Magnetic resonance imaging (MRI) showed decreased and increased signal intensities for the lesion on T1- and T2-weighted imaging, respectively, whereas diffusion restriction with a high signal intensity and a low apparent diffusion coefficient were apparent on diffusion-weighted imaging. Dynamic contrast-enhanced MRI showed strong enhancement in the hepatic artery phase with subsequent washout in the portal venous and equilibrium phases and typical hypointensity in the hepatobiliary phase in segment 4 of the liver. Based on these findings, HCC of cT2N0M0 cStage II (Union for International Cancer Control Seventh Edition, UICC 7th edition) was diagnosed.

Figure 1.

Multiphase computed tomography (CT) on admission showing juvenile hepatocellular carcinoma that developed in a normal liver. a) Image taken before the administration of contrast medium shows a tumor in the S4 segment of the liver. b-d) Findings of contrast-enhanced CT. A solid hepatic mass is seen in the S4 segment of the liver. The uptake of the contrast agent in the hepatic arterial phase (b) is strong, with subsequent washout in the portal venous phase (c) and the equilibrium phase (d).

The patient underwent surgical resection of segment 4, as her hepatic reserve was considered adequate for resection. The operation and postoperative clinical course were uneventful, and the patient was discharged on postoperative day 7.

A postoperative examination of the tumor specimen showed a 50×30-mm lesion with expansive growth (Fig. 2a). A histological examination of the non-tumorous portions of the specimen showed no fibrosis (Fig. 2b), and no infiltration of inflammatory cells into the portal areas or hepatic lobules was evident (Fig. 2b). No fatty deposits were identified in hepatocytes (Fig. 2b). The pathological report indicated poorly differentiated HCC, as follows: fc (capsule formation) (+), fc-inf (infiltration) (+), sf (septum formation) (+), s0, n0, Vp1, Vv1, Va0, b0, p0, sm (-) pT2 N0 M0 p Stage II (UICC, 7th edition) (Fig. 2c).

Figure 2.

A postoperative examination shows a tumor 50×30 mm in size with expansive growth. a) Resected tumor. b) Hematoxylin and Eosin (H&E) staining of the noncancerous portions showing no fibrosis and no inflammatory infiltration to the portal areas and hepatic lobules. c, d) H&E staining of the tumor showing partial fatty changes, a solid nest structure, and a false duct structure, indicating poorly differentiated hepatocellular carcinoma. The tumor cells show invasion into a capsule with partial vascular invasion.

She gave birth to her second child 15 months after surgery, and at the time of writing this manuscript, at 5 years post-operation, she has had no recurrence of the disease. We conducted follow-up investigations such as blood tests, including tumor marker evaluations, every month, abdominal US every three months, and abdominal CT every six months.

Discussion

Approximately 80% of primary liver cancers are HCC, and 80% of all HCC patients have chronic hepatitis or liver cirrhosis with persistent HBV or HCV infection and a history of alcohol intake (1-6). Recently, the incidence of non-B non-C-type HCC, which may be due to alcoholic hepatitis, nonalcoholic steatohepatitis, hemochromatosis, primary biliary cirrhosis (PBC), or drugs such as oral contraceptive pill (7-11), has been reported to be increasing. In Japan, HCV infection often causes chronic hepatitis or liver cirrhosis, and HCC caused by HCV often develops in middle-aged patients (12,13). The frequency of HCC in patients ＜35 years old is 0.89%, and only 0.14% are ＜25 years old (6,12). In carcinogenesis of HCC in young patients, the roles of HBV DNA integration or the HBV HBx protein have been reported (14,15). HCC that occurs unrelated to hepatitis or liver cirrhosis is extremely rare (3.2%) in Japan (12). Fibrolamellar HCC (FLC) is a special type of liver cancer (16,17) that develops in young patients and is unrelated to hepatitis or liver cirrhosis. It is characterized by a large tumor with calcification and a central scar (17,18).

In the present case, the patient was a young woman, at only 23 years old. Furthermore, in this case, hepatitis virus-related markers such as HBsAg, HBsAb, HBcAb, HCVAb were all negative, and neither HBV-DNA nor HCV-RNA was detected. In the postoperative examination of pathological specimens, the background liver appeared normal and no findings suggestive of chronic hepatitis were detected and the pathological findings were also different from FLC. As far as we search in Pubmed and medical journal ‘Igaku Chuo Zasshi (ICHUSHI)’ up to 2021, only 17 cases of non-B non-C HCC without chronic hepatitis or liver cirrhosis in the liver have been reported (Table 2). Although approximately half of those cases involved patients who were under thirty years old, only two cases, showed HCC without previous history, family history, blood transfusion history, drinking history or oral administration other than this patient. The patient was definitively underweight and BMI was low. However, her weight did not change preoperatively, and she had not experienced any changes in her body shape during her life. Further, blood testing revealed no evidence of malnutrition, and no evidence of fatty liver from malnutrition was seen in the background liver on postoperative pathology, so we do not believe that underweight status affected the development of HCC in this case. Therefore, we consider this case as extremely rare.

Table 2.

Juvenile Hepatocellular Carcinoma without Hepatitis Infection: Summary of Case Reports.

No.		Age (years)	Sex	HBsAg/Ab	HBcAb	HBV-DNA	HCV-Ab	Family history	Past history	Drinking/smoking
1	22)	25	F	-/-	-	-	-	-	Mycoplasma pneumonia	-/-
2	23)	23	F	-/-	-	-	-	Chronic hepatitis	Congenital cataract	-/-
3	8)	17	M	-/-	-	-	-	-	Bone fracture	-/-
4	24)	28	M	-/-	ND	-	-	-	-	-/+
5	25)	20	M	-/-	-	-	-	-	-	ND/ND
6	26)	20	M	-/-	-	-	-	-	Precocious puberty	ND/ND
7	27)	25	F	-/-	-	ND	-	ND	Epilepsy	ND/ND
8	28)	25	F	-/-	-	-	-	-	Ovarian cyst	-/-
9	29)	26	F	-/-	-	ND	ND	ND	ND	ND
10	30)	39	F	-/-	-	-	-	ND	ND	-/-
11	31)	41	M	-/-	-	-	-	-	-	-/-
12	32)	31	F	-/-	-	-	-	ND	Pyogenic spondylitis	ND
13	33)	31	M	-/-	-	-	-	-	Appendicitis	+/-
14	34)	40	F	-/-	ND	-	-	-	-	-/ND
15	35)	26	M	-/-	-	-	-	-	-	+/+
16	36)	30	M	-/-	-	-	-	-	Asthma	-/ND
17	37)	20’s	M	-/-	-	-	-	-	-	-/-
18	Onishi et al.	23	F	-/-	-	-	-	-	-	-/-
No.		Transfusion recording	Drug	AFP	PIVKAII	Treatment	Recurrence	Outcome (after treatment)
1	22)	-	ND	35,200	14.4	TAE	No recurrence	Alive 11 months
2	23)	-	-	10,320	Normal	TAE	Brain metastasis (2 years)	Died 2 years
3	8)	+	-	<3.0	<1.0	TAE, Ope	No recurrence	Alive 19 months
4	24)	-	-	37,000	18,100	ND	No recurrence	Died 16 days
5	25)	-	-	181.8	75,000	Ope, TAE, PEIT	Intrahepatic (7 months)	Alive 36 months
6	26)	ND	ND	25,100	292	Ope	No recurrence	Alive 30 months
7	27)	ND	Phenytoin	5,011	6,022	TAE, Ope	No recurrence	Alive 21 months
8	28)	-	-	1.2	329	Ope	No recurrence	Alive 108 months
9	29)	ND	ND	>300	ND	Palliative chemo	No recurrence	Died 3 months
10	30)	-	-	Normal	Normal	Ope	ND	ND
11	31)	-	-	ND	ND	BSC	ND	Died 3 months
12	32)	ND	-	4.1	39	Ope	No recurrence	Alive 31 months
13	33)	-	-	4.8	41	Ope	ND	Alive 24 months
14	34)	+	ND	ND	ND	BSC	ND	Died 8 days
15	35)	-	-	Normal	Normal	Ope	ND	ND
16	36)	-	-	2.3	24	Ope	-	Alive 10 months
17	37)	ND	-	76,860	74,849	Chemotherapy	ND	Died 9 months
18	Onishi et al.	-	-	941.8	1,170	Ope	-	Alive 60 months

M: male, F: female, ND: not described, TAE: transcatheter arterial embolization, Ope: operation, PEIT: percutaneous ethanol injection therapy, BSC: best supportive care

Recently, methods for genome-wide association analyses have advanced dramatically, and some reports have provided genomic information for HCC. However, HCC is a heterogeneous disease, with characteristics not only due to the cause, but also due to the genetic characteristics of the tumor, as the process of multicentric carcinogenesis differs between individual cases. In addition to identifying gene mutations for whole-genome sequencing, viral integration can also be identified. In recent years, not only the HBV genome, but also the adeno-associated virus type 2 genome has been reported to become integrated into HCC, and many cases without known risk factors have been reported. In our case, genome sequencing thus appears important for clarifying the genetic characteristics of carcinogenesis.

In general, HCC that develops in young patients often progresses and shows a low degree of differentiation on histology (19,20). Recurrence within one year or pathological vascular invasion at the time of initial resection is said to be a factor contributing to poor prognosis at the time of recurrence (21) and follow-up within the short term using various modalities is desirable after surgical resection. In our case, vascular invasion (Vp1, Vv1) was seen in the postoperative pathological tissue, so the risk of recurrence was considered high. We conducted follow-up observations such as blood tests including tumor markers every month, abdominal ultrasonography every three months, and abdominal CT every 6 months. As of 5 years after surgery, she is undergoing follow-up with no recurrence, and we will continue follow-up observation in the future.

In conclusion, we experienced present an extremely rare case of non-B non-C HCC occurred in normal liver in at 23 years old. No recurrence has been observed for 5 years, however, careful follow-up is required due to the risk of recurrence.

The authors state that they have no Conflict of Interest (COI).