Hepatocellular Carcinoma in Biliary Atresia: King’s CollegeHospital Experience

Nedim Had�zi�c, MD, Alberto Quaglia, MD, Bernard Portmann, MD, Saravanakumar Paramalingam, MD, Nigel D. Heaton, MD,

Mohamed Rela, MD, Giorgina Mieli-Vergani, PhD, and Mark Davenport, MD

Objectives To establish risks for development of hepatocellular carcinoma (HCC) in children with biliary atresia(BA), the most common chronic liver disease of childhood.Study design In our tertiary referral center database we have identified children with BAwho had development ofor have been incidentally found to have HCC. Their demographic, clinical, radiologic, and histologic features wereanalyzed.Results Between 1990 and 2008, 387 infants were diagnosed with BA at our center. Of these, three (0.8 %) whounderwent operation at a median age of 68 (range 66 to 71) days had development of a histologically proven HCCdetected at a median age of 2.1 (range 1.8 to 4.9) years. Another two, referred later, were diagnosed with HCC ontheir liver explants at ages 1.1 and 17.75 years, respectively. Overall, two had elevated serum levels of alpha-fetoprotein. All five children underwent successful liver transplantation at a median age of 2.1 years (range 1.1 to17.75) and remain well after a median of 2.5 (range 2 to 5.7) years.Conclusion HCC develops in a small percentage of children with BA. Serum alpha-fetoprotein levels and ultra-sound screening are helpful but not absolute markers of the malignant change. In the absence of the extrahepaticinvolvement, liver transplantation represents an effective treatment. (J Pediatr 2011;159:617-22).

Biliary atresia (BA) is an obstructive cholangiopathy of the newborn that, if untreated, leads to biliary cirrhosis and end-stage liver disease.1 Treatment is largely surgical, with an initial attempt to restore bile flow by excision of usually solidextrahepatic biliary remnants and biliary reconstruction (Kasai portoenterostomy [KPE]). In large centers, more than

half of infants will clear their jaundice but still have a degree of chronic liver disease (CLD).2 BA remains the most commonpediatric indication for liver transplantation (LT), but approximately one-third of children will reach adulthood withoutundergoing transplantation.3

Malignant change is a well-recognized complication of CLD fromwhatever cause.4-6 This is usually hepatocellular carcinoma(HCC). In children, HCC is the second-most common liver tumor, after hepatoblastoma.6,7 Between 1979 and 1996 thereported incidence of HCC in the United States has been declining from 0.45 to 0.29 per million children.7 Approximately65% of all HCCs occur in children older than 10 years, and they are of sporadic nature.6 Some genetic conditions, such astyrosinemia type I8 and bile salt export pump (BSEP) deficiency9 represent examples where HCC develops on a strikingly shorttimescale, often within the first few years of life. A number of other hepatic disorders have been described with HCC in child-hood, althoughmuch less frequently.6 Apart from increased cellular turnover, pathophysiological mechanisms of the neoplastictransformation in CLD remain poorly understood.

Occasional case reports have described HCC in BA,10-16 but there have been no studies on its relative incidence in a largecohort. The aim of this study was to estimate the risk of malignant transformation in BA and define optimal management.

AFP Alpha-fetoprotein

BA Biliary atresia

BSEP Bile salt export pump

CLD Chronic liver disease

CT Computed tomography

HCC Hepatocellular carcinoma

KPE Kasai portoenterostomy

LT Liver transplantation

MDR Multi-drug resistance

Methods

King’s College Hospital is the largest tertiary referral center for infants and children with liver diseases in the United Kingdom.Annually, between 25 and 30 infants are diagnosed with BA and treated with corrective biliary surgery, typically KPE. If this failsthen they are considered for LT.17

From the Paediatric Liver Centre (N.H., S.P., G.M-V.,M.D.) and the Institute of Liver Studies (N.H., A.Q., B.P.,N.H., M.R., G.M-V.), King’s College Hospital, DenmarkHill, London, United Kingdom

This abstract was presented at 59th Annual Meeting ofAmerican association for Study of Liver Disease, October3- November 5, 2008, San Francisco, CA.

The authors declare no conflicts of interest.

0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc.

All rights reserved. 10.1016/j.jpeds.2011.03.004

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Our prospectively acquired database of children with BA(from January 1990 to December 2008) was examined toidentify those who were subsequently diagnosed with HCC.Archived histologic material was retrospectively reexaminedby two histopathologists, unaware of the clinical details. Inaddition to standard histologic techniques, the following an-tibodies were used: monoclonal Ki-67 (Mib-1) (1/200), CD34(QBEnd 10) (1/100) (both Dako, Ely, United Kingdom),beta-catenin (1/50) (Novocastra, Newcastle, United King-dom), glypican 3 (1G12) (1/100) (Menarini Winnersh, Berk-shire, United Kingdom), and polyclonal rabbit alpha-feto-protein (1/400) (Dako). Data are quoted as median (range)unless otherwise indicated.

Results

Over the period of the study, 387 infants were diagnosed withBA. Of these, three (0.8%) had development of histologicallyproven HCC, detected at a median age of 2.1 (1.8 to 4.9)years. They all had isolated type 3 BA, with initial biliary sur-gery performed at a median age of 68 (66 to 71) days. Allthree patients had undergone KPE. During the same timeperiod, two additional children, originally not treated atour center, were diagnosed with BA and HCC: (1) a childwho had undergone KPE overseas was referred for follow-up and eventually diagnosed with HCC (patient 4); and (2)a child referred to us for LT because of cryptogenic end-stage CLD, had features of BA and incidental HCC in his ex-planted liver (patient 5). Histologic diagnosis of BA wasreconfirmed in patients 1 to 3 by reviewing the presentationliver biopsy specimens and bile duct remnants for this study.In patient 4, for whom the original biopsy specimen was notavailable, the operative notes and histologic study of the ex-planted liver were compatible with BA. There were no clinicalfeatures of Alagille syndrome and multi-drug resistance(MDR) polypeptide-3 was immunohistochemically well ex-pressed in the liver tissue in all patients.

Case ReportsCase 1. A white boy underwent KPE at 66 days of age. Hecleared his jaundice to a normal serum bilirubin level (<20mmol/L) and remained well until 38 months of age when hebecame suddenly jaundiced (bilirubin 232 mmol/L). Radio-nucleotide scanning and percutaneous transhepatic cholangi-ography suggested aRoux loopobstruction thatwas correctedsurgically, and the patient’s bilirubin level fell to 31 mmol/Lthereafter. During routine post-KPE ultrasound surveillance,a focal parenchymal lesion was noted at 28 months. Abdom-inal magnetic resonance imaging did not suggest malignantfeatures, and serum levels of alpha-fetoprotein (AFP) re-mained normal (<2 kU/L [normal range <7 kU/L]) through-out. At 40 months of age, another nodule appeared,prompting biphasic computed tomography (CT) scanning,which showed arterialization of the original, but not of thenew lesion. The child was listed for LT, and hepatectomy con-firmed a 54-mm-diameter, well-differentiated HCC. The sec-ond lesion had features of adenomatous hyperplasia. The

618

patient’s post-transplantation recovery was uneventful, andhe was discharged on tacrolimus and prednisolone. He re-mains well at 2.5 years after LT.

Case 2. A white girl underwent KPE at age 71 days. Shenever cleared the jaundice and had development of ascitesand intractable pruritus during the second year of life. Atage 26 months she received a cadaveric LT: two smallHCCs were found incidentally in her explanted liver. Herstored preoperative blood sample showed serum AFP of1259 kU/L. Five days after LT her serum AFP levels decreasedto 97 kU/L. The postoperative course was complicated by oneepisode of cellular rejection that was treated with steroids.The patient remains well at 4.1 years after LT, on tacrolimusand mycophenolate mofetil.

Case 3. A girl of South-Asian origin, but born in the UnitedKingdom, underwent KPE at 68 days. She never cleared herjaundice and after one episode of gastrointestinal bleedingassociated with the development of ascites was listed for LTat age 15 months. Four months later she was noted to haverising serum AFP (51 kU/L to 220 kU/L to 777 kU/L), butno focal lesions could be shown on ultrasonography. How-ever, 3 months later the patient had development ofa 27-mm arterialized nodule within the right lobe, evidenton biphasic CT scanning, and retroperitoneal and mesentericadenopathy with right portal vein branch thrombosis. Bythen her serum AFP was 22 687 kU/L. The patient was prior-itized on the waiting list and underwent LT at age 2 years. Theexplanted liver confirmed the nodule as HCC, with anothersmaller HCC (19 mm) detected in the right lobe. Preopera-tive AFP peaked at 139 929 kU/L, but sharply declined (61kU/L) 1 month after LT and became normal (<2 kU/L) 6months later. The patient remains well on tacrolimus andmycophenolate at 2.5 years after LT.

Case 4. A white girl with severe visual impairment causedby macular degeneration had had successful KPE performedat 49 days in Cyprus. Because of mild chronic cholestasis (bil-irubin 70 mmol/L), she was referred to our center at age 14years for follow-up. Routine ultrasonography at 17 yearsidentified a large focal lesion (approximate diameter 10cm), suggestive of adenoma. The patient was clinically well,and her serum AFP level was <2 kU/L. She was listed fortransplantation and 6 months later received a liver graft:the hepatectomy specimen showed a 105-mm–diameterHCC. She remains well on tacrolimus and sirolimus at 5.7years after LT.

Case 5. A boy from a consanguineous Arab family, born inthe United Kingdom, had development of progressive chole-static liver disease. Liver biopsy performed at 21 days of ageshowed features of nonspecific giant cell hepatitis. Thepatient remained jaundiced, and at 6 months the liver biopsywas repeated and now showed features of ‘‘large bile duct ob-struction’’ with bridging fibrosis. Progressive cholestasis withintractable pruritus and gastrointestinal bleeding prompted

Had�zi�c et al

Table I. Some clinical features of children with BA and HCC

Patient,sex Age at KPE (d) Age at HCC diagosis (y) Age at LT (y) HCC size (mm) Comment

Follow-up afterLT (y)

1, M 66 4.9 5.1 54 - 2.52, F 71 2.1 2.1 A-11

B-9Incidental 4.1

3, F 68 1.8 2.1 A-19B-25

- 2.5

4, F 49 17.75 17.75 105 - 5.75, M n/a 1.1 1.1 6 Incidental 2.0

October 2011 ORIGINAL ARTICLES

referral to our center for consideration of LT. A living-relatedLT was performed at 1.1 years of age. Hepatectomy showedbiliary cirrhosis with severe cholestasis, advanced ductope-nia, and an absence of the extrahepatic biliary tract and gallbladder. A small (6-mm diameter) HCC was found in theleft lobe. The patient remains well receiving tacrolimus andprednisolone at 2 years after LT.

Further clinical and biochemical features are summarizedin Tables I and II, respectively. All patients had stagingabdominal and chest CT at the time of diagnosis of HCC.None showed evidence of extrahepatic spread. Asa consequence, no child received chemotherapy before orafter LT. After a median follow-up of 2.5 (2 to 5.7) years,all five patients are well with excellent graft function,normal serum AFP, and no signs of HCC recurrence.

Histologic FeaturesNeoplasms in patients 2, 3, and 5 show features of smallmoderately differentiated HCC with microscopic vascularinvasion in patients 2 and 3 (Figure 1). All demonstratea diffuse sinusoidal capillarization with CD34-positiveimmunostaining and a high proliferative rate within thetumors in patients 3 and 5. Two of these tumors alsostained positively for AFP, in parallel to their strikinglyelevated serum AFP levels. Only one lesion (patient 3)showed patchy and weak stain for glypican, whereas theothers were negative.18 One tumor showed strong nuclearexpression of beta-catenin.19

HCC in patients 1 and 4 were much larger and consisted ofwell-differentiated hepatocellular lesions devoid of portalstructures with patchy, yet significant capillarization of thethin stromal vessels (Figure 2). The proliferation rate waslow, but the size of the lesions, clear cell change, andmicroscopic stromal invasion at the periphery of HCC inpatient 1 and focal pelioid changes and cell dyscohesion inpatient 4 were suggestive of well-differentiated HCCs. They

Table II. Biochemical features of the patients at the timeof liver transplantation

PatientBilirubin

(mmol/L)Albumin(g/L) INR

Platelets(� 109/L)

AFP(kU/L)

1 33 41 0.91 181 <22 614 29 1.75 51 12603 186 22 1.29 112 139 9294 70 43 1.0 126 <25 339 37 1.15 232 5

INR, international normalized ratio.

Hepatocellular Carcinoma in Biliary Atresia: King’s College Hosp

did not stain for AFP or show nuclear expression of beta-catenin. One of the two (patient 1) stained for glypican.The appearance was clearly different from the segmental ormacronodular regenerative parenchymal expansion at timesobserved in the livers of patients with BA after KPE.20

None of the lesions showed features of hepatoblastoma.Background explanted livers in patients 2, 3, and 5 show

advanced biliary cirrhosis with characteristic loss of intrahe-patic bile ducts and severe cholestasis. Features of previousKPE were present in patients 2 and 3, whereas in patient 5,who had no previous surgery, the gallbladder was absentwith some ductopenia in association with both scarringand ulcerations of residual perihilar ducts, in keeping witha diagnosis of untreated BA.Liver explants in patients 1 and 4 showed severe bridging

fibrosis, ductopenia, and cholestasis. In patient 1 there wasalso evidence of occlusion of small portal vein branches and pa-renchymal nodular regenerative hyperplasia, and patient 3 alsohad venoocclusive lesions of the main portal vein branches.Histologic features of the explanted material are pre-

sented in Table III (available at www.jpeds.com). Forpatient 4, diagnosed with BA outside our institution, thehistologic material taken at the time of KPE could not beassessed, but we demonstrated positive MDR protein 3immunostaining, excluding the possibility that MDRprotein 3 deficiency could be the cause of liver disease.Additional immunohistochemical information is shown inTable IV (available at www.jpeds.com).

Discussion

Children with surgically corrected BA require life-long med-ical follow-up to monitor progression of their almost inevita-ble CLD. A study of long-term survivors from our centershowed that even in a cohort with completely normal bio-chemical liver function, more than half have histologic evi-dence of cirrhosis.3 Our current study suggests thatmalignant transformation may affect around 1% of childrenborn with BA at some point in their lives, with the likelihoodthat this will increase given an increasing proportion of age-ing cirrhotic native liver survivors. Our experience suggeststhat all children with BA should be regarded as having a po-tential for HCC development and urgently considered for LTwhen this diagnosis is clinically suspected.HCC remains a rare condition in children.4,5 The incidence

of sporadic HCC, seen more commonly in adolescents,

ital Experience 619

Figure 2. Patient 1. A, The tumor is a well differentiatedhepatocellular neoplasm composed of bland hepatocyteswith no evident atypia and low proliferative activity. Anunpaired artery is present in the center of the field. (Hema-toxylin & eosin; original magnification � 400.) B, A peripheralarea of tumor with clear cell change (right side) is separatedfrom background liver (top left) by a rim of fibrous stroma.(Hematoxylin & eosin; original magnification � 200.)

Figure 1. Patient 3. A, A 19-mm pale subcapsular tumor(arrow) is present in the lateral aspect of the right lobe. B, Thetumor is composed of highly cellular population of moderatelyatypical hepatoid cells. Mitotic activity is evident (arrow) (He-matoxylin & eosin; original magnification� 200.)C, Clusters oftumor cells are present in the lumen of perilesional thin-walledvascular spaces indicating vascular invasion. (Hematoxylin &eosin; original magnification � 400.)

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remains static and appears to be declining in those with un-derlying CLD.7 This may be related to improvements in med-ical therapy, such as treatment of tyrosinemia type I withnitisinone, early LT for those conditions with a known pro-pensity for malignant transformation (eg, BSEP deficiency),universal hepatitis B vaccination, and antiviral treatment.6

There is a lower prevalence of HCC related to CLD in childrenthan in adults, although the reasons are likely to be multifac-torial.4,6 These might include differences in immune re-sponse, increasing exposure to alcohol, increasing insulinresistance, and longer exposure to the initiating agent.

Our study group represents the usual spectrum of patientsafter undergoing KPE in terms of age at surgery, clinical re-

620

sponse, medical complication rates, or biochemical indexes.One child of age 1.1 year in our series did not have previousbiliary surgery, similar to a previously reported 10-month-old child who was also found to have a 7-mm incidentalHCC identified during primary LT.16 These observations in-dicate that HCC can develop early in infancy, even in chil-dren who had not undergone KPE.After KPE, dominant regenerative areas frequently de-

velop in the liver and can become large and nodular, mak-ing their differentiation from HCC difficult.20 Serum AFPand ultrasound screening are useful but, in our experience,not absolute markers of malignant transformation. Onlytwo children from our series had elevated serum AFP levels,in keeping with positive AFP staining in their tumors, andthe three smaller lesions (less than 11 mm) in patients 2and 5 were not identified by ultrasonography before LT.Nevertheless, these two clinical tests, performed on a regular

Had�zi�c et al

October 2011 ORIGINAL ARTICLES

basis, should continue to be the mainstay of HCC surveil-lance in pediatric CLD. At our center we now perform liverultrasonography and serum AFP in all children with BAevery 6 months. Any new focal lesion detected on ultraso-nography should be promptly investigated further withradiologic imaging, including multiphasic CT, primarily toassess its degree of arterialization, which has been suggestedto be one of the key radiologic discriminants betweenbenign and malignant lesions.21 Even then a high degreeof suspicion should be maintained, because in one of ourpatients arterialization only became evident on repeat imag-ing. Novel methods of liver imaging, such as bubble contrastultrasonography,22 may offer the possibility for morefrequent monitoring of suspected focal changes with a com-parable accuracy to CT, but without the side effects of therepeated radiation exposures.

Histologically, the tumors from this study could bebroadly divided into two groups. In the first (three youngerpatients) the tumors were of relatively small size (range 6to 25 mm) and showed classical features of HCC, includingarchitectural changes, cytologic atypia, proliferative activity,presence of necrosis, and vascular invasion in various combi-nations. In the other group (two older patients) the tumorswere larger (54 and 105 mm diameter) and well differenti-ated, with no or low proliferative activity, no necrosis or vas-cular invasion, and were associated with changes of nodularregenerative or adenomatous hyperplasia within the lesion orin the adjacent liver. The degree of differentiation raised thedifferential diagnosis of massive nodular expansion that canoccasionally follow occlusive venopathy with nodular regen-erative hyperplasia in the noncirrhotic liver.23 In this situa-tion, the mass lesions had a more complex architecture,with features resembling focal nodular hyperplasia,24 the lat-ter also rarely reported in BA.20 In contrast, the liver lesionsin patients 1 and 4 showed a monomorphic hepatocellularcomponent with a clear cell change, discrete pseudoglandularstructures, absence of ductular reaction, and focally infiltra-tive margins, all in keeping with a well-differentiated HCC.Glypican and beta-catenin immunostaining, recently sug-gested to be useful in differentiation between dysplasticchanges and HCC in adults,18,19 was not helpful in this smallseries. The two different patterns of histologic changes in ourseries could suggest different tumor biologic conditions, withdifferent growth rate, doubling time, and potential for recur-rence after LT. Two histologically different lesions in theexplant of our patient 1 and a recent case report, where radio-logic evolution of a 38-mm focal lesion to a 95-mm histolog-ically well-differentiated HCC was demonstrated in a youngadult with BA over a follow-up of almost 15 years,15 seem tosupport this concept of slow evolution from nodular regen-erative hyperplasia to HCC.

The medical management of children with CLD who havedevelopment of HCC is poorly defined.25 The publishedguidelines refer to sporadic HCC, often mirroring hepato-blastoma or adult HCC protocols, which involve combinedchemotherapy and resection.26,27 Patients with BA are likelyto have advanced biliary disease, making resection more chal-

Hepatocellular Carcinoma in Biliary Atresia: King’s College Hosp

lenging. Moreover, some of the important adjuvant treat-ments such as radioablation, chemoembolization, orsorafenib are presently not approved for use in children.Our clinical decision not to use chemotherapy was basedon reported poor responsiveness of HCC to chemotherapyin children,26 but also to avoid serious infectious or immuno-logic complications early after LT. All patients were, however,staged radiologically, including the ones where the malig-nancy was an incidental finding. In hindsight, the decisionabout performing transplantation on a child with a 105-mm AFP-negative hepatic mass would have been muchmore difficult had we known that this was histologicallyHCC, because its size was outside the standard LT criteria.28

It may well be that the tumors in the context of BA should beconsidered for LT with more flexible clinical criteria usedthan those in sporadic HCC. This could become an impor-tant issue for adult hepatologists because a considerablenumber of children who do not undergo transplantationafter KPE will survive into adulthood.3,29

In conclusion, we report that HCC represents a rare butsignificant complication of CLD inherent to BA. Screeningwith serial AFP and ultrasonography remains the mainstayof diagnosis, although it is still far from perfect. Timely LT(without adjuvant chemotherapy if there is no extrahepaticdisease) appears to be safe and effective. n

Submitted for publication Aug 24, 2010; last revision received Feb 1, 2011;

accepted Mar 2, 2011.

Reprint requests: Nedim Hadzic, MD, Paediatric Liver Service, King’s College

Hospital, Denmark Hill, London SE5 9RS, United Kingdom. E-mail: nedim.

hadzic@kcl.ac.uk

References

1. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet 2009;374:

1704-13.

2. Davenport M, Caponcelli E, Livesey E, Hadzic N, Howard ER. Surgical

outcome in biliary atresia: etiology affects the influence of age at surgery.

Ann Surg 2008;247:694-8.

3. Hadzic N, Tizzard SA, Davenport M, Singer J, Howard ER, Mieli-

Vergani G. Long term outcome of biliary atresia; is chronic liver disease

inevitable? J Pediatr Gastroenterol Nutr 2003;37:430-3.

4. Finegold MJ. Tumors of the liver. Semin Liver Dis 1994;14:270-81.

5. Emre S, McKenna GJ. Liver tumors in children. Pediatr Transplant 2004;

8:632-8.

6. Rosenthal P. Hepatocarcinoma in viral and metabolic liver disease.

J Pediatr Gastroenterol Nutr 2008;46:370-5.

7. Darbari A, Sabin KM, Shapiro CN, Schwarz KB. Epidemiology of pri-

mary hepatic malignancies in U.S. children. Hepatology 2003;38:560-6.

8. van Spronsen FJ, Bijleveld CM, vanMaldegem BT,Wijburg FA. Hepato-

cellular carcinoma in hereditary tyrosinemia type I despite 2-(2 nitro-4-3

trifluoro- methylbenzoyl)-1, 3-cyclohexanedione treatment. J Pediatr

Gastroenterol Nutr 2005;40:90-3.

9. Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC,

et al. Hepatocellular carcinoma in ten children under five years of age

with bile salt export pump deficiency. Hepatology 2006;44:478-86.

10. Van WJ, Halgrimson CG, Giles G, Lilly J, Martineau G, Starzl TE. Liver

transplantation in biliary atresia with concomitant hepatoma. S Afr Med

J 1972;46:885-9.

11. Esquivel CO, Guti�errez C, Cox KL, Garcia-Kennedy R, Berquist W,

ConcepcionW.Hepatocellular carcinoma and liver cell dysplasia in chil-

dren with chronic liver disease. J Pediatr Surg 1994;29:1465-9.

ital Experience 621

THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 159, No. 4

12. Kohno M, Kitatani H, Wada H, Kajimoto T, Matuno H,

Tanino M, et al. Hepatocellular carcinoma complicating biliary cir-

rhosis caused by biliary atresia: report of a case. J Pediatr Surg

1995;30:1713-6.

13. Tatekawa Y, Asonuma K, Uemoto S, Inomata Y, Tanaka K. Liver trans-

plantation for biliary atresia associated with malignant hepatic tumors.

J Pediatr Surg 2001;36:436-9.

14. Brunati A, Feruzi Z, Sokal E, Smets F, Fervaille C, Gosseye S, et al. Early

occurrence of hepatocellular carcinoma in biliary atresia treated by liver

transplantation. Pediatr Transplant 2007;11:117-9.

15. Hol L, van den Bos IC, Hussain SM, Zondervan PE, de Man RA. Hepa-

tocellular carcinoma complicating biliary atresia after Kasai portoenter-

ostomy. Eur J Gastroenterol Hepatol 2008;20:227-31.

16. Iida T, Zendejas IR, Kayler LK, Magliocca JF, Kim RD, Hemming AW,

et al. Hepatocellular carcinoma in a 10-month-old biliary atresia child.

Pediatr Transplant 2009;13:1048-9.

17. Davenport M, De Ville de Goyet J, Stringer MD, Mieli-Vergani G,

Kelly DA, McClean P, Spitz L. Seamless management of biliary

atresia in England and Wales (1999-2002). Lancet 2004;363:

1354-7.

18. Anatelli F, Chuang ST, Yang XJ, Wang HL. Value of glypican 3 immu-

nostaining in the diagnosis of hepatocellular carcinoma on needle

biopsy. Am J Clin Pathol 2008;130:219-23.

19. Huang H, Fujii H, Sankila A, Mahler-Araujo BM, Matsuda M,

Cathomas G, et al. Beta-catenin mutations are frequent in human hepa-

tocellular carcinomas associated with hepatitis C virus infection. Am J

Pathol 1999;155:1795-801.

622

20. Okugawa Y, Uchida K, Inoue M, Kawamoto A, Ohtake K, Sakurai H,

et al. Focal nodular hyperplasia in biliary atresia patient after Kasai

hepatic portoenterostomy. Pediatr Surg Int 2008;24:609-12.

21. Robinson P. Hepatocellular carcinoma: development and early detec-

tion. Cancer Imaging 2008;8:S128-31.

22. Burns PN, Wilson SR, Simpson DH. Pulse inversion imaging of liver

blood flow: improved method for characterizing focal masses with

microbubble contrast. Invest Radiol 2000;35:58-71.

23. Kondo F, Koshima Y, Ebara M. Nodular lesions associated with abnor-

mal liver circulation. Intervirology 2004;47:277-87.

24. Fischer HP, Zhou H. Nodular lesions of liver parenchyma caused by

pathological vascularisation/perfusion. Pathologe 2006;27:273-83.

25. Arikan C, Kilic M, Nart D, Ozgenc F, Ozkan Y, Tokat Y, et al. Hepato-

cellular carcinoma in children and effect of living-donor liver transplan-

tation on outcome. Pediatr Transplant 2006;10:42-7.

26. Czaudema P,McKinlay G, Perilongo G, Brown J, Shafford E, AronsonD,

et al. Hepatocellular carcinoma in children: results of the first prospec-

tive study of the International Society of Pediatric Oncology Group.

J Clin Oncol 2002;20:2798-804.

27. Bruix J, Sherman M. Management of hepatocellular carcinoma. Practice

Guidelines Committee, American Association for the Study of Liver Dis-

eases. Hepatology 2005;42:1208-36.

28. http://optn.transplant.hrsa.gov/policiesAndBylaws/policies.asp 3.6 Or-

gan Distribution: Allocation of livers [accessed Nov 2010]

29. Lykavieris P, ChardotC, SokhnM,Gauthier F, Valayer J, BernardO.Out-

come in adulthood of biliary atresia: a study of 63 patients who survived

for over 20 years with their native liver. Hepatology 2005;41:366-71.

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Table III. Histopathologic features of the tumors

Patient LocationNo. oflesions Size

Vascularinvasion Background liver

1 R lobe 1 54 mm No Bridging fibrosis, venoocclusive lesions and nodular regenerativehyperplasia, ductopenia, cholestasis

2 R lobeL lobe

2 11 mm9 mm

Yes Cirrhosis, ductopenia, cholestasis,BSEP/MDR3 immunostain normal

3 R lobe 2 25 mm19 mm

Yes Cirrhosis, ductopenia, cholestasis, venoocclusive lesions of mainportal vein branches, regenerative macronodules � 2

4 R lobe 1 105 mm No Severe biliary bridging fibrosis (stage 3), moderate ductopenia,cholestasis, MDR3 immunostain normal

5 L lobe 1 6 mm No Cirrhosis, ductopenia, cholestasis, absent gallbladder,BSEP/MDR3 immunostain normal

Table IV. Immunohistochemical staining of the tumors in explants

Patient Ki67 (%) AFP b-catenin (nuclear) CD34 Glypican

1 <5 Neg 0 + (Patchy) ++2 1-2 ++ 0 ++ (Widespread) Neg3 20-30 ++ 0 ++ (Widespread) + (Weak)4 <1 Neg 0 + (Focally diffuse) Neg5 20-30 Neg + ++ (Widespread) Neg

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Hepatocellular Carcinoma in Biliary Atresia: King’s College Hospital Experience 622.e1