- Email: [email protected]
Hepatocellular Carcinoma in Biliary Atresia: King’s College Hospital Experience
Hepatocellular Carcinoma in Biliary Atresia: King’s College Hospital Experience Nedim Hadzic, 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 BA who had development of or have been incidentally found to have HCC. Their demographic, clinical, radiologic, and histologic features were analyzed. Results Between 1990 and 2008, 387 infants were diagnosed with BA at our center. Of these, three (0.8 %) who underwent operation at a median age of 68 (range 66 to 71) days had development of a histologically proven HCC detected at a median age of 2.1 (range 1.8 to 4.9) years. Another two, referred later, were diagnosed with HCC on their liver explants at ages 1.1 and 17.75 years, respectively. Overall, two had elevated serum levels of alphafetoprotein. All five children underwent successful liver transplantation at a median age of 2.1 years (range 1.1 to 17.75) 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 ultrasound screening are helpful but not absolute markers of the malignant change. In the absence of the extrahepatic involvement, liver transplantation represents an effective treatment. (J Pediatr 2011;159:617-22).
B
iliary atresia (BA) is an obstructive cholangiopathy of the newborn that, if untreated, leads to biliary cirrhosis and endstage liver disease.1 Treatment is largely surgical, with an initial attempt to restore bile flow by excision of usually solid extrahepatic 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 common pediatric indication for liver transplantation (LT), but approximately one-third of children will reach adulthood without undergoing transplantation.3 Malignant change is a well-recognized complication of CLD from whatever 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 the reported incidence of HCC in the United States has been declining from 0.45 to 0.29 per million children.7 Approximately 65% of all HCCs occur in children older than 10 years, and they are of sporadic nature.6 Some genetic conditions, such as tyrosinemia type I8 and bile salt export pump (BSEP) deficiency9 represent examples where HCC develops on a strikingly short timescale, often within the first few years of life. A number of other hepatic disorders have been described with HCC in childhood, although much less frequently.6 Apart from increased cellular turnover, pathophysiological mechanisms of the neoplastic transformation 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 large cohort. The aim of this study was to estimate the risk of malignant transformation in BA and define optimal management.
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 fails then they are considered for LT.17 AFP BA BSEP CLD CT HCC KPE LT MDR
Alpha-fetoprotein Biliary atresia Bile salt export pump Chronic liver disease Computed tomography Hepatocellular carcinoma Kasai portoenterostomy Liver transplantation Multi-drug resistance
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, Denmark Hill, London, United Kingdom This abstract was presented at 59th Annual Meeting of American association for Study of Liver Disease, October 3- 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 to identify those who were subsequently diagnosed with HCC. Archived histologic material was retrospectively reexamined by two histopathologists, unaware of the clinical details. In addition to standard histologic techniques, the following antibodies 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 Kingdom), glypican 3 (1G12) (1/100) (Menarini Winnersh, Berkshire, United Kingdom), and polyclonal rabbit alpha-fetoprotein (1/400) (Dako). Data are quoted as median (range) unless otherwise indicated.
Results Over the period of the study, 387 infants were diagnosed with BA. Of these, three (0.8%) had development of histologically proven 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 surgery performed at a median age of 68 (66 to 71) days. All three patients had undergone KPE. During the same time period, two additional children, originally not treated at our center, were diagnosed with BA and HCC: (1) a child who had undergone KPE overseas was referred for followup and eventually diagnosed with HCC (patient 4); and (2) a child referred to us for LT because of cryptogenic endstage CLD, had features of BA and incidental HCC in his explanted liver (patient 5). Histologic diagnosis of BA was reconfirmed in patients 1 to 3 by reviewing the presentation liver biopsy specimens and bile duct remnants for this study. In patient 4, for whom the original biopsy specimen was not available, the operative notes and histologic study of the explanted liver were compatible with BA. There were no clinical features of Alagille syndrome and multi-drug resistance (MDR) polypeptide-3 was immunohistochemically well expressed in the liver tissue in all patients. Case Reports Case 1. A white boy underwent KPE at 66 days of age. He cleared his jaundice to a normal serum bilirubin level (<20 mmol/L) and remained well until 38 months of age when he became suddenly jaundiced (bilirubin 232 mmol/L). Radionucleotide scanning and percutaneous transhepatic cholangiography suggested a Roux loop obstruction that was corrected surgically, and the patient’s bilirubin level fell to 31 mmol/L thereafter. During routine post-KPE ultrasound surveillance, a focal parenchymal lesion was noted at 28 months. Abdominal magnetic resonance imaging did not suggest malignant features, and serum levels of alpha-fetoprotein (AFP) remained normal (<2 kU/L [normal range <7 kU/L]) throughout. At 40 months of age, another nodule appeared, prompting biphasic computed tomography (CT) scanning, which showed arterialization of the original, but not of the new lesion. The child was listed for LT, and hepatectomy confirmed a 54-mm-diameter, well-differentiated HCC. The second lesion had features of adenomatous hyperplasia. The 618
Vol. 159, No. 4 patient’s post-transplantation recovery was uneventful, and he was discharged on tacrolimus and prednisolone. He remains well at 2.5 years after LT.
Case 2. A white girl underwent KPE at age 71 days. She never cleared the jaundice and had development of ascites and intractable pruritus during the second year of life. At age 26 months she received a cadaveric LT: two small HCCs were found incidentally in her explanted liver. Her stored preoperative blood sample showed serum AFP of 1259 kU/L. Five days after LT her serum AFP levels decreased to 97 kU/L. The postoperative course was complicated by one episode of cellular rejection that was treated with steroids. The patient remains well at 4.1 years after LT, on tacrolimus and mycophenolate mofetil.
Case 3. A girl of South-Asian origin, but born in the United Kingdom, underwent KPE at 68 days. She never cleared her jaundice and after one episode of gastrointestinal bleeding associated with the development of ascites was listed for LT at age 15 months. Four months later she was noted to have rising serum AFP (51 kU/L to 220 kU/L to 777 kU/L), but no focal lesions could be shown on ultrasonography. However, 3 months later the patient had development of a 27-mm arterialized nodule within the right lobe, evident on biphasic CT scanning, and retroperitoneal and mesenteric adenopathy with right portal vein branch thrombosis. By then her serum AFP was 22 687 kU/L. The patient was prioritized on the waiting list and underwent LT at age 2 years. The explanted liver confirmed the nodule as HCC, with another smaller HCC (19 mm) detected in the right lobe. Preoperative AFP peaked at 139 929 kU/L, but sharply declined (61 kU/L) 1 month after LT and became normal (<2 kU/L) 6 months later. The patient remains well on tacrolimus and mycophenolate at 2.5 years after LT.
Case 4. A white girl with severe visual impairment caused by macular degeneration had had successful KPE performed at 49 days in Cyprus. Because of mild chronic cholestasis (bilirubin 70 mmol/L), she was referred to our center at age 14 years for follow-up. Routine ultrasonography at 17 years identified a large focal lesion (approximate diameter 10 cm), suggestive of adenoma. The patient was clinically well, and her serum AFP level was <2 kU/L. She was listed for transplantation and 6 months later received a liver graft: the hepatectomy specimen showed a 105-mm–diameter HCC. She remains well on tacrolimus and sirolimus at 5.7 years after LT. Case 5. A boy from a consanguineous Arab family, born in the United Kingdom, had development of progressive cholestatic liver disease. Liver biopsy performed at 21 days of age showed features of nonspecific giant cell hepatitis. The patient remained jaundiced, and at 6 months the liver biopsy was repeated and now showed features of ‘‘large bile duct obstruction’’ with bridging fibrosis. Progressive cholestasis with intractable pruritus and gastrointestinal bleeding prompted et al Hadzic
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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 after LT (y)
1, M 2, F
66 71
4.9 2.1
5.1 2.1
Incidental
2.5 4.1
3, F
68
1.8
2.1
-
2.5
4, F 5, M
49 n/a
17.75 1.1
17.75 1.1
54 A-11 B-9 A-19 B-25 105 6
Incidental
5.7 2.0
referral to our center for consideration of LT. A living-related LT was performed at 1.1 years of age. Hepatectomy showed biliary cirrhosis with severe cholestasis, advanced ductopenia, and an absence of the extrahepatic biliary tract and gall bladder. A small (6-mm diameter) HCC was found in the left lobe. The patient remains well receiving tacrolimus and prednisolone at 2 years after LT. Further clinical and biochemical features are summarized in Tables I and II, respectively. All patients had staging abdominal and chest CT at the time of diagnosis of HCC. None showed evidence of extrahepatic spread. As a consequence, no child received chemotherapy before or after 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 Features Neoplasms in patients 2, 3, and 5 show features of small moderately differentiated HCC with microscopic vascular invasion in patients 2 and 3 (Figure 1). All demonstrate a diffuse sinusoidal capillarization with CD34-positive immunostaining and a high proliferative rate within the tumors in patients 3 and 5. Two of these tumors also stained positively for AFP, in parallel to their strikingly elevated serum AFP levels. Only one lesion (patient 3) showed patchy and weak stain for glypican, whereas the others were negative.18 One tumor showed strong nuclear expression of beta-catenin.19 HCC in patients 1 and 4 were much larger and consisted of well-differentiated hepatocellular lesions devoid of portal structures with patchy, yet significant capillarization of the thin stromal vessels (Figure 2). The proliferation rate was low, but the size of the lesions, clear cell change, and microscopic stromal invasion at the periphery of HCC in patient 1 and focal pelioid changes and cell dyscohesion in patient 4 were suggestive of well-differentiated HCCs. They Table II. Biochemical features of the patients at the time of liver transplantation Patient 1 2 3 4 5
Bilirubin (mmol/L)
Albumin (g/L)
INR
33 614 186 70 339
41 29 22 43 37
0.91 1.75 1.29 1.0 1.15
INR, international normalized ratio.
Platelets ( 109/L) 181 51 112 126 232
AFP (kU/L) <2 1260 139 929 <2 5
did not stain for AFP or show nuclear expression of betacatenin. One of the two (patient 1) stained for glypican. The appearance was clearly different from the segmental or macronodular regenerative parenchymal expansion at times observed 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 intrahepatic bile ducts and severe cholestasis. Features of previous KPE were present in patients 2 and 3, whereas in patient 5, who had no previous surgery, the gallbladder was absent with some ductopenia in association with both scarring and ulcerations of residual perihilar ducts, in keeping with a diagnosis of untreated BA. Liver explants in patients 1 and 4 showed severe bridging fibrosis, ductopenia, and cholestasis. In patient 1 there was also evidence of occlusion of small portal vein branches and parenchymal nodular regenerative hyperplasia, and patient 3 also had venoocclusive lesions of the main portal vein branches. Histologic features of the explanted material are presented in Table III (available at www.jpeds.com). For patient 4, diagnosed with BA outside our institution, the histologic material taken at the time of KPE could not be assessed, but we demonstrated positive MDR protein 3 immunostaining, excluding the possibility that MDR protein 3 deficiency could be the cause of liver disease. Additional immunohistochemical information is shown in Table IV (available at www.jpeds.com).
Discussion Children with surgically corrected BA require life-long medical follow-up to monitor progression of their almost inevitable CLD. A study of long-term survivors from our center showed that even in a cohort with completely normal biochemical liver function, more than half have histologic evidence of cirrhosis.3 Our current study suggests that malignant transformation may affect around 1% of children born with BA at some point in their lives, with the likelihood that this will increase given an increasing proportion of ageing cirrhotic native liver survivors. Our experience suggests that all children with BA should be regarded as having a potential for HCC development and urgently considered for LT when this diagnosis is clinically suspected. HCC remains a rare condition in children.4,5 The incidence of sporadic HCC, seen more commonly in adolescents,
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Figure 1. Patient 3. A, A 19-mm pale subcapsular tumor (arrow) is present in the lateral aspect of the right lobe. B, The tumor is composed of highly cellular population of moderately atypical hepatoid cells. Mitotic activity is evident (arrow) (Hematoxylin & eosin; original magnification 200.) C, Clusters of tumor cells are present in the lumen of perilesional thin-walled vascular spaces indicating vascular invasion. (Hematoxylin & eosin; original magnification 400.)
remains static and appears to be declining in those with underlying CLD.7 This may be related to improvements in medical therapy, such as treatment of tyrosinemia type I with nitisinone, early LT for those conditions with a known propensity 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 children than in adults, although the reasons are likely to be multifactorial.4,6 These might include differences in immune response, increasing exposure to alcohol, increasing insulin resistance, and longer exposure to the initiating agent. Our study group represents the usual spectrum of patients after undergoing KPE in terms of age at surgery, clinical re620
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Figure 2. Patient 1. A, The tumor is a well differentiated hepatocellular neoplasm composed of bland hepatocytes with no evident atypia and low proliferative activity. An unpaired artery is present in the center of the field. (Hematoxylin & eosin; original magnification 400.) B, A peripheral area of tumor with clear cell change (right side) is separated from background liver (top left) by a rim of fibrous stroma. (Hematoxylin & eosin; original magnification 200.)
sponse, medical complication rates, or biochemical indexes. One child of age 1.1 year in our series did not have previous biliary surgery, similar to a previously reported 10-monthold child who was also found to have a 7-mm incidental HCC identified during primary LT.16 These observations indicate that HCC can develop early in infancy, even in children who had not undergone KPE. After KPE, dominant regenerative areas frequently develop in the liver and can become large and nodular, making their differentiation from HCC difficult.20 Serum AFP and ultrasound screening are useful but, in our experience, not absolute markers of malignant transformation. Only two children from our series had elevated serum AFP levels, in keeping with positive AFP staining in their tumors, and the three smaller lesions (less than 11 mm) in patients 2 and 5 were not identified by ultrasonography before LT. Nevertheless, these two clinical tests, performed on a regular et al Hadzic
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October 2011 basis, should continue to be the mainstay of HCC surveillance in pediatric CLD. At our center we now perform liver ultrasonography and serum AFP in all children with BA every 6 months. Any new focal lesion detected on ultrasonography should be promptly investigated further with radiologic imaging, including multiphasic CT, primarily to assess its degree of arterialization, which has been suggested to be one of the key radiologic discriminants between benign and malignant lesions.21 Even then a high degree of suspicion should be maintained, because in one of our patients arterialization only became evident on repeat imaging. Novel methods of liver imaging, such as bubble contrast ultrasonography,22 may offer the possibility for more frequent monitoring of suspected focal changes with a comparable accuracy to CT, but without the side effects of the repeated radiation exposures. Histologically, the tumors from this study could be broadly divided into two groups. In the first (three younger patients) the tumors were of relatively small size (range 6 to 25 mm) and showed classical features of HCC, including architectural changes, cytologic atypia, proliferative activity, presence of necrosis, and vascular invasion in various combinations. In the other group (two older patients) the tumors were larger (54 and 105 mm diameter) and well differentiated, with no or low proliferative activity, no necrosis or vascular invasion, and were associated with changes of nodular regenerative or adenomatous hyperplasia within the lesion or in the adjacent liver. The degree of differentiation raised the differential diagnosis of massive nodular expansion that can occasionally follow occlusive venopathy with nodular regenerative hyperplasia in the noncirrhotic liver.23 In this situation, the mass lesions had a more complex architecture, with features resembling focal nodular hyperplasia,24 the latter also rarely reported in BA.20 In contrast, the liver lesions in patients 1 and 4 showed a monomorphic hepatocellular component with a clear cell change, discrete pseudoglandular structures, absence of ductular reaction, and focally infiltrative margins, all in keeping with a well-differentiated HCC. Glypican and beta-catenin immunostaining, recently suggested to be useful in differentiation between dysplastic changes and HCC in adults,18,19 was not helpful in this small series. The two different patterns of histologic changes in our series could suggest different tumor biologic conditions, with different growth rate, doubling time, and potential for recurrence after LT. Two histologically different lesions in the explant of our patient 1 and a recent case report, where radiologic evolution of a 38-mm focal lesion to a 95-mm histologically well-differentiated HCC was demonstrated in a young adult with BA over a follow-up of almost 15 years,15 seem to support this concept of slow evolution from nodular regenerative hyperplasia to HCC. The medical management of children with CLD who have development of HCC is poorly defined.25 The published guidelines refer to sporadic HCC, often mirroring hepatoblastoma or adult HCC protocols, which involve combined chemotherapy and resection.26,27 Patients with BA are likely to have advanced biliary disease, making resection more chal-
lenging. Moreover, some of the important adjuvant treatments such as radioablation, chemoembolization, or sorafenib are presently not approved for use in children. Our clinical decision not to use chemotherapy was based on reported poor responsiveness of HCC to chemotherapy in children,26 but also to avoid serious infectious or immunologic complications early after LT. All patients were, however, staged radiologically, including the ones where the malignancy was an incidental finding. In hindsight, the decision about performing transplantation on a child with a 105mm AFP-negative hepatic mass would have been much more difficult had we known that this was histologically HCC, because its size was outside the standard LT criteria.28 It may well be that the tumors in the context of BA should be considered for LT with more flexible clinical criteria used than those in sporadic HCC. This could become an important issue for adult hepatologists because a considerable number of children who do not undergo transplantation after KPE will survive into adulthood.3,29 In conclusion, we report that HCC represents a rare but significant complication of CLD inherent to BA. Screening with serial AFP and ultrasonography remains the mainstay of diagnosis, although it is still far from perfect. Timely LT (without adjuvant chemotherapy if there is no extrahepatic disease) 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. [email protected]
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, MieliVergani 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 primary hepatic malignancies in U.S. children. Hepatology 2003;38:560-6. 8. van Spronsen FJ, Bijleveld CM, van Maldegem BT, Wijburg FA. Hepatocellular 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, Gutierrez C, Cox KL, Garcia-Kennedy R, Berquist W, Concepcion W. Hepatocellular carcinoma and liver cell dysplasia in children with chronic liver disease. J Pediatr Surg 1994;29:1465-9.
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12. Kohno M, Kitatani H, Wada H, Kajimoto T, Matuno H, Tanino M, et al. Hepatocellular carcinoma complicating biliary cirrhosis 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 transplantation 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. Hepatocellular carcinoma complicating biliary atresia after Kasai portoenterostomy. 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 immunostaining 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 hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol 1999;155:1795-801.
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Vol. 159, No. 4 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 detection. 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 abnormal 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. Hepatocellular carcinoma in children and effect of living-donor liver transplantation on outcome. Pediatr Transplant 2006;10:42-7. 26. Czaudema P, McKinlay G, Perilongo G, Brown J, Shafford E, Aronson D, et al. Hepatocellular carcinoma in children: results of the first prospective 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 Diseases. Hepatology 2005;42:1208-36. 28. http://optn.transplant.hrsa.gov/policiesAndBylaws/policies.asp 3.6 Organ Distribution: Allocation of livers [accessed Nov 2010] 29. Lykavieris P, Chardot C, Sokhn M, Gauthier F, Valayer J, Bernard O. Outcome 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 Location
No. of lesions
Size
Vascular invasion
1
R lobe
1
54 mm
No
2
2 2
4
R lobe
1
11 mm 9 mm 25 mm 19 mm 105 mm
Yes
3
R lobe L lobe R lobe
5
L lobe
1
6 mm
No
Patient
Background liver Bridging fibrosis, venoocclusive lesions and nodular regenerative hyperplasia, ductopenia, cholestasis Cirrhosis, ductopenia, cholestasis, BSEP/MDR3 immunostain normal Cirrhosis, ductopenia, cholestasis, venoocclusive lesions of main portal vein branches, regenerative macronodules 2 Severe biliary bridging fibrosis (stage 3), moderate ductopenia, cholestasis, MDR3 immunostain normal Cirrhosis, ductopenia, cholestasis, absent gallbladder, BSEP/MDR3 immunostain normal
Yes No
Table IV. Immunohistochemical staining of the tumors in explants Patient 1 2 3 4 5
Ki67 (%)
AFP
b-catenin (nuclear)
CD34
Glypican
<5 1-2 20-30 <1 20-30
Neg ++ ++ Neg Neg
0 0 0 0 +
+ (Patchy) ++ (Widespread) ++ (Widespread) + (Focally diffuse) ++ (Widespread)
++ Neg + (Weak) Neg Neg
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Study design In our tertiary referral center database we have identified children with BA who had development of or have been incidentally found to have HCC. Their demographic, clinical, radiologic, and histologic features were analyzed. Results Between 1990 and 2008, 387 infants were diagnosed with BA at our center. Of these, three (0.8 %) who underwent operation at a median age of 68 (range 66 to 71) days had development of a histologically proven HCC detected at a median age of 2.1 (range 1.8 to 4.9) years. Another two, referred later, were diagnosed with HCC on their liver explants at ages 1.1 and 17.75 years, respectively. Overall, two had elevated serum levels of alphafetoprotein. All five children underwent successful liver transplantation at a median age of 2.1 years (range 1.1 to 17.75) 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 ultrasound screening are helpful but not absolute markers of the malignant change. In the absence of the extrahepatic involvement, liver transplantation represents an effective treatment. (J Pediatr 2011;159:617-22).
B
iliary atresia (BA) is an obstructive cholangiopathy of the newborn that, if untreated, leads to biliary cirrhosis and endstage liver disease.1 Treatment is largely surgical, with an initial attempt to restore bile flow by excision of usually solid extrahepatic 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 common pediatric indication for liver transplantation (LT), but approximately one-third of children will reach adulthood without undergoing transplantation.3 Malignant change is a well-recognized complication of CLD from whatever 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 the reported incidence of HCC in the United States has been declining from 0.45 to 0.29 per million children.7 Approximately 65% of all HCCs occur in children older than 10 years, and they are of sporadic nature.6 Some genetic conditions, such as tyrosinemia type I8 and bile salt export pump (BSEP) deficiency9 represent examples where HCC develops on a strikingly short timescale, often within the first few years of life. A number of other hepatic disorders have been described with HCC in childhood, although much less frequently.6 Apart from increased cellular turnover, pathophysiological mechanisms of the neoplastic transformation 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 large cohort. The aim of this study was to estimate the risk of malignant transformation in BA and define optimal management.
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 fails then they are considered for LT.17 AFP BA BSEP CLD CT HCC KPE LT MDR
Alpha-fetoprotein Biliary atresia Bile salt export pump Chronic liver disease Computed tomography Hepatocellular carcinoma Kasai portoenterostomy Liver transplantation Multi-drug resistance
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, Denmark Hill, London, United Kingdom This abstract was presented at 59th Annual Meeting of American association for Study of Liver Disease, October 3- 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 to identify those who were subsequently diagnosed with HCC. Archived histologic material was retrospectively reexamined by two histopathologists, unaware of the clinical details. In addition to standard histologic techniques, the following antibodies 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 Kingdom), glypican 3 (1G12) (1/100) (Menarini Winnersh, Berkshire, United Kingdom), and polyclonal rabbit alpha-fetoprotein (1/400) (Dako). Data are quoted as median (range) unless otherwise indicated.
Results Over the period of the study, 387 infants were diagnosed with BA. Of these, three (0.8%) had development of histologically proven 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 surgery performed at a median age of 68 (66 to 71) days. All three patients had undergone KPE. During the same time period, two additional children, originally not treated at our center, were diagnosed with BA and HCC: (1) a child who had undergone KPE overseas was referred for followup and eventually diagnosed with HCC (patient 4); and (2) a child referred to us for LT because of cryptogenic endstage CLD, had features of BA and incidental HCC in his explanted liver (patient 5). Histologic diagnosis of BA was reconfirmed in patients 1 to 3 by reviewing the presentation liver biopsy specimens and bile duct remnants for this study. In patient 4, for whom the original biopsy specimen was not available, the operative notes and histologic study of the explanted liver were compatible with BA. There were no clinical features of Alagille syndrome and multi-drug resistance (MDR) polypeptide-3 was immunohistochemically well expressed in the liver tissue in all patients. Case Reports Case 1. A white boy underwent KPE at 66 days of age. He cleared his jaundice to a normal serum bilirubin level (<20 mmol/L) and remained well until 38 months of age when he became suddenly jaundiced (bilirubin 232 mmol/L). Radionucleotide scanning and percutaneous transhepatic cholangiography suggested a Roux loop obstruction that was corrected surgically, and the patient’s bilirubin level fell to 31 mmol/L thereafter. During routine post-KPE ultrasound surveillance, a focal parenchymal lesion was noted at 28 months. Abdominal magnetic resonance imaging did not suggest malignant features, and serum levels of alpha-fetoprotein (AFP) remained normal (<2 kU/L [normal range <7 kU/L]) throughout. At 40 months of age, another nodule appeared, prompting biphasic computed tomography (CT) scanning, which showed arterialization of the original, but not of the new lesion. The child was listed for LT, and hepatectomy confirmed a 54-mm-diameter, well-differentiated HCC. The second lesion had features of adenomatous hyperplasia. The 618
Vol. 159, No. 4 patient’s post-transplantation recovery was uneventful, and he was discharged on tacrolimus and prednisolone. He remains well at 2.5 years after LT.
Case 2. A white girl underwent KPE at age 71 days. She never cleared the jaundice and had development of ascites and intractable pruritus during the second year of life. At age 26 months she received a cadaveric LT: two small HCCs were found incidentally in her explanted liver. Her stored preoperative blood sample showed serum AFP of 1259 kU/L. Five days after LT her serum AFP levels decreased to 97 kU/L. The postoperative course was complicated by one episode of cellular rejection that was treated with steroids. The patient remains well at 4.1 years after LT, on tacrolimus and mycophenolate mofetil.
Case 3. A girl of South-Asian origin, but born in the United Kingdom, underwent KPE at 68 days. She never cleared her jaundice and after one episode of gastrointestinal bleeding associated with the development of ascites was listed for LT at age 15 months. Four months later she was noted to have rising serum AFP (51 kU/L to 220 kU/L to 777 kU/L), but no focal lesions could be shown on ultrasonography. However, 3 months later the patient had development of a 27-mm arterialized nodule within the right lobe, evident on biphasic CT scanning, and retroperitoneal and mesenteric adenopathy with right portal vein branch thrombosis. By then her serum AFP was 22 687 kU/L. The patient was prioritized on the waiting list and underwent LT at age 2 years. The explanted liver confirmed the nodule as HCC, with another smaller HCC (19 mm) detected in the right lobe. Preoperative AFP peaked at 139 929 kU/L, but sharply declined (61 kU/L) 1 month after LT and became normal (<2 kU/L) 6 months later. The patient remains well on tacrolimus and mycophenolate at 2.5 years after LT.
Case 4. A white girl with severe visual impairment caused by macular degeneration had had successful KPE performed at 49 days in Cyprus. Because of mild chronic cholestasis (bilirubin 70 mmol/L), she was referred to our center at age 14 years for follow-up. Routine ultrasonography at 17 years identified a large focal lesion (approximate diameter 10 cm), suggestive of adenoma. The patient was clinically well, and her serum AFP level was <2 kU/L. She was listed for transplantation and 6 months later received a liver graft: the hepatectomy specimen showed a 105-mm–diameter HCC. She remains well on tacrolimus and sirolimus at 5.7 years after LT. Case 5. A boy from a consanguineous Arab family, born in the United Kingdom, had development of progressive cholestatic liver disease. Liver biopsy performed at 21 days of age showed features of nonspecific giant cell hepatitis. The patient remained jaundiced, and at 6 months the liver biopsy was repeated and now showed features of ‘‘large bile duct obstruction’’ with bridging fibrosis. Progressive cholestasis with intractable pruritus and gastrointestinal bleeding prompted et al Hadzic
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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 after LT (y)
1, M 2, F
66 71
4.9 2.1
5.1 2.1
Incidental
2.5 4.1
3, F
68
1.8
2.1
-
2.5
4, F 5, M
49 n/a
17.75 1.1
17.75 1.1
54 A-11 B-9 A-19 B-25 105 6
Incidental
5.7 2.0
referral to our center for consideration of LT. A living-related LT was performed at 1.1 years of age. Hepatectomy showed biliary cirrhosis with severe cholestasis, advanced ductopenia, and an absence of the extrahepatic biliary tract and gall bladder. A small (6-mm diameter) HCC was found in the left lobe. The patient remains well receiving tacrolimus and prednisolone at 2 years after LT. Further clinical and biochemical features are summarized in Tables I and II, respectively. All patients had staging abdominal and chest CT at the time of diagnosis of HCC. None showed evidence of extrahepatic spread. As a consequence, no child received chemotherapy before or after 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 Features Neoplasms in patients 2, 3, and 5 show features of small moderately differentiated HCC with microscopic vascular invasion in patients 2 and 3 (Figure 1). All demonstrate a diffuse sinusoidal capillarization with CD34-positive immunostaining and a high proliferative rate within the tumors in patients 3 and 5. Two of these tumors also stained positively for AFP, in parallel to their strikingly elevated serum AFP levels. Only one lesion (patient 3) showed patchy and weak stain for glypican, whereas the others were negative.18 One tumor showed strong nuclear expression of beta-catenin.19 HCC in patients 1 and 4 were much larger and consisted of well-differentiated hepatocellular lesions devoid of portal structures with patchy, yet significant capillarization of the thin stromal vessels (Figure 2). The proliferation rate was low, but the size of the lesions, clear cell change, and microscopic stromal invasion at the periphery of HCC in patient 1 and focal pelioid changes and cell dyscohesion in patient 4 were suggestive of well-differentiated HCCs. They Table II. Biochemical features of the patients at the time of liver transplantation Patient 1 2 3 4 5
Bilirubin (mmol/L)
Albumin (g/L)
INR
33 614 186 70 339
41 29 22 43 37
0.91 1.75 1.29 1.0 1.15
INR, international normalized ratio.
Platelets ( 109/L) 181 51 112 126 232
AFP (kU/L) <2 1260 139 929 <2 5
did not stain for AFP or show nuclear expression of betacatenin. One of the two (patient 1) stained for glypican. The appearance was clearly different from the segmental or macronodular regenerative parenchymal expansion at times observed 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 intrahepatic bile ducts and severe cholestasis. Features of previous KPE were present in patients 2 and 3, whereas in patient 5, who had no previous surgery, the gallbladder was absent with some ductopenia in association with both scarring and ulcerations of residual perihilar ducts, in keeping with a diagnosis of untreated BA. Liver explants in patients 1 and 4 showed severe bridging fibrosis, ductopenia, and cholestasis. In patient 1 there was also evidence of occlusion of small portal vein branches and parenchymal nodular regenerative hyperplasia, and patient 3 also had venoocclusive lesions of the main portal vein branches. Histologic features of the explanted material are presented in Table III (available at www.jpeds.com). For patient 4, diagnosed with BA outside our institution, the histologic material taken at the time of KPE could not be assessed, but we demonstrated positive MDR protein 3 immunostaining, excluding the possibility that MDR protein 3 deficiency could be the cause of liver disease. Additional immunohistochemical information is shown in Table IV (available at www.jpeds.com).
Discussion Children with surgically corrected BA require life-long medical follow-up to monitor progression of their almost inevitable CLD. A study of long-term survivors from our center showed that even in a cohort with completely normal biochemical liver function, more than half have histologic evidence of cirrhosis.3 Our current study suggests that malignant transformation may affect around 1% of children born with BA at some point in their lives, with the likelihood that this will increase given an increasing proportion of ageing cirrhotic native liver survivors. Our experience suggests that all children with BA should be regarded as having a potential for HCC development and urgently considered for LT when this diagnosis is clinically suspected. HCC remains a rare condition in children.4,5 The incidence of sporadic HCC, seen more commonly in adolescents,
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Figure 1. Patient 3. A, A 19-mm pale subcapsular tumor (arrow) is present in the lateral aspect of the right lobe. B, The tumor is composed of highly cellular population of moderately atypical hepatoid cells. Mitotic activity is evident (arrow) (Hematoxylin & eosin; original magnification 200.) C, Clusters of tumor cells are present in the lumen of perilesional thin-walled vascular spaces indicating vascular invasion. (Hematoxylin & eosin; original magnification 400.)
remains static and appears to be declining in those with underlying CLD.7 This may be related to improvements in medical therapy, such as treatment of tyrosinemia type I with nitisinone, early LT for those conditions with a known propensity 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 children than in adults, although the reasons are likely to be multifactorial.4,6 These might include differences in immune response, increasing exposure to alcohol, increasing insulin resistance, and longer exposure to the initiating agent. Our study group represents the usual spectrum of patients after undergoing KPE in terms of age at surgery, clinical re620
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Figure 2. Patient 1. A, The tumor is a well differentiated hepatocellular neoplasm composed of bland hepatocytes with no evident atypia and low proliferative activity. An unpaired artery is present in the center of the field. (Hematoxylin & eosin; original magnification 400.) B, A peripheral area of tumor with clear cell change (right side) is separated from background liver (top left) by a rim of fibrous stroma. (Hematoxylin & eosin; original magnification 200.)
sponse, medical complication rates, or biochemical indexes. One child of age 1.1 year in our series did not have previous biliary surgery, similar to a previously reported 10-monthold child who was also found to have a 7-mm incidental HCC identified during primary LT.16 These observations indicate that HCC can develop early in infancy, even in children who had not undergone KPE. After KPE, dominant regenerative areas frequently develop in the liver and can become large and nodular, making their differentiation from HCC difficult.20 Serum AFP and ultrasound screening are useful but, in our experience, not absolute markers of malignant transformation. Only two children from our series had elevated serum AFP levels, in keeping with positive AFP staining in their tumors, and the three smaller lesions (less than 11 mm) in patients 2 and 5 were not identified by ultrasonography before LT. Nevertheless, these two clinical tests, performed on a regular et al Hadzic
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October 2011 basis, should continue to be the mainstay of HCC surveillance in pediatric CLD. At our center we now perform liver ultrasonography and serum AFP in all children with BA every 6 months. Any new focal lesion detected on ultrasonography should be promptly investigated further with radiologic imaging, including multiphasic CT, primarily to assess its degree of arterialization, which has been suggested to be one of the key radiologic discriminants between benign and malignant lesions.21 Even then a high degree of suspicion should be maintained, because in one of our patients arterialization only became evident on repeat imaging. Novel methods of liver imaging, such as bubble contrast ultrasonography,22 may offer the possibility for more frequent monitoring of suspected focal changes with a comparable accuracy to CT, but without the side effects of the repeated radiation exposures. Histologically, the tumors from this study could be broadly divided into two groups. In the first (three younger patients) the tumors were of relatively small size (range 6 to 25 mm) and showed classical features of HCC, including architectural changes, cytologic atypia, proliferative activity, presence of necrosis, and vascular invasion in various combinations. In the other group (two older patients) the tumors were larger (54 and 105 mm diameter) and well differentiated, with no or low proliferative activity, no necrosis or vascular invasion, and were associated with changes of nodular regenerative or adenomatous hyperplasia within the lesion or in the adjacent liver. The degree of differentiation raised the differential diagnosis of massive nodular expansion that can occasionally follow occlusive venopathy with nodular regenerative hyperplasia in the noncirrhotic liver.23 In this situation, the mass lesions had a more complex architecture, with features resembling focal nodular hyperplasia,24 the latter also rarely reported in BA.20 In contrast, the liver lesions in patients 1 and 4 showed a monomorphic hepatocellular component with a clear cell change, discrete pseudoglandular structures, absence of ductular reaction, and focally infiltrative margins, all in keeping with a well-differentiated HCC. Glypican and beta-catenin immunostaining, recently suggested to be useful in differentiation between dysplastic changes and HCC in adults,18,19 was not helpful in this small series. The two different patterns of histologic changes in our series could suggest different tumor biologic conditions, with different growth rate, doubling time, and potential for recurrence after LT. Two histologically different lesions in the explant of our patient 1 and a recent case report, where radiologic evolution of a 38-mm focal lesion to a 95-mm histologically well-differentiated HCC was demonstrated in a young adult with BA over a follow-up of almost 15 years,15 seem to support this concept of slow evolution from nodular regenerative hyperplasia to HCC. The medical management of children with CLD who have development of HCC is poorly defined.25 The published guidelines refer to sporadic HCC, often mirroring hepatoblastoma or adult HCC protocols, which involve combined chemotherapy and resection.26,27 Patients with BA are likely to have advanced biliary disease, making resection more chal-
lenging. Moreover, some of the important adjuvant treatments such as radioablation, chemoembolization, or sorafenib are presently not approved for use in children. Our clinical decision not to use chemotherapy was based on reported poor responsiveness of HCC to chemotherapy in children,26 but also to avoid serious infectious or immunologic complications early after LT. All patients were, however, staged radiologically, including the ones where the malignancy was an incidental finding. In hindsight, the decision about performing transplantation on a child with a 105mm AFP-negative hepatic mass would have been much more difficult had we known that this was histologically HCC, because its size was outside the standard LT criteria.28 It may well be that the tumors in the context of BA should be considered for LT with more flexible clinical criteria used than those in sporadic HCC. This could become an important issue for adult hepatologists because a considerable number of children who do not undergo transplantation after KPE will survive into adulthood.3,29 In conclusion, we report that HCC represents a rare but significant complication of CLD inherent to BA. Screening with serial AFP and ultrasonography remains the mainstay of diagnosis, although it is still far from perfect. Timely LT (without adjuvant chemotherapy if there is no extrahepatic disease) 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. [email protected]
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, MieliVergani 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 primary hepatic malignancies in U.S. children. Hepatology 2003;38:560-6. 8. van Spronsen FJ, Bijleveld CM, van Maldegem BT, Wijburg FA. Hepatocellular 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, Gutierrez C, Cox KL, Garcia-Kennedy R, Berquist W, Concepcion W. Hepatocellular carcinoma and liver cell dysplasia in children with chronic liver disease. J Pediatr Surg 1994;29:1465-9.
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12. Kohno M, Kitatani H, Wada H, Kajimoto T, Matuno H, Tanino M, et al. Hepatocellular carcinoma complicating biliary cirrhosis 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 transplantation 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. Hepatocellular carcinoma complicating biliary atresia after Kasai portoenterostomy. 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 immunostaining 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 hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol 1999;155:1795-801.
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Vol. 159, No. 4 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 detection. 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 abnormal 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. Hepatocellular carcinoma in children and effect of living-donor liver transplantation on outcome. Pediatr Transplant 2006;10:42-7. 26. Czaudema P, McKinlay G, Perilongo G, Brown J, Shafford E, Aronson D, et al. Hepatocellular carcinoma in children: results of the first prospective 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 Diseases. Hepatology 2005;42:1208-36. 28. http://optn.transplant.hrsa.gov/policiesAndBylaws/policies.asp 3.6 Organ Distribution: Allocation of livers [accessed Nov 2010] 29. Lykavieris P, Chardot C, Sokhn M, Gauthier F, Valayer J, Bernard O. Outcome 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 Location
No. of lesions
Size
Vascular invasion
1
R lobe
1
54 mm
No
2
2 2
4
R lobe
1
11 mm 9 mm 25 mm 19 mm 105 mm
Yes
3
R lobe L lobe R lobe
5
L lobe
1
6 mm
No
Patient
Background liver Bridging fibrosis, venoocclusive lesions and nodular regenerative hyperplasia, ductopenia, cholestasis Cirrhosis, ductopenia, cholestasis, BSEP/MDR3 immunostain normal Cirrhosis, ductopenia, cholestasis, venoocclusive lesions of main portal vein branches, regenerative macronodules 2 Severe biliary bridging fibrosis (stage 3), moderate ductopenia, cholestasis, MDR3 immunostain normal Cirrhosis, ductopenia, cholestasis, absent gallbladder, BSEP/MDR3 immunostain normal
Yes No
Table IV. Immunohistochemical staining of the tumors in explants Patient 1 2 3 4 5
Ki67 (%)
AFP
b-catenin (nuclear)
CD34
Glypican
<5 1-2 20-30 <1 20-30
Neg ++ ++ Neg Neg
0 0 0 0 +
+ (Patchy) ++ (Widespread) ++ (Widespread) + (Focally diffuse) ++ (Widespread)
++ Neg + (Weak) Neg Neg
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