Pediatric hepatocellular carcinoma

Table 1 Clinical characteristic of children with hepatocellular carcinoma in series from East

Study → Ref. (yr)	Mooreet al[7](2004)	Wanget al[38](2017)	Chenet al[10,29] (1988, 1998)	Hsuet al[28](1987)	Zhanget al[12](2013)	Arikanet al[13](2006)	Palaniappanet al[26](2016)
Region	South Africa	China	Taiwan	Taiwan	China	Turkey	India
No. of subjects	68	65	44, 55	51	45	13 (Incidental diagnosis in 3)	12 (8 diagnosed in explant livers)
Males (%)	68 (78 in HBV subgroup)	80	Males dominated	77	93	46	75
Age (yr)	Mean 10.5	Median 17 (8-20)	-	Mean 11 (4-15)	Mean 13.5 (3-18)	6.4 ± 4.8	Median 5.9 (1.6-15.4)
Age-group (n or %)	91% > 6 yr of age	-	-	39% < 9 yr of age	-	-	< 5 yr→3 5-10 yr→7 > 10 yr→2
Size (cm)	-	10.2 ± 4.1	-	-	> 5 cm in 73% > 10 cm in 67%	Median 3.4 (0.5-8)	22.5 (2-40)
Multifocality	-	62%	62%	-	56% Satellite lesions in 18%	92% Median number of nodules 3 (1-10)	42% Median number of nodules 1 (1-5)
Etiology	67% HBV	82% HBV	100% HBV	100% HBV	71% HBV	6 Tyr 6 HBV 1 GSD1	5 Tyr 2 BA 1 BSEP 1 MDR3 1 NSPILBD 1 PSC 1 Caroli’s
Histology (n or %)	HCC 87% FLHCC 13%	-	-	-	-	Well diff 2 Mod diff 4 Poorly diff 6	Well diff 8 Mod diff 4 (High grade dysplasia or nodules in adjoining liver in 50%)
Cirrhosis	-	-	71%, 68%	74% (95%) in < 9 yr of age	47% Child A/B/C 32/8/5	100% Mean CTP 11.1 ± 3.1 and PELD 19.7 ± 2.4 (1-44)	-
AFP	High in 69%	> 25 ng/mL in 91%	-	-	93999 ± 31228 ng/mL High in 87%	8000-250000 ng/dL High in 92%	Median AFP 7.3(1.2-28000) IU/L High AFP (> 100 IU/L) in 42%
Extent or stage (n or %)	-	TNM Stage III/IV in 74%	-	Advance stage in 98%	-	TNM stage I (20%), IV (80%) Advance disease in 92%	-
Vascular invasion	-	31%	42% PV 17% IVC	-	47%	54%	17%
Metastases	-	17%	29%	-	24%	0	-
Resectability	-	40%	< 10%, 18%	13%	27%	NA	NA
Outside Milan	NA	NA	NA	NA	NA	NA	NA

AFP: Alpha-fetoprotein; BA: Biliary atresia; BSEP: Bile salt export pump deficiency (PFIC2); diff: Differentiated; FLHCC: Fibrolamellar variant of HCC; GSD: Glycogen storage disease; HBV: Hepatitis-B virus; IVC: Inferior vena cava; LT: Liver transplantation; MDR3: Multidrug resistance protein3 deficiency (PFIC3); NA: Not assessed; NSPILBD: Non-syndromic paucity of bile ducts; PRETEXT: Pretreatment tumor extent evaluation; PSC: Primary sclerosing cholangitis; PV: Portal vein; TNM: Tumor node metastasis stage; Tyr: Tyrosinemia; Mod: Moderately.

Table 2 Clinical characteristics of children with hepatocellular carcinoma in series from West

Study→Ref. (yr)	SEER[8,15,30] (2013, 2013, 2014)	POG[16](2002)	SIOPEL 1[27] (2002)	Lacket al[31](1983)	Phamet al[17](2007)	Ismailet al[22](2009)	Romanoet al[18](2011)	Beaunoyeret al[23](2007)
Region	United States	United States	Europe	United States	United States	Poland	Italy	United States
Number of subjects	238, 80, 218	46	39	32	22	21	10	10
Males (%)	58	57	72	63	50	-	40	60
Age (yr)	12.9 ± 5.2	-	Median 12 (4-15)	Mean 9.7 (0.5-21)	13.1 ± 1.1 (2-18 )	Median 11.1 (2-18)	Median 1.8 (0.5-7.2)	Median 10.1 (4.4-16.3)
Age-group (%)	0-4 (8-9) 5-9 (14-16) 10-14 (27-29) 15-19 (48-49)	< 1 y (6.5) 1-9 y (37) ≥ 10 y (56.5)	-	-	-	≤ 2 (5) 2-10 (38) ≥ 10 (57)	< 2 (50) 2-5 (30) ≥ 5 (20)	3-12 (70) ≥ 13 (30)
Size (cm)	0-5 (21%) 5.1-10 (24%) 10.1-15 (36%) > 15 (19%)	-	Median 14 (7-26) cm	-	11.8 ± 0.6 (5-25) cm	-	-	Median 5.8 (2-10.5) cm > 5 cm in 60%
Multifocality	Satellite lesions 28%	-	56% (4 diffuse)	-	-	-	50% (2-10 in No.)	70%
Etiology	-	-	13 HBV 1 Tyr 1 Biliary	-	-	4 Tyr 2 HBV 1 HCV 1 A1ATD 1 AIH 1 PFIC 11 no liver ds	3 BA 3 PFIC2 2 Tyr 1 CC 1 GSD4	4 Viral (3HBV) 1 Tyr 1 Alagille’s 1 PFIC 3 No Liver ds
Histology (n or %)	HCC NOS 58%-74% FLHCC 24%-41% Clear cell 1%-2%	HCC 78% FLHCC 22%	Epithelial 75% FLHCC 15% Poorly diff or clear cell 10%	HCC 84% FLHCC 16%	-	High grade2 (29%) Low grade (52%) FLHCC (19%)	G1 (1) G2 (6) G3 (3)2 No FLHCC	HCC in 9 FLHCC in 1
Cirrhosis	-	-	38%	16%	-	52%	100%	50%
AFP	-	≥ 20 ng/mL in 67%	Median 9677 (1-1400000) ng/mL > 10 ng/mL in 69%	-	-	1.7-713000 IU/mL	Median 2322 (3-35000) ng/mL	Median 446927 ng/mL
Extent or Stage (n or %)	Local 27%-28% Regional 35%-37% Distant 34%-35%	Stage I (8), II (0), III (25), IV (13)1	PRETEXT I (1), II (14), III (11), IV (13)	-	CCG/POG Stage I (60%), II (11.5%), III (17%), IV (11.5%)1	PRETEXT I (4), II (7), III (5), IV (5)	PRETEXT I (4), II (1), III (1), IV (4)	TNM Stage I (0), II (3), III (7), IV (0) T2 (3), T3 (6), T4 (1)
Vascular invasion	48%	-	21%	-	-	29%	20%	30%
Metastases	35%	-	Lung 31% Other 18%		-	0	-	-
Resectability	25%	22%	36%	22%	67%	48%	NA (All LT)	NA
Outside Milan	-	-	-	-	-	86%	60%	70%

¹Staging done as I, complete gross resection with pathologically negative margins; II, gross total resection with microscopic residual disease at margins; III, gross total resection with nodal involvement or tumor spill; and IV, metastatic disease with either complete or incomplete resection or biopsy;

²Grade as per Edmondson and Steiner. A1ATD: Alpha-1 antitrypsin deficiency; AFP: Alpha-fetoprotein; AIH: Autoimmune hepatitis; BA: Biliary atresia; CC: Choledochal cyst; CCG: Children’s cancer group; diff: Differentiated; FLHCC: Fibrolamellar variant of HCC; GSD: Glycogen storage disease; HBV: Hepatitis-B virus; HCV: Hepatitis-C virus; LT: Liver transplantation; NA: Not assessed; PFIC: Progressive familial intrahepatic cholestasis; PRETEXT: Pretreatment tumor extent evaluation; POG: Pediatric oncology group; SEER: Surveillance epidemiology and end-results; SIOPEL: Group for epithelial liver tumors of the international society of pediatric oncology; TNM: Tumor node metastasis stage; Tyr: Tyrosinemia.

Table 3 Changing outcome of children with hepatocellular carcinoma over last 4 decades

Study (yr)Ref.	Number of patients	Factors governingoutcome	Intervention (s)done	Survival
Conservative treatment (Observation and resection)
Lack et al[31] (1983)	32 (5FLHCC)	Higher resectability and overall survival with FLHCC	Observation Resection	5 yr 7% MST of HCC 4.2 mo and FLHCC 28.5 mo
Wu et al[96] (1987)	20	-	-	5 yr 0; MST 4.7 mo
Hsu et al[28] (1987)	51	Early HBeAg seroconversion with severe liver injury predispose to HCC	Observation Resection	1 yr 10.5%
Chen et al[29] (1988)	44	No difference in survival with chemotherapy	Observation Resection	5 yr 7%
Ni et al[97] (1991)	71	Favorable prognosis with resectability and absence of icterus	Observation Resection	1 yr 10%, 5 yr 4%
Lee et al[6] (1998)	28	-	-	5 yr 17%
Hsiao et al[98] (2009)	13	-	-	DFS 30%
Allan et al[8] (2014) SEER database	218	Reduced mortality associated with resectability (OR = 0.18), non-Hispanic (OR = 0.52), local disease (OR = 0.46)	-	5 yr 24%, 10 yr 23%, 20 yr 8%
Mixed treatments (chemotherapy/TACE/liver transplantation)
Tagge et al[99] (1992)	21	Total hepatectomy and LT improved survival in those with unresectable disease	Surgery in 15 (6 PH, 7 LT, 2 Exenteration and MOT) Pre-operative CT in 2 Observation in 6	1 yr 29%
Chen et al[10] (1998)	55	Good outcome with resection, poor with unsatisfactory resection & metastases Distant metastases carries worst prognosis	Resection CT Observation	MST with resection 23 mo, CT 3 mo and no treatment 2 mo
Moore et al[7] (2004)	68	-	Resection ± CT TACE Observation	> 5y 11% MST 4 mo
Pham et al[17] (2007)	22	-	Surgery ± CT	OS 5 yr 30% MST 23 mo
Zhang et al[12] (2013)	45	Low overall survival with metastases & non-resectability, but unrelated to HBsAg positivity Large tumor size, early metastasis, bilateral involvement, and PV invasion precluded resection	Resection TACE Observation	1 yr 34%, 3 yr 4%, 5 yr 4% MST 6 mo (Resection 28.6 mo, TACE 4 mo, None 5 mo, presence of metastases 4 mo)
McAteer et al[15] (2013) SEER database	238	Lower hazard of death with surgery (HR = 0.23) and lymphadenectomy (HR = 0.26) More hazard of death with female gender (HR = 2.07), older age (> 5 yr, HR > 5) and distant metastases (HR = 3.4)	Surgery in 112 No surgery in 118 Unknown in 8	OS 5 yr for 0-4 yr age 53%, 5-19 yr age 32% OS 5 yr for males 40%, females 26% DFS 5 yr for localized 61%, regional 39% and metastatic 9% DFS 5 yr 70% with lymphadenectomy vs 57% without
McAteer et al[30] (2013) SEER database	80	Lower hazard of death with LT as compared to resection (HR = 0.05)	Surgery (LT 20, resection 60)	OS 5 y with LT 85%, Resection 53%
Wang et al[38] (2017)	65	Initial treatment allocation predicted OS (TACE HR = 0.298, Resection HR = 0.105 with No treatment as reference)	Resection TACE No treatment	For moderate stage disease: Median OS longer with resection (38 mo) vs TACE (13.6 mo) vs No treatment (1.8 mo). For advanced disease: Median OS longer with TACE (7.1 mo) vs no treatment (2.3 mo)
Chemotherapy
Czauderna et al[27] (2002) SIOPEL 1	39	Poor outcome related to metastases and higher PRETEXT stage	CT in 37, followed by resection	OS 5 yr 28% EFS 5 yr 17% 93% deaths due to tumour progression
Katzenstein et al[16] (2002) CCG/POG	46	Poor outcome with recurrent disease Favourable prognosis with stage I and normal AFP Comparable survival between 2 regimens	CT (CDDP + Vincristine + 5-FU vs CDDP + Doxo)	EFS 5 yr 19% (Stage I 88%, III 8%, IV 0) OS 5 yr 19% (Stage I 88%, III 23%, IV 10%)
Murawski et al[100] (2016) SIOPEL 2 and 3	85	Complete tumor resection and tumor free margins predict OS	Primary surgery (if feasible) à Super-PLADO (CDDP, Doxo and Carbo) à Assessment for LT	Response to CT in 40% OS at 5 yr 22% 5-yr OS with complete resection 63% vs 59% with LT 5-yr OS with macroscopically involved margins 14%
Liver transplantation
Reyes et al[101] (2000)	19	Risk for recurrence with vascular and LN invasion, distant metastases, size of tumor and male gender	LT ± Systemic or intra-arterial neoadjuvant CT	1 yr 79% 3 yr 68% 5 yr 63%
Austin et al[24] (2006) UNOS database	41	Primary cause of death: Metastatic or recurrent disease Pretransplant medical disease and era of LT associated with graft and patient survival	All LT	1 yr 86% 3 yr 63% 5 yr 58%
Arikan et al[13] (2006)	13	-	LT in 7 Observation in 6	Overall 1 yr 53%, 4 yr 27% (With LT 1 yr 72%, 4 yr 72%) No recurrence at 36 mo with LT
Beaunoyer et al[23] (2007)	10	1 out of 7 outside MC had recurrence, died	LT in all Pre-LT CT in 5	OS 1 yR 100%, 5 yR 83% RFS 5 yr 89%
Sevmis et al[14] (2008)	9	1 out of 4 outside MC had recurrence, excised	LT in all Pre-LT CT in 3	100% survival at 19.8 ± 10.6 (7-32) mo Recurrence in 1 out of 4 outside MC, excised
Ismail et al[22] (2009)	21	Mortality related to recurrence and PRETEXT stage in the non-LT group, but not in the LT group	LT 11 Non-LT 10 (Resection in 8 - 4 after CT)	OS with LT 72% at median 43 mo and Non-LT 40% at median 66 mo Recurrence after LT in 1/11 and after resection in 6/8
Romano et al[18] (2011)	10	-	All primary LT No CT / resection	80% RFS at median FU of 4 y (1-11 y)
Palaniappan et al[26] (2016)	12	1 Multifocal + 2 with microvascular invasion 2 underwent TACE before LT	All primary LT (8 diagnosed incidentally in explant livers)	92% OS at a median of 5 (1-27) mo
Baumann et al[25] (2018) ELTR data	175	Survival better in children with inherited liver disease than without (HR = 0.29) and vs adults with HCC with inherited liver disease (HR = 0.27) Survival rate increased with increasing age in non-inherited group	All LT	OS at 5 yr: Patient 58% and Graft 56% Patient survival at 5 yr and 10 yr Inherited: 81% and 81% Non-inherited: 53% and 45%

AFP: Alpha-fetoprotein; Carbo: Carboplatin; CDDP: Cisplatin; CCG: Children’s cancer group; CT: Chemotherapy; DFS: Disease free survival; EFS: Event-free survival; ELTR: European Liver Transplant Registry; FLHCC: Fibrolamellar variant of HCC; FU: Follow-up; 5-FU: 5-Fluorouracil; HR: Hazard ratio; LN: Lymph-node; LT: Liver transplantation; MC: Milan criteria; MOT: Multi-organ transplantation; MST: Median survival time; OR: Odd’s ratio; OS: Overall survival; PH: Partial hepatectomy; POG: Pediatric Oncology group; PRETEXT: Pretreatment tumor extent evaluation; RFS: Recurrence free survival; SEER: Surveillance epidemiology and end-results; SIOPEL: Group for epithelial liver tumors of the international society of pediatric oncology; TACE: Trans-arterial chemoembolization.