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Unresectable hepatic tumors in childhood and the role of liver transplantation
Unresectable Hepatic Tumors in Childhood and the Role of Liver Transplantation By Orthodoxos
A. Achilleos, Laura J. Buist, Deirdre A. Kelly, Faro Raafat, Paul McMaster, Antony D. Mayer, and John A.C. Buckels Birmingham, England
l Liver transplantation has been performed in five children with unresectable hepatic tumors who did not have extrahepatic metastases at the time of surgery. Two of the children had hepatoblastomas, one had an infantile hemangioendothelioma, and two had a hepatoma. The two children who had hepatoblastoma are well (37 and 25 months posttransplant) and have no evidence of recurrence. The child with infantile hemangioendothelioma had a successful operation, with good quality of life, but died of tumor recurrence 41 months after transplantation. Both children with hepatomas died, one of graft failure owing to chronic rejection and the other of tumor recurrence 5 months posttransplant. These results suggest that liver transplantation may be successful in children with unresectable hepatic tumors without extrahepatic spread and should be considered particularly for the treatment of hepatoblastoma. Copyright o 1996 by W.B. Saunders Company INDEX lioma,
WORDS: Hepatoblastoma, hepatocellular carcinoma,
infantile hemangioendotheliver transplantation.
B
ECAUSE complete surgical excision is the only chance of cure for patients with primary liver tumors, the indications for liver transplantation include unresectable malignant tumors confined to the liver.’ However, since 1967 when Starzl performed the first orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) on a M-month-old girl who survived 13 months*,‘), the efficacy of OLT for primary tumors of the liver has remained uncertain. Although the early survival rate after transplantation for primary liver tumor is excellent,4 the incidence of recurrence after OLT is high, and may depend on histology.1-6 Nevertheless, a number of malignant tumors in adults, and as well as in children, have been treated effectively with total hepatectomy and OLT.1,7-‘2 CASE
REPORTS
We report on five children who have undergone OLT for treatment of unresectable hepatic tumors. Data were collected for all patients and included age, gender, symptoms at time of presentation, classification of tumor. extension of gross disease at the time of transplantation, histological features, type of operation. pre- and posttransplant chemotherapy or radiotherapy, complications, recurrence, graft survival, and current status. The age range of the children was 3 to 12years. There were three boys and two girls. Two children had hepatoblastoma. one had infantile hemangioendothelioma, and two had hepatoma; one with underlying tyrosinemia and the other developing in a cirrhotic liver secondary to hepatitis B. JournalofPediatr/cSurgery,
Vol31,
No 11 (November),
1996: pp 1563.1567
Disease at Time of Transplantation All patients had intrahepatic disease only at the time of transplantation. All received standard immunosuppression consisting of cyclosporine, azathioprine, and steroids, and alphafetoprotein levels (AFP) were monitored monthly.
Case 1 This girl (3.25 years of age) had hepatoblastoma; she presented with a palpable abdominal mass and abdominal pain. She had markedly high serum AFP levels (670,000 kU/L) at the time of presentation. Abdominal ultrasonography and a computed tomography (CT) scan showed multifocal tumor m both lobes of the liver. There was no extrahepatic tumor. Angiography showed compression of the portal vein and proximal inferior vena cava; both renal veins were distended. Despite some response to preoperative chemotherapy, the tumor remained unresectable and the patient underwent transplantation of a reduced-size liver (segments II and III).17.1J She had a laparotomy for hepatic bleeding 8 days posttransplantation, and subsequently she experienced hepatic artery thrombosis, hepatic abscess, biliary obstruction, and biliary sludge, which were treated conservatively. Hepatic artery signal was obtained by Doppler ultrasonography 40 days post-OLT. She remains well 37 months posttransplantatlon.
Case 2 This 6.9-year-old boy presented with weight loss, anorexia, a palpable abdominal mass, abdominal pain, lethargy, and pallor. His serum AFP levels were markedly high (500.000 kU/L). Abdominal ultrasonography and a CT scan showed a unifocal tumor at the right lobe of the liver with portal vein thrombosis, which was confirmed by angiography. There was no disease in kidneys and chest. A hver biopsy confirmed hepatoblastoma. Despite response to preoperative chemotherapy, the tumor remained unresectable and the patient had transplantation with a whole liver graft. The thrombosed portal vein was excised and reconstructed with an interpositional vein graft. He remains well 25 months after transplantation.
Case 3 This 2.9-year-old girl presented with abdominal mass, hepatomegaly, splenomegaly, lumbar lordosis, and remarkable increase in girth. AFP levels were negative. and radiological examination showed a large unifocal tumor that involved both lobes of the liver and the major biliary ducts. There was no disease in the kidneys or
From the Lrver and Hepatobdiary Untt, Queen Elizabeth Hospital, and the Liver Unrt and Department of Histopathology, Children i Hosprtal, Birmingham, England. DrAchdleos 1s funded by the Greek State Scolarshrp Foundation. Address reprint requests to Orthodoxos A. Achrlleos. MD, Liver & Hepatobihaty Umt (Lnw Laboratories), The Queen Ehzabeth Hospltal, Edgbaston, Birmingham B15 2TH, England. Copynght rii I996 by W. B. Saunders Company 0022.3168i9613111-0022$03 0010 1563
ACHILLEOS ET AL
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chest. The result of a skeletal survey was negative. The diagnosis of infantile hemangioendothelioma type II was confirmed by needle and open liver biopsy. The patient was treated with high-dose steroids, with no improvement. The tumor increased rapidly, producing lumbar lordosis and vena cava obstruction with ankle edema, and she underwent transplantation with a whole liver graft. In the posttransplant period, a biliaty leak and Ebstein-Barr virus infection developed, which were treated conservatively. Twentynine months posttransplant, a metastatic vertebral hemangioendothelioma, type II (confirmed histologically and histocytochemitally), was removed by spinal laminectomy and treated with radiotherapy. She died of multiple metastases 12 months after the laminectomy (41 months after transplantation).
Case 4 This patient, a 4.9-year-old boy, presented with rickets, anaemia, and splenomegaly, and was found to have tyrosinemia type I. Seven months later his serum AFP levels began to increase (from 770 kU/L to 1,700 kU/L). Hepatic dysplasia was noted on a liver biopsy specimen, and radiological examination showed multifocal changes in both lobes of the liver. The patient underwent transplantation with a whole liver graft. The surface of the resected liver showed mixed cirrhosis, with nodules of up to 2 cm in diameter. Histological examination showed a well-differentiated HCC. There were no extrahepatic metastases. Postoperative complications included small bowel perforation, and retransplantation for chronic rejection I year after the first transplant. He died 5 months after placement of the second graft because of chronic rejection. There was no evidence of tumor recurrence.
Case 5 This 12-year-old boy had chronic active hepatitis (CAH) secondary to hepatitis B, and a tumor developed in his liver. At that time the AFP levels were slightly elevated. The CT scan showed a multifocal hepatic mass (11 cm in diameter) at the right lobe and numerous nodules in both lobes. He received preoperative chemotherapy and radiotherapy, without any response, and underwent transplantation with a whole liver graft. Hepatectomy of the old liver showed a HCC of 11 cm in diameter at the right lobe and numerous other nodules in both lobes. Histological examination showed a moderately differentiated HCC; the porta hepatis contained two hyperplastic lymph nodes and an extrahepatic nodule of tumor. Seven days posttransplantation, the patient underwent biliary reconstruction because of a biliary leak. Pulmonary metastases developed 5 months postoperatively and he died.
Histological Characteristics of the Hepatectomy Specimens In the patients with hepatoblastoma (cases 1 and 2B), the tumors were necrotic with some areas of viable epithelial and mesenchyma1 neoplastic cells. In the patient with hemangioendothelioma (case 3) the biopsy specimen showed a dense fibroconnective tissue with numerous tiny capillaries and some larger vascular channels, lined by plump endothelial cells, in both lobes of the liver. In this case, factor VIII-related antigen was detected immunocytochemically as being present within the tumor cells. In the patients with hepatoma (cases 4 and 5) both lobes of the liver were involved. There was diffuse dysplasia and disturbance of architecture with pericellular fibrosis. confirming HCC. RESULTS
The two children with hepatoblastoma (cases 1 and 2) are well 37 and 25 months posttransplantation,
with no evidence of tumor recurrence. Both attend normal school, their growth is excellent (height and weight are above the 25th and 50th percentiles, respectively), and their AFP levels are below 2 KU/L. The patient with infantile hemangioendothelioma (case 3) who died 41 months after transplantation because of tumor recurrence had a good quality of life, with normal growth and development, for more than 3 years. Both patients with hepatoma died. The patient with tyrosinemia type I and hepatoma (case 4) died 17 months after the first transplantation, and 5 months after the retransplantation, because of secondary graft failure owing to chronic rejection. The second patient with hepatoma (case 5) died of pulmonary metastases 5 months after the operation. DISCUSSION
Primary hepatic malignancy accounts for approximately 5% of all paediatric neoplasms.13 The primary tumors have been associated with a variety of congenital hepatic disorders, extrahepatic anomalies, and metabolic disorders. Hepatoblastoma is the third most common intraabdominal malignant tumor in childhood, after nephroblastoma and neuroblastoma. It usually occurs in children under 3 years of age. It arises from primitive epithelial cells of the fetal liver, usually in a noncirrhotic liver,15 it has a peak incidence in early infancy, and at least 50% of the cases are diagnosed during the first year of life.16 The tumors involve the right lobe of the liver in approximately 75%.13 More than 25 cases of hepatoblastoma reportedly have been associated with a family history of FAP.” In contrast, hepatoma is rare in children under 3 years of age. Typically, the diagnosis is made between 10 and 14 years of age, and the male:female ratio is 10:1.r8 There is a geographical variation, however, and the larger series of cases of childhood hepatoma from other areas of the world, particularly the Far East, are closely related to hepatitis B surface antigen and cirrhosis.1y-22 A significant number of children have an underlying disorder such as cirrhosis, tyrosinemia type I, or glycogen storage disease. The incidence of hepatoma in cases of tyrosinemia type I is at least 37%.23 Hemangioendothelioma is a soft tissue malignant tumor characterized by its epithelioid appearance and vascular endothelial histogenesis. The presence of immunohistochemical staining for factor VIIIrelated antigen in the tumor is considered a prerequisite for the confirmation of hemangioendothelioma.24 There are two basic histological patterns of hemangioendotheIioma.25 Type I is characterized by irregularly
HEPATIC
TUMORS
dilated and compressed vascular spaces lined by immature endothelial cells, separated by a supporting fibrous tissue and intermingled with small bile ductules. Type II lesions are made up of larger, more hyperchromatic and pleomorphic endothelial cells with no evidence of interspersed biliary ductules. The diagnosis of the original liver tumor in our case was made from a needle biopsy specimen; it can be difficult to differentiate it from angiosarcoma. However, the diagnosis was confirmed histologically and immunocytochemically by open biopsy and following hepatectomy. Angiosarcoma is extremely rare at this age. Type II hemangioendothelioma is more aggressive than type I (much more common) and can be multicentric and/or metastasize.‘h Infantile hemangioendothelioma is considered to be the most common vascular liver tumor in infancy.?‘The term of infantile is perhaps a misnomer, but it applies to the type of lesion rather than the patient’s age. But again, although the tumor in our case was diagnosed when the patient was 2 years 9 months of age, we do not know how long it had been present. The incidence of this tumor is greatest in the first 6 months of life.‘5,‘7 However, in a 1971 review, Dehner and Ishak reported the diagnosis of infantile hemangioendothelioma type II in two cases (age 18 months and 4 years).‘5 Selby et al reported on a group of 91 patients who had infantile hemangioendothelioma of the liver; most ranged from premature infants to 3 year olds, but there was one 18 year old.” Females seem to be affected more often.?‘,‘” Various forms of therapy for vascular tumors of the liver have been recommended, including steroids therapy and/or radiotherapy, hepatic resection, hepatic artery ligation, alpha interferon therapy, and liver transplantation.‘“~Z5.Zy-J~ Steroids have been used successfully in cases of extensive nonresectable tumors since 1969 and 1970,“AJs and they were the first choice in 1989 (when our patient presented) because other treatments (ie, embolization, surgical excision, and radiotherapy) provided more uncertain results at that time.“’ Interferon alpha-2a recently appeared to have a beneficial effect on a variety of progressive and life-threatening angiomatous diseases of infancy and childhood.J”,3h,“7 However, interferon-a is not a potent angiogenesis inhibitor and requires prolonged therapy.“‘JhJ8 Hepatic artery ligation, which is another treatment option, was first reported by de Lorimier et al in 1967.“” Various opinions have been reported since then regarding its relative beneficial effects, and some surgeons continue to avoid it.JU Recently, Davenport et al recommended hepatic artery ligation for a bilobar multifocal hemangioendothelioma of the liver.“’ However, dearterialization of
the liver is well tolerated in humans if liver perfusion and oxygenation are maintained via the portal vein and if sepsis is avoided. Hepatoblastomas and hepatomas account for up to 98% of primary malignant liver tumors in children.13,41 Most tumors are best managed by preoperative chemotherapy and delayed resection, but there are rare instances of small localized tumors in infants that can be managed appropriately by primary resection.i3,41,JZ Chemotherapy makes the tumor more compact, less vascular, and more resistant to surgical manipulation. 33Improvements in anesthesia and postoperative care have greatly diminished the complications of surgery, and up to 85%13 of the liver can be resected safely. Full regeneration of the liver is normally completed between 3 and 6 months after surgery.‘” Previously reported resection rates for malignant tumors in pediatric patients are 60% for hepatoblastoma and 33% for hepatoma.J3-45 Approximately 50% of the patients have unresectable disease at the time of presentation, but during the last 12 years several studies have shown a significant reduction in tumor size with the use of chemotherapy. OLT has been indicated for children with unresectable tumors with extension in both lobes, vascular invasion, involvement of the hilum and the major ducts, unsuccessful resection, and tumor recurrence in the liver.lJn~Js All five reported cases were unresectable because of extension of the tumor, vascular invasion, and compression. In cases 1 and 2, liver replacement was necessary because of tumor extension and the involvement of the portal vein and/or inferior vena cava. Bench surgery has been confined to situations and tumor stages otherwise deemed untreatable, or to situations where resection would not have been sufficiently radical. 4hHowever, it could not be considered in these two cases because the tumor was found (by ultrasonography) to cause obstruction of the portal vein at the porta hepatis and (during the recipient’s hepatectomy) to infiltrate both the extrahepatic and intrahepatic portal veins. Liver transplantation was successful in these patients who had hepatoblastoma; they are alive, without evidence of recurrence, 37 and 25 months posttransplantation. This compares favorably with other published results, ie, a 50% l-year survival rate for 12 children with liver tumors,‘.4a and survival of the three patients (cases 3, 4, and 5) who had infantile hemangioendothelioma or hepatoma. In 1989, Pierro et al reported 11 cases of hepatoblastoma unresectable because of involvement of both lobes or because of the size of the tumor.J4 Eight of the 11 cases responded to chemotherapy,
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with a reduction in size of greater than 50%. Complete resection was successful in seven cases, and the patients were alive (disease-free) at 4 to 42 months. In 1992, Reynolds et al reported on 37 children with unresectable hepatoblastoma who received preoperative chemotherapy. 45 Twenty-nine responded to the chemotherapy (in two cases the tumor disappeared; in another, chemotherapy was used in combination with radiation), and 26 had significant tumour reduction and complete surgical resection of the tumor, with complete remission in 20 cases. The other six patients had disease progression and died (one after transplantation). Eight of the 37 patients had an inadequate response to chemotherapy (two had liver transplantation with complete remission of the tumor, and six died of disease progression). In 1988, Ringer et al included two children with hepatoblastoma in their larger series of patients who underwent transplantation for hepatobiliary malignancy.lO One child was alive 6 years after transplantation, and the other died of sepsis. However, in 1991, Koneru et al reported on 12 children who had received 13 liver grafts for unresectable hepatoblastoma, and six of the patients were living in 1992.l~~~ In this group of patients, nine received chemotherapy before and five after the transplantation. In case 3, liver replacement was necessary because of rapid progression of the tumor and obstruction of the vena cava. Our case treated in 1989 was not considered suitable for hepatic artery ligation because the tumor involved the porta hepatis, reducing the blood flow to the liver through the portal vein. Marino et al reported on 10 adults who underwent liver transplantation because of unresectable epithelioid hemangioendothelioma, eight of them were alive when the report was writtenz4 and one patient had survived 11 years. An adult patient who had transplantation for the same tumor (operated on by our group) had recurrent disease 7 years posttransplantation.
ET AL
Long-term survival without any specific therapy has been reported by Ishak et al.48Because of the rarity of these tumors and the unpredictability of metastasis and recurrence, it is difficult to recommend a particular therapeutic approach. In cases 4 and 5, OLT was necessary because of multifocal tumor tissue in both lobes of the liver. In 1993, Yandza et al reported on two children (both 8.5 years of age) who had early primary hepatocellular carcinoma secondary to maternal transmission of hepatitis B. Both children were alive (24 and 27 months post-OLT) at the time of the report.22 In 1993, Van Thiel et al reported an 11-year Pittsburgh experience with 181 liver transplantations for tumors; 102 were done for hepatocellular carcinoma, 12 for epitheliohemangioendothelioma, and six for hepatoblastoma.49 The results of this study, which included adults and children, show that the combination of chemotherapy and surgery was better than either treatment alone, and that the early results with chemotherapy pre- and post-OLT were better than those of treatment with chemotherapy only pre-OLT. The longest survivor of any liver transplantation in the world (as of 1991) was a child who had the procedure in January 1970, because of an incidental hepatoma.50 This series, which includes long-term results of transplantation for primary and metastatic hepatic tumors in adults and children in transplantation centers, has shown that cases of hepatoblastoma, epithelioid hemangioendothelioma, incidental hepatoma, and fibrolamellar carcinoma are the best suited for liver transplantation,50,51 which concurs with our data. We recommend that liver transplantation be considered for nonmetastatic unresectable tumors, particularly hepatoblastoma. ACKNOWLEDGMENT The authors acknowledge Susan Paris and Bridget K. Gunson for their assistance with data collection.
REFERENCES tion in hepatocellular carcinoma. Transplant Int 5:S196-S197,1992 1. Koneru B, Flye MW, Busuttil RW, et al: Liver transplantation for hepatoblastoma. Ann Surg 213:118-121, 1991 (suppl I) 2. Ismail T, Angrisani L, Gunson BK, et al: Primary hepatic 8. Pichlmayer R: Liver transplantation in primary hepatocellumalignancy: The role of liver transplantation. Br J Surg 77:983-987, lar carcinoma. J Hepatol18:151-153, 1993 1990 9. McPeake JR, OLGrady JG, Zaman S, et al: Liver transplanta3. Iwatsuki S, Starzl TE: Personal experience with 411 hepatic tion for primary hepatocellular carcinoma: tumour size and numresection. Ann Surg 208:421-432, 1988 ber determine outcome. J Hepatol18:226-234, 1993 4. Haug CE, Jenkins RL, Rohrer RJ, et al: Liver transplantation 10. Ringe B, Wittekind C, Bechstein WO, et al: The role of liver for primary hepatic cancer. Transplantation 53:376-382,199Z transplantation in hepatobiliary malignancy. Ann Surg 209:88-98, 5. Iwatsuki S, Gordon RD, Shaw BW, et al: Role of liver 1989 transplantation in cancer therapy. Ann Surg 202:401-407,1985 6. Pichlmayer R: Is there a place for liver grafting for malig11. Koneru B, Gassavilla A, Bowman J, et al: Liver transplantanancy? Transplant Proc 20:478-482,1988 (suppl 1) tion for malignant tumours. Gastroenterol Clin North Am 17:1777. Jaurrieta E, Fabregat J, Figueras J, et al: Liver transplanta193,1988
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12. O&Grady JG, Poison RJ, Rolles K, et al: Liver transplantation for malignant disease. Arm Surg 207:373-379, 1988 13. Howard ER, Heaton ND: Benign and malignant tumours, in Howard ER (ed): Surgery of Liver Disease in Children, chap 13. Oxford, Great Britain, Butterworth, 1991, pp 126-142 14. Strong R, Ong TH, Pillay P, et al: A new method of segmental orthotopic liver transplantation. Surgery 104:104-107, 1988 15. Okuda K: Primary liver cancer in Japan. Cancer 45:26632669,198O 16. Fraumeni JF, Miller RW, Hill JA: Primary carcinoma of the liver in childhood: An epidemiologic study. J Nat1 Cancer Inst 4o:iO87-1099,1968 17. Garber JE, Li FP, Kingston JE, et al: Hepatoblastorna and familial adenomatous polyposis. J Nat1 Cancer Inst 80:1626-1628, 1988 18. Dehner LP: Hepatic tumours in the pediatric age group: A dinstinctive clinicopathologic spectrum. Perspect Pediatr Path01 4:217-268,1978 19. Shimoda T, Uchida T, Miyata H, et al: A 6-year-old boy having hepatocellular carcinoma associated with hepatitis B surface antigenemia. Am J Clin Path01 74:827-831,198O 20. Chen WJ, Lee JC, Hung WT: Primary malignant tumour of liver in infants and children in Taiwan. J Pediatr Surg 23:457-461, 1988 21. Wu TC, Tong MJ, Hwang B, et al: Primary hepatocellular carcinoma and hepatitis B infection during childhood. Hepatology 7:46-48,1987 22. Yandza T, Alvarez F, Laurent J, et al: Pediatric liver transplantation for primary hepatocellular carcinoma associated with hepatitis virus infection. Transpl Int 6:95-98,1993 23. Weinberg AG, Mize CE, Worthen HG: The occurrence of hepatoma in the chronic form of hereditary tyrosinaemia. J Pediatr Surg 88:434-438,1976 24. Marino IR, Todo S, Tzakis AG, et al: Treatment of hepatic haemangioendothelioma with liver transplantation. Cancer 62:20792084,1988 25. Dehner LP, Ishak KG: Vascular tumors of the liver in infants and children. Arch Path01 92:101-111, 1971 26. Dehner LP: Liver, gallbladder and extrahepatic biliary tract, in Dehner LP (ed): Paediatric Surgical Pathology, (ed 2), chap 7. Baltimore, MD, Williams & Wilkins, 1987, pp 483-488 27. Selby DM, Stocker JT, Waclawiw MA, et al: Infantile haemangioendothelioma of the liver. Hepatology 20:39-451994 28. Dachman AH, Lichtestein JE, Friedman AC, et al: Infantile haemangioendothelioma of the liver: A radiologic-pathologicclinical correlation. AIR 140:1091-1096, 1983 29. Matolo NM, Johnson DG, City SL: Surgical treatment of hepatic haemangioma in the newborn. Arch Surg 106:725-727, 1973 30. Cohen RC, Myers NA: Diagnosis and management of hepatic hemangiomas in childhood. J Pediatr Surg 21:6-9,1986 31. Enjolras 0, Riche MC, Merland JJ, et al: Management of alarming hemangiomas in infancy: A review of 25 cases. Pediatrics 85:491-498,199O 32. Davenport M, Hansen L, Heaton ND, et al: Hemangioendothelioma of the liver in infants. J Petiatr Surg 30:44-48,1995 33. Ezekowitz RAB, Phil D, Mulliken JB, et al: Interferon
1567 alfa-2a therapy for life threatening hemangiomas of infancy. N Engl J Med 326:1456-1463,1992 34. Brown SH, Fonkalsrud E: Successful treatment of hepatic haemangioendothelioma with corticosteroids. JAMA 208:24732474,1969 35. Touloukian RJ: Hepatic hemangioendothelioma during infancy: Pathology, diagnosis, and treatment with prednisone. Pediatrics 45:71-76,197O 36. White CW, Wolf SJ, Korones DN, et al: Treatment of childhood diseases with recombinant interferon alpha-2a. J Pediatr 118:59-66, 1991 37. White CW, Sondheimer HM, Crouch EC, et al: Treatment of pulmonary hemangiomatosis with recombinant interferon alpha2a. N Engl J Med 320:1197-1200,1989 38. O’Reilly MS, Brem H, Folkman J: Treatment of murins hemangioendotheliomas with the angiogenesis inhibitor AGM1470. J Pediatr Surg 30:325-330,1995 39. de Lorimier AA, Simpson EB, Baum RS, et al: Hepatic artery ligation for hepatic hemangiomatosis. N Engl J Med 277:333-337,1967 40. Nguyen L, Shandling B, Ein S, et al: Hepatic hemangioma in childhood: Medical management or surgical management? J Pediatr Surg 17:576-579, 1982 41. Gauthier F, Valayer J, Thai BL, et al: Hepatoblastoma and hepatocarcinoma in children: Analysis of a series of 29 cases. J Pediatr Surg 21:424-429,1986 42. Pazdur R, Bready B, Cangir A, et al: Pediatric hepatic tumours: Clinical trials conducted in the United States. J Surg Oncol3:127-130,1993 43. Gulglielmi M, Perilongo G, Cecchetto G, et al: Rationale and results of the International Society of Pediatric Oncology (SIOP) Italian pilot study on childhood hepatoma: Surgical resection d’ emblee or after primary chemotherapy? J Surg Oncol 3:122-126.1993 44. Pierro A, Langevin AM, Filler RM, et al: Preoperative chemotherapy in “unresectahle” hepatoblastoma. J Pediatr Surg 24:24-29,1989 45. Reynolds M, Douglass EC, Finegold M, et al: Chemotherapy can convert unresectable hepatoblastoma. J Pediatr Surg 27:10801084,1992 46. Pichlmayr R, Grosse H, Hauss J, et al: Technique and preliminary results of extracorporeal liver surgery (bench procedure) and of surgery on the situ perfused liver. Br J Surg 77:21-26, 1990 47. Clements D, Hubscher S, West R, et al: Epithelioid haemangioendothelioma. A case report. J Hepatol2:441-449,1986 48. Ishak KG, Sesterrhenn IA, Goodman MZD, et al: Epithelioid hemangioendothelioma of the liver: A clinicopathology and follow-up study of 32 cases. Hum Path01 15:839-852,1984 49. Van Thiel DH, Carr B, Iwatsuki S, et al: The 11-year Pittsburg experience with liver transplantation for hepatocellular carcinoma: 1981-1991. J Surg Oncol3:78-82,1993 50. Penn I: Hepatic transplantation for primary and metastatic cancers of the liver. Surgery 110:726-735,199l 51. Pichlmayr R, Weimann A, Ringe B: Indications for liver transplantation in hepatobiliary malignancy. Hepatology 20:33S40s. 1994 (suppl2)
A. Achilleos, Laura J. Buist, Deirdre A. Kelly, Faro Raafat, Paul McMaster, Antony D. Mayer, and John A.C. Buckels Birmingham, England
l Liver transplantation has been performed in five children with unresectable hepatic tumors who did not have extrahepatic metastases at the time of surgery. Two of the children had hepatoblastomas, one had an infantile hemangioendothelioma, and two had a hepatoma. The two children who had hepatoblastoma are well (37 and 25 months posttransplant) and have no evidence of recurrence. The child with infantile hemangioendothelioma had a successful operation, with good quality of life, but died of tumor recurrence 41 months after transplantation. Both children with hepatomas died, one of graft failure owing to chronic rejection and the other of tumor recurrence 5 months posttransplant. These results suggest that liver transplantation may be successful in children with unresectable hepatic tumors without extrahepatic spread and should be considered particularly for the treatment of hepatoblastoma. Copyright o 1996 by W.B. Saunders Company INDEX lioma,
WORDS: Hepatoblastoma, hepatocellular carcinoma,
infantile hemangioendotheliver transplantation.
B
ECAUSE complete surgical excision is the only chance of cure for patients with primary liver tumors, the indications for liver transplantation include unresectable malignant tumors confined to the liver.’ However, since 1967 when Starzl performed the first orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) on a M-month-old girl who survived 13 months*,‘), the efficacy of OLT for primary tumors of the liver has remained uncertain. Although the early survival rate after transplantation for primary liver tumor is excellent,4 the incidence of recurrence after OLT is high, and may depend on histology.1-6 Nevertheless, a number of malignant tumors in adults, and as well as in children, have been treated effectively with total hepatectomy and OLT.1,7-‘2 CASE
REPORTS
We report on five children who have undergone OLT for treatment of unresectable hepatic tumors. Data were collected for all patients and included age, gender, symptoms at time of presentation, classification of tumor. extension of gross disease at the time of transplantation, histological features, type of operation. pre- and posttransplant chemotherapy or radiotherapy, complications, recurrence, graft survival, and current status. The age range of the children was 3 to 12years. There were three boys and two girls. Two children had hepatoblastoma. one had infantile hemangioendothelioma, and two had hepatoma; one with underlying tyrosinemia and the other developing in a cirrhotic liver secondary to hepatitis B. JournalofPediatr/cSurgery,
Vol31,
No 11 (November),
1996: pp 1563.1567
Disease at Time of Transplantation All patients had intrahepatic disease only at the time of transplantation. All received standard immunosuppression consisting of cyclosporine, azathioprine, and steroids, and alphafetoprotein levels (AFP) were monitored monthly.
Case 1 This girl (3.25 years of age) had hepatoblastoma; she presented with a palpable abdominal mass and abdominal pain. She had markedly high serum AFP levels (670,000 kU/L) at the time of presentation. Abdominal ultrasonography and a computed tomography (CT) scan showed multifocal tumor m both lobes of the liver. There was no extrahepatic tumor. Angiography showed compression of the portal vein and proximal inferior vena cava; both renal veins were distended. Despite some response to preoperative chemotherapy, the tumor remained unresectable and the patient underwent transplantation of a reduced-size liver (segments II and III).17.1J She had a laparotomy for hepatic bleeding 8 days posttransplantation, and subsequently she experienced hepatic artery thrombosis, hepatic abscess, biliary obstruction, and biliary sludge, which were treated conservatively. Hepatic artery signal was obtained by Doppler ultrasonography 40 days post-OLT. She remains well 37 months posttransplantatlon.
Case 2 This 6.9-year-old boy presented with weight loss, anorexia, a palpable abdominal mass, abdominal pain, lethargy, and pallor. His serum AFP levels were markedly high (500.000 kU/L). Abdominal ultrasonography and a CT scan showed a unifocal tumor at the right lobe of the liver with portal vein thrombosis, which was confirmed by angiography. There was no disease in kidneys and chest. A hver biopsy confirmed hepatoblastoma. Despite response to preoperative chemotherapy, the tumor remained unresectable and the patient had transplantation with a whole liver graft. The thrombosed portal vein was excised and reconstructed with an interpositional vein graft. He remains well 25 months after transplantation.
Case 3 This 2.9-year-old girl presented with abdominal mass, hepatomegaly, splenomegaly, lumbar lordosis, and remarkable increase in girth. AFP levels were negative. and radiological examination showed a large unifocal tumor that involved both lobes of the liver and the major biliary ducts. There was no disease in the kidneys or
From the Lrver and Hepatobdiary Untt, Queen Elizabeth Hospital, and the Liver Unrt and Department of Histopathology, Children i Hosprtal, Birmingham, England. DrAchdleos 1s funded by the Greek State Scolarshrp Foundation. Address reprint requests to Orthodoxos A. Achrlleos. MD, Liver & Hepatobihaty Umt (Lnw Laboratories), The Queen Ehzabeth Hospltal, Edgbaston, Birmingham B15 2TH, England. Copynght rii I996 by W. B. Saunders Company 0022.3168i9613111-0022$03 0010 1563
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chest. The result of a skeletal survey was negative. The diagnosis of infantile hemangioendothelioma type II was confirmed by needle and open liver biopsy. The patient was treated with high-dose steroids, with no improvement. The tumor increased rapidly, producing lumbar lordosis and vena cava obstruction with ankle edema, and she underwent transplantation with a whole liver graft. In the posttransplant period, a biliaty leak and Ebstein-Barr virus infection developed, which were treated conservatively. Twentynine months posttransplant, a metastatic vertebral hemangioendothelioma, type II (confirmed histologically and histocytochemitally), was removed by spinal laminectomy and treated with radiotherapy. She died of multiple metastases 12 months after the laminectomy (41 months after transplantation).
Case 4 This patient, a 4.9-year-old boy, presented with rickets, anaemia, and splenomegaly, and was found to have tyrosinemia type I. Seven months later his serum AFP levels began to increase (from 770 kU/L to 1,700 kU/L). Hepatic dysplasia was noted on a liver biopsy specimen, and radiological examination showed multifocal changes in both lobes of the liver. The patient underwent transplantation with a whole liver graft. The surface of the resected liver showed mixed cirrhosis, with nodules of up to 2 cm in diameter. Histological examination showed a well-differentiated HCC. There were no extrahepatic metastases. Postoperative complications included small bowel perforation, and retransplantation for chronic rejection I year after the first transplant. He died 5 months after placement of the second graft because of chronic rejection. There was no evidence of tumor recurrence.
Case 5 This 12-year-old boy had chronic active hepatitis (CAH) secondary to hepatitis B, and a tumor developed in his liver. At that time the AFP levels were slightly elevated. The CT scan showed a multifocal hepatic mass (11 cm in diameter) at the right lobe and numerous nodules in both lobes. He received preoperative chemotherapy and radiotherapy, without any response, and underwent transplantation with a whole liver graft. Hepatectomy of the old liver showed a HCC of 11 cm in diameter at the right lobe and numerous other nodules in both lobes. Histological examination showed a moderately differentiated HCC; the porta hepatis contained two hyperplastic lymph nodes and an extrahepatic nodule of tumor. Seven days posttransplantation, the patient underwent biliary reconstruction because of a biliary leak. Pulmonary metastases developed 5 months postoperatively and he died.
Histological Characteristics of the Hepatectomy Specimens In the patients with hepatoblastoma (cases 1 and 2B), the tumors were necrotic with some areas of viable epithelial and mesenchyma1 neoplastic cells. In the patient with hemangioendothelioma (case 3) the biopsy specimen showed a dense fibroconnective tissue with numerous tiny capillaries and some larger vascular channels, lined by plump endothelial cells, in both lobes of the liver. In this case, factor VIII-related antigen was detected immunocytochemically as being present within the tumor cells. In the patients with hepatoma (cases 4 and 5) both lobes of the liver were involved. There was diffuse dysplasia and disturbance of architecture with pericellular fibrosis. confirming HCC. RESULTS
The two children with hepatoblastoma (cases 1 and 2) are well 37 and 25 months posttransplantation,
with no evidence of tumor recurrence. Both attend normal school, their growth is excellent (height and weight are above the 25th and 50th percentiles, respectively), and their AFP levels are below 2 KU/L. The patient with infantile hemangioendothelioma (case 3) who died 41 months after transplantation because of tumor recurrence had a good quality of life, with normal growth and development, for more than 3 years. Both patients with hepatoma died. The patient with tyrosinemia type I and hepatoma (case 4) died 17 months after the first transplantation, and 5 months after the retransplantation, because of secondary graft failure owing to chronic rejection. The second patient with hepatoma (case 5) died of pulmonary metastases 5 months after the operation. DISCUSSION
Primary hepatic malignancy accounts for approximately 5% of all paediatric neoplasms.13 The primary tumors have been associated with a variety of congenital hepatic disorders, extrahepatic anomalies, and metabolic disorders. Hepatoblastoma is the third most common intraabdominal malignant tumor in childhood, after nephroblastoma and neuroblastoma. It usually occurs in children under 3 years of age. It arises from primitive epithelial cells of the fetal liver, usually in a noncirrhotic liver,15 it has a peak incidence in early infancy, and at least 50% of the cases are diagnosed during the first year of life.16 The tumors involve the right lobe of the liver in approximately 75%.13 More than 25 cases of hepatoblastoma reportedly have been associated with a family history of FAP.” In contrast, hepatoma is rare in children under 3 years of age. Typically, the diagnosis is made between 10 and 14 years of age, and the male:female ratio is 10:1.r8 There is a geographical variation, however, and the larger series of cases of childhood hepatoma from other areas of the world, particularly the Far East, are closely related to hepatitis B surface antigen and cirrhosis.1y-22 A significant number of children have an underlying disorder such as cirrhosis, tyrosinemia type I, or glycogen storage disease. The incidence of hepatoma in cases of tyrosinemia type I is at least 37%.23 Hemangioendothelioma is a soft tissue malignant tumor characterized by its epithelioid appearance and vascular endothelial histogenesis. The presence of immunohistochemical staining for factor VIIIrelated antigen in the tumor is considered a prerequisite for the confirmation of hemangioendothelioma.24 There are two basic histological patterns of hemangioendotheIioma.25 Type I is characterized by irregularly
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dilated and compressed vascular spaces lined by immature endothelial cells, separated by a supporting fibrous tissue and intermingled with small bile ductules. Type II lesions are made up of larger, more hyperchromatic and pleomorphic endothelial cells with no evidence of interspersed biliary ductules. The diagnosis of the original liver tumor in our case was made from a needle biopsy specimen; it can be difficult to differentiate it from angiosarcoma. However, the diagnosis was confirmed histologically and immunocytochemically by open biopsy and following hepatectomy. Angiosarcoma is extremely rare at this age. Type II hemangioendothelioma is more aggressive than type I (much more common) and can be multicentric and/or metastasize.‘h Infantile hemangioendothelioma is considered to be the most common vascular liver tumor in infancy.?‘The term of infantile is perhaps a misnomer, but it applies to the type of lesion rather than the patient’s age. But again, although the tumor in our case was diagnosed when the patient was 2 years 9 months of age, we do not know how long it had been present. The incidence of this tumor is greatest in the first 6 months of life.‘5,‘7 However, in a 1971 review, Dehner and Ishak reported the diagnosis of infantile hemangioendothelioma type II in two cases (age 18 months and 4 years).‘5 Selby et al reported on a group of 91 patients who had infantile hemangioendothelioma of the liver; most ranged from premature infants to 3 year olds, but there was one 18 year old.” Females seem to be affected more often.?‘,‘” Various forms of therapy for vascular tumors of the liver have been recommended, including steroids therapy and/or radiotherapy, hepatic resection, hepatic artery ligation, alpha interferon therapy, and liver transplantation.‘“~Z5.Zy-J~ Steroids have been used successfully in cases of extensive nonresectable tumors since 1969 and 1970,“AJs and they were the first choice in 1989 (when our patient presented) because other treatments (ie, embolization, surgical excision, and radiotherapy) provided more uncertain results at that time.“’ Interferon alpha-2a recently appeared to have a beneficial effect on a variety of progressive and life-threatening angiomatous diseases of infancy and childhood.J”,3h,“7 However, interferon-a is not a potent angiogenesis inhibitor and requires prolonged therapy.“‘JhJ8 Hepatic artery ligation, which is another treatment option, was first reported by de Lorimier et al in 1967.“” Various opinions have been reported since then regarding its relative beneficial effects, and some surgeons continue to avoid it.JU Recently, Davenport et al recommended hepatic artery ligation for a bilobar multifocal hemangioendothelioma of the liver.“’ However, dearterialization of
the liver is well tolerated in humans if liver perfusion and oxygenation are maintained via the portal vein and if sepsis is avoided. Hepatoblastomas and hepatomas account for up to 98% of primary malignant liver tumors in children.13,41 Most tumors are best managed by preoperative chemotherapy and delayed resection, but there are rare instances of small localized tumors in infants that can be managed appropriately by primary resection.i3,41,JZ Chemotherapy makes the tumor more compact, less vascular, and more resistant to surgical manipulation. 33Improvements in anesthesia and postoperative care have greatly diminished the complications of surgery, and up to 85%13 of the liver can be resected safely. Full regeneration of the liver is normally completed between 3 and 6 months after surgery.‘” Previously reported resection rates for malignant tumors in pediatric patients are 60% for hepatoblastoma and 33% for hepatoma.J3-45 Approximately 50% of the patients have unresectable disease at the time of presentation, but during the last 12 years several studies have shown a significant reduction in tumor size with the use of chemotherapy. OLT has been indicated for children with unresectable tumors with extension in both lobes, vascular invasion, involvement of the hilum and the major ducts, unsuccessful resection, and tumor recurrence in the liver.lJn~Js All five reported cases were unresectable because of extension of the tumor, vascular invasion, and compression. In cases 1 and 2, liver replacement was necessary because of tumor extension and the involvement of the portal vein and/or inferior vena cava. Bench surgery has been confined to situations and tumor stages otherwise deemed untreatable, or to situations where resection would not have been sufficiently radical. 4hHowever, it could not be considered in these two cases because the tumor was found (by ultrasonography) to cause obstruction of the portal vein at the porta hepatis and (during the recipient’s hepatectomy) to infiltrate both the extrahepatic and intrahepatic portal veins. Liver transplantation was successful in these patients who had hepatoblastoma; they are alive, without evidence of recurrence, 37 and 25 months posttransplantation. This compares favorably with other published results, ie, a 50% l-year survival rate for 12 children with liver tumors,‘.4a and survival of the three patients (cases 3, 4, and 5) who had infantile hemangioendothelioma or hepatoma. In 1989, Pierro et al reported 11 cases of hepatoblastoma unresectable because of involvement of both lobes or because of the size of the tumor.J4 Eight of the 11 cases responded to chemotherapy,
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with a reduction in size of greater than 50%. Complete resection was successful in seven cases, and the patients were alive (disease-free) at 4 to 42 months. In 1992, Reynolds et al reported on 37 children with unresectable hepatoblastoma who received preoperative chemotherapy. 45 Twenty-nine responded to the chemotherapy (in two cases the tumor disappeared; in another, chemotherapy was used in combination with radiation), and 26 had significant tumour reduction and complete surgical resection of the tumor, with complete remission in 20 cases. The other six patients had disease progression and died (one after transplantation). Eight of the 37 patients had an inadequate response to chemotherapy (two had liver transplantation with complete remission of the tumor, and six died of disease progression). In 1988, Ringer et al included two children with hepatoblastoma in their larger series of patients who underwent transplantation for hepatobiliary malignancy.lO One child was alive 6 years after transplantation, and the other died of sepsis. However, in 1991, Koneru et al reported on 12 children who had received 13 liver grafts for unresectable hepatoblastoma, and six of the patients were living in 1992.l~~~ In this group of patients, nine received chemotherapy before and five after the transplantation. In case 3, liver replacement was necessary because of rapid progression of the tumor and obstruction of the vena cava. Our case treated in 1989 was not considered suitable for hepatic artery ligation because the tumor involved the porta hepatis, reducing the blood flow to the liver through the portal vein. Marino et al reported on 10 adults who underwent liver transplantation because of unresectable epithelioid hemangioendothelioma, eight of them were alive when the report was writtenz4 and one patient had survived 11 years. An adult patient who had transplantation for the same tumor (operated on by our group) had recurrent disease 7 years posttransplantation.
ET AL
Long-term survival without any specific therapy has been reported by Ishak et al.48Because of the rarity of these tumors and the unpredictability of metastasis and recurrence, it is difficult to recommend a particular therapeutic approach. In cases 4 and 5, OLT was necessary because of multifocal tumor tissue in both lobes of the liver. In 1993, Yandza et al reported on two children (both 8.5 years of age) who had early primary hepatocellular carcinoma secondary to maternal transmission of hepatitis B. Both children were alive (24 and 27 months post-OLT) at the time of the report.22 In 1993, Van Thiel et al reported an 11-year Pittsburgh experience with 181 liver transplantations for tumors; 102 were done for hepatocellular carcinoma, 12 for epitheliohemangioendothelioma, and six for hepatoblastoma.49 The results of this study, which included adults and children, show that the combination of chemotherapy and surgery was better than either treatment alone, and that the early results with chemotherapy pre- and post-OLT were better than those of treatment with chemotherapy only pre-OLT. The longest survivor of any liver transplantation in the world (as of 1991) was a child who had the procedure in January 1970, because of an incidental hepatoma.50 This series, which includes long-term results of transplantation for primary and metastatic hepatic tumors in adults and children in transplantation centers, has shown that cases of hepatoblastoma, epithelioid hemangioendothelioma, incidental hepatoma, and fibrolamellar carcinoma are the best suited for liver transplantation,50,51 which concurs with our data. We recommend that liver transplantation be considered for nonmetastatic unresectable tumors, particularly hepatoblastoma. ACKNOWLEDGMENT The authors acknowledge Susan Paris and Bridget K. Gunson for their assistance with data collection.
REFERENCES tion in hepatocellular carcinoma. Transplant Int 5:S196-S197,1992 1. Koneru B, Flye MW, Busuttil RW, et al: Liver transplantation for hepatoblastoma. Ann Surg 213:118-121, 1991 (suppl I) 2. Ismail T, Angrisani L, Gunson BK, et al: Primary hepatic 8. Pichlmayer R: Liver transplantation in primary hepatocellumalignancy: The role of liver transplantation. Br J Surg 77:983-987, lar carcinoma. J Hepatol18:151-153, 1993 1990 9. McPeake JR, OLGrady JG, Zaman S, et al: Liver transplanta3. Iwatsuki S, Starzl TE: Personal experience with 411 hepatic tion for primary hepatocellular carcinoma: tumour size and numresection. Ann Surg 208:421-432, 1988 ber determine outcome. J Hepatol18:226-234, 1993 4. Haug CE, Jenkins RL, Rohrer RJ, et al: Liver transplantation 10. Ringe B, Wittekind C, Bechstein WO, et al: The role of liver for primary hepatic cancer. Transplantation 53:376-382,199Z transplantation in hepatobiliary malignancy. Ann Surg 209:88-98, 5. Iwatsuki S, Gordon RD, Shaw BW, et al: Role of liver 1989 transplantation in cancer therapy. Ann Surg 202:401-407,1985 6. Pichlmayer R: Is there a place for liver grafting for malig11. Koneru B, Gassavilla A, Bowman J, et al: Liver transplantanancy? Transplant Proc 20:478-482,1988 (suppl 1) tion for malignant tumours. Gastroenterol Clin North Am 17:1777. Jaurrieta E, Fabregat J, Figueras J, et al: Liver transplanta193,1988
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12. O&Grady JG, Poison RJ, Rolles K, et al: Liver transplantation for malignant disease. Arm Surg 207:373-379, 1988 13. Howard ER, Heaton ND: Benign and malignant tumours, in Howard ER (ed): Surgery of Liver Disease in Children, chap 13. Oxford, Great Britain, Butterworth, 1991, pp 126-142 14. Strong R, Ong TH, Pillay P, et al: A new method of segmental orthotopic liver transplantation. Surgery 104:104-107, 1988 15. Okuda K: Primary liver cancer in Japan. Cancer 45:26632669,198O 16. Fraumeni JF, Miller RW, Hill JA: Primary carcinoma of the liver in childhood: An epidemiologic study. J Nat1 Cancer Inst 4o:iO87-1099,1968 17. Garber JE, Li FP, Kingston JE, et al: Hepatoblastorna and familial adenomatous polyposis. J Nat1 Cancer Inst 80:1626-1628, 1988 18. Dehner LP: Hepatic tumours in the pediatric age group: A dinstinctive clinicopathologic spectrum. Perspect Pediatr Path01 4:217-268,1978 19. Shimoda T, Uchida T, Miyata H, et al: A 6-year-old boy having hepatocellular carcinoma associated with hepatitis B surface antigenemia. Am J Clin Path01 74:827-831,198O 20. Chen WJ, Lee JC, Hung WT: Primary malignant tumour of liver in infants and children in Taiwan. J Pediatr Surg 23:457-461, 1988 21. Wu TC, Tong MJ, Hwang B, et al: Primary hepatocellular carcinoma and hepatitis B infection during childhood. Hepatology 7:46-48,1987 22. Yandza T, Alvarez F, Laurent J, et al: Pediatric liver transplantation for primary hepatocellular carcinoma associated with hepatitis virus infection. Transpl Int 6:95-98,1993 23. Weinberg AG, Mize CE, Worthen HG: The occurrence of hepatoma in the chronic form of hereditary tyrosinaemia. J Pediatr Surg 88:434-438,1976 24. Marino IR, Todo S, Tzakis AG, et al: Treatment of hepatic haemangioendothelioma with liver transplantation. Cancer 62:20792084,1988 25. Dehner LP, Ishak KG: Vascular tumors of the liver in infants and children. Arch Path01 92:101-111, 1971 26. Dehner LP: Liver, gallbladder and extrahepatic biliary tract, in Dehner LP (ed): Paediatric Surgical Pathology, (ed 2), chap 7. Baltimore, MD, Williams & Wilkins, 1987, pp 483-488 27. Selby DM, Stocker JT, Waclawiw MA, et al: Infantile haemangioendothelioma of the liver. Hepatology 20:39-451994 28. Dachman AH, Lichtestein JE, Friedman AC, et al: Infantile haemangioendothelioma of the liver: A radiologic-pathologicclinical correlation. AIR 140:1091-1096, 1983 29. Matolo NM, Johnson DG, City SL: Surgical treatment of hepatic haemangioma in the newborn. Arch Surg 106:725-727, 1973 30. Cohen RC, Myers NA: Diagnosis and management of hepatic hemangiomas in childhood. J Pediatr Surg 21:6-9,1986 31. Enjolras 0, Riche MC, Merland JJ, et al: Management of alarming hemangiomas in infancy: A review of 25 cases. Pediatrics 85:491-498,199O 32. Davenport M, Hansen L, Heaton ND, et al: Hemangioendothelioma of the liver in infants. J Petiatr Surg 30:44-48,1995 33. Ezekowitz RAB, Phil D, Mulliken JB, et al: Interferon
1567 alfa-2a therapy for life threatening hemangiomas of infancy. N Engl J Med 326:1456-1463,1992 34. Brown SH, Fonkalsrud E: Successful treatment of hepatic haemangioendothelioma with corticosteroids. JAMA 208:24732474,1969 35. Touloukian RJ: Hepatic hemangioendothelioma during infancy: Pathology, diagnosis, and treatment with prednisone. Pediatrics 45:71-76,197O 36. White CW, Wolf SJ, Korones DN, et al: Treatment of childhood diseases with recombinant interferon alpha-2a. J Pediatr 118:59-66, 1991 37. White CW, Sondheimer HM, Crouch EC, et al: Treatment of pulmonary hemangiomatosis with recombinant interferon alpha2a. N Engl J Med 320:1197-1200,1989 38. O’Reilly MS, Brem H, Folkman J: Treatment of murins hemangioendotheliomas with the angiogenesis inhibitor AGM1470. J Pediatr Surg 30:325-330,1995 39. de Lorimier AA, Simpson EB, Baum RS, et al: Hepatic artery ligation for hepatic hemangiomatosis. N Engl J Med 277:333-337,1967 40. Nguyen L, Shandling B, Ein S, et al: Hepatic hemangioma in childhood: Medical management or surgical management? J Pediatr Surg 17:576-579, 1982 41. Gauthier F, Valayer J, Thai BL, et al: Hepatoblastoma and hepatocarcinoma in children: Analysis of a series of 29 cases. J Pediatr Surg 21:424-429,1986 42. Pazdur R, Bready B, Cangir A, et al: Pediatric hepatic tumours: Clinical trials conducted in the United States. J Surg Oncol3:127-130,1993 43. Gulglielmi M, Perilongo G, Cecchetto G, et al: Rationale and results of the International Society of Pediatric Oncology (SIOP) Italian pilot study on childhood hepatoma: Surgical resection d’ emblee or after primary chemotherapy? J Surg Oncol 3:122-126.1993 44. Pierro A, Langevin AM, Filler RM, et al: Preoperative chemotherapy in “unresectahle” hepatoblastoma. J Pediatr Surg 24:24-29,1989 45. Reynolds M, Douglass EC, Finegold M, et al: Chemotherapy can convert unresectable hepatoblastoma. J Pediatr Surg 27:10801084,1992 46. Pichlmayr R, Grosse H, Hauss J, et al: Technique and preliminary results of extracorporeal liver surgery (bench procedure) and of surgery on the situ perfused liver. Br J Surg 77:21-26, 1990 47. Clements D, Hubscher S, West R, et al: Epithelioid haemangioendothelioma. A case report. J Hepatol2:441-449,1986 48. Ishak KG, Sesterrhenn IA, Goodman MZD, et al: Epithelioid hemangioendothelioma of the liver: A clinicopathology and follow-up study of 32 cases. Hum Path01 15:839-852,1984 49. Van Thiel DH, Carr B, Iwatsuki S, et al: The 11-year Pittsburg experience with liver transplantation for hepatocellular carcinoma: 1981-1991. J Surg Oncol3:78-82,1993 50. Penn I: Hepatic transplantation for primary and metastatic cancers of the liver. Surgery 110:726-735,199l 51. Pichlmayr R, Weimann A, Ringe B: Indications for liver transplantation in hepatobiliary malignancy. Hepatology 20:33S40s. 1994 (suppl2)