Review
Copyright ©The Author(s) 2018.
World J Gastroenterol. Sep 21, 2018; 24(35): 3980-3999
Published online Sep 21, 2018. doi: 10.3748/wjg.v24.i35.3980
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)
RegionSouth AfricaChinaTaiwanTaiwanChinaTurkeyIndia
No. of subjects686544, 55514513 (Incidental diagnosis in 3)12 (8 diagnosed in explant livers)
Males (%)68 (78 in HBV subgroup)80Males dominated77934675
Age (yr)Mean 10.5Median 17 (8-20)-Mean 11 (4-15)Mean 13.5 (3-18)6.4 ± 4.8Median 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)
Etiology67% HBV82% HBV100% HBV100% HBV71% HBV6 Tyr 6 HBV 1 GSD15 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 6Well diff 8 Mod diff 4 (High grade dysplasia or nodules in adjoining liver in 50%)
Cirrhosis--71%, 68%74% (95%) in < 9 yr of age47% Child A/B/C 32/8/5100% Mean CTP 11.1 ± 3.1 and PELD 19.7 ± 2.4 (1-44)-
AFPHigh 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%NANA
Outside MilanNANANANANANANA
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)
RegionUnited StatesUnited StatesEuropeUnited StatesUnited StatesPolandItalyUnited States
Number of subjects238, 80, 21846393222211010
Males (%)5857726350-4060
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%
MultifocalitySatellite 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 ds3 BA 3 PFIC2 2 Tyr 1 CC 1 GSD44 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 FLHCCHCC 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/mLMedian 2322 (3-35000) ng/mLMedian 446927 ng/mL
Extent or Stage (n or %)Local 27%-28% Regional 35%-37% Distant 34%-35%StageI (8), II (0), III (25), IV (13)1PRETEXT I (1), II (14), III (11), IV (13)-CCG/POG Stage I (60%), II (11.5%), III (17%), IV (11.5%)1PRETEXT 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 invasion48%-21%--29%20%30%
Metastases35%-Lung 31% Other 18%-0--
Resectability25%22%36%22%67%48%NA (All LT)NA
Outside Milan-----86%60%70%
Table 3 Changing outcome of children with hepatocellular carcinoma over last 4 decades
Study (yr)Ref.Number of patientsFactors governingoutcomeIntervention (s)doneSurvival
Conservative treatment (Observation and resection)
Lack et al[31] (1983)32 (5FLHCC)Higher resectability and overall survival with FLHCCObservation Resection5 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)51Early HBeAg seroconversion with severe liver injury predispose to HCCObservation Resection1 yr 10.5%
Chen et al[29] (1988)44No difference in survival with chemotherapyObservation Resection5 yr 7%
Ni et al[97] (1991)71Favorable prognosis with resectability and absence of icterusObservation Resection1 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 database218Reduced 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)21Total hepatectomy and LT improved survival in those with unresectable diseaseSurgery in 15 (6 PH, 7 LT, 2 Exenteration and MOT) Pre-operative CT in 2 Observation in 61 yr 29%
Chen et al[10] (1998)55Good outcome with resection, poor with unsatisfactory resection & metastases Distant metastases carries worst prognosisResection CT ObservationMST 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 ± CTOS 5 yr 30% MST 23 mo
Zhang et al[12] (2013)45Low overall survival with metastases & non-resectability, but unrelated to HBsAg positivity Large tumor size, early metastasis, bilateral involvement, and PV invasion precluded resectionResection TACE Observation1 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 database238Lower 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 8OS 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 database80Lower 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)65Initial treatment allocation predicted OS (TACE HR = 0.298, Resection HR = 0.105 with No treatment as reference)Resection TACE No treatmentFor 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 139Poor outcome related to metastases and higher PRETEXT stageCT in 37, followed by resectionOS 5 yr 28% EFS 5 yr 17% 93% deaths due to tumour progression
Katzenstein et al[16] (2002) CCG/POG46Poor outcome with recurrent disease Favourable prognosis with stage I and normal AFP Comparable survival between 2 regimensCT (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 385Complete tumor resection and tumor free margins predict OSPrimary surgery (if feasible) à Super-PLADO (CDDP, Doxo and Carbo) à Assessment for LTResponse 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)19Risk for recurrence with vascular and LN invasion, distant metastases, size of tumor and male genderLT ± Systemic or intra-arterial neoadjuvant CT1 yr 79% 3 yr 68% 5 yr 63%
Austin et al[24] (2006) UNOS database41Primary cause of death: Metastatic or recurrent disease Pretransplant medical disease and era of LT associated with graft and patient survivalAll LT1 yr 86% 3 yr 63% 5 yr 58%
Arikan et al[13] (2006)13-LT in 7 Observation in 6Overall 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)101 out of 7 outside MC had recurrence, diedLT in all Pre-LT CT in 5OS 1 yR 100%, 5 yR 83% RFS 5 yr 89%
Sevmis et al[14] (2008)91 out of 4 outside MC had recurrence, excisedLT in all Pre-LT CT in 3100% survival at 19.8 ± 10.6 (7-32) mo Recurrence in 1 out of 4 outside MC, excised
Ismail et al[22] (2009)21Mortality related to recurrence and PRETEXT stage in the non-LT group, but not in the LT groupLT 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 / resection80% RFS at median FU of 4 y (1-11 y)
Palaniappan et al[26] (2016)121 Multifocal + 2 with microvascular invasion 2 underwent TACE before LTAll primary LT (8 diagnosed incidentally in explant livers)92% OS at a median of 5 (1-27) mo
Baumann et al[25] (2018) ELTR data175Survival 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 groupAll LTOS 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%