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Liver transplant for relapsed undifferentiated embryonal sarcoma in a young child
Journal of Pediatric Surgery (2009) 44, E1–E3
www.elsevier.com/locate/jpedsurg
Liver transplant for relapsed undifferentiated embryonal sarcoma in a young child Michael J. Kelly a , Laura Martin b , Maria Alonso c , Rachel A. Altura a,⁎ a
Division of Pediatric Hematology-Oncology, Department of Pediatrics, Hasbro Children's Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA b Division of Pediatric Hematology-Oncology, Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH 43205, USA c Departments of Surgery and Pediatrics, Cincinnati Children's Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA Received 10 July 2009; revised 8 September 2009; accepted 10 September 2009
Key words: Liver; Sarcoma; Transplant; Child
Abstract Undifferentiated embryonal sarcoma of the liver is a rare hepatic malignancy of childhood with a historically poor prognosis. Recent improvements in outcomes have been reported in small numbers of cases with the use of combination therapy involving aggressive surgical resection and chemotherapy. Complete surgical resection is frequently difficult to achieve when the location of the tumor is along the margins of the major hepatic vessels (portal vein, hepatic vein, and hepatic artery). Here we report a case of undifferentiated embryonal sarcoma of the liver that recurred along surgical hepatic vein margins in a 9-year-old boy who subsequently underwent orthotopic liver transplantation from a cadaveric donor. The patient has been in continuous clinical remission for the last 5 years. © 2009 Elsevier Inc. All rights reserved.
Undifferentiated embryonal sarcoma of the liver (UESL) is a rare hepatic malignancy in childhood [1]. Early case series in the 1970s and 1980s reported the dismal prognosis of this disease with most patients dying of local recurrence or metastatic disease [2,3]. Steady improvements in outcome have been made by treating UESL with aggressive surgical resection and with chemotherapy known to have activity against sarcomas [4]. We report a case of recurrent UESL that was treated with secondary chemotherapy and total surgical resection with liver transplantation who has been in continuous remission for 5 years.
⁎ Corresponding author. Tel.: +1 401 444 5171; fax: +1 401 444 8845. E-mail address: [email protected] (R.A. Altura). 0022-3468/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2009.09.008
1. Case report A 7-year-old boy presented to the emergency department with acute severe abdominal pain. The pain was preceded by approximately 1 year of right shoulder pain. An enlarged, irregular liver was palpated on physical examination, and a computed tomography (CT) scan revealed a large septated cystic hepatic mass. The patient underwent exploratory laparotomy and biopsy. During exploration, it was discovered that the mass had ruptured preoperatively. On pathologic evaluation, the tumor was moderately cellular with a prominent myxoid background pattern. Frequent mitoses and areas of necrosis were observed. Immunoperoxidase staining was positive for wide spectrum keratin, α-1antitrypsin, vimentin, and poly-specific desmin. Epithelial
E2 membrane antigen (EMA), pan-keratin, actin, S-100, factor VIII antigen, CD31, CD34, α-fetoprotein, monoclonal desmin, myogenin, myoD1, and smooth muscle actin were negative. The mass was diagnosed as UESL. The clinical staging workup consisted of bilateral bone marrow biopsies, a chest CT, and a bone scan, all of which were negative for evidence of metastatic disease. The patient underwent 15 weeks of chemotherapy with vincristine, actinomycin, ifosfamide, and adriamycin (doxorubicin) (VAIA) based on the success achieved using this regimen for UESL by the Italian and German Soft Tissue Sarcoma Cooperative Study Group [4]. A right hepatic trisegmentectomy was performed in attempt to completely resect the tumor. Intraoperatively, the mass measured approximately 8 cm, was encapsulated, and was densely adherent to the right diaphragm. Although he required a diaphragmatic resection, the margins of the diaphragm at the resection site were observed to be free of tumor. The patient then completed an additional 10 weeks of VAIA chemotherapy without complications. After completing therapy, the patient did well. Abdominal CT scans were performed every 3 months to monitor for disease recurrence. Fifteen months after the completion of chemotherapy, the patient developed recurrent right shoulder pain. An abdominal CT scan at that time showed a 4.3-cm lesion abutting the hepatic and portal veins that appeared unresectable by imaging (Fig. 1). A staging workup was again negative for metastatic disease. Chemotherapy was restarted with a combination of etoposide and carboplatinum for 2 cycles. Unfortunately, there was no evidence of response to this chemotherapy regimen by imaging, and subsequently, the patient was restarted on VAIA chemotherapy. He received VAIA for another 15 weeks and was
Fig. 1 Pretransplant abdominal CT scan demonstrating the 4.3-cm mass adjacent to the hepatic and portal veins.
M.J. Kelly et al. then listed for liver transplant with the United Network for Organ Sharing. At the initial listing, a pediatric end-stage liver disease score of 29 was requested, which resulted in an indeterminate vote at the Regional Review Board level. After further review, this was amended to a pediatric end-stage liver disease of 24, and we received approval for transplant. A living related donor transplant was not considered because of the proximity of the recurrence to the inferior vena cava. A split-liver transplant would only have been considered if it were possible to resect and reconstruct the retrohepatic inferior vena cava. Ten weeks later, he successfully underwent orthotopic liver transplant without complications. At the time of transplant, there was an identified backup recipient for the donor organ. The posttransplant immunosuppressive regimen consisted of prednisone, tacrolimus, and mycophenolate mofetil (Cellcept, Roche Pharmaceuticals, Nutley, NJ). The prednisone was weaned off, and he remains on the other medications. He is in good health and disease free 5 years later.
2. Discussion Undifferentiated embryonal sarcoma of the liver is an extremely rare malignancy of childhood. Malignant liver tumors account for approximately 1% of pediatric tumors in the United States [1]. Hepatoblastoma and hepatocelluar carcinoma are by far the most common malignant liver tumors, accounting for approximately 43% and 23%, respectively, of hepatic malignancies in childhood [1]. Undifferentiated embryonal sarcoma of the liver is the third most common malignant liver tumor comprising approximately 6% of hepatic malignancies in childhood [1]. It primarily occurs between the ages of 5 and 10 and does not have a sex predilection [2]. The tumors are usually single, large, and cystic. A pseudocapsule often surrounds the sarcoma and separates it from normal hepatic tissue. Histology shows undifferentiated sarcomatous cells with large areas of necrosis and hemorrhage. The tumor often displays a large number of mitoses along with atypical mitoses [2]. A comprehensive report of 31 cases of UESL described this malignancy as very aggressive. Most of the patients died within a year of diagnosis despite treatment with surgery, chemotherapy, and/or radiation therapy [2]. A case series from St Jude Children's Research Hospital, Memphis, Tennessee of patients with UESL and hepatic rhabdomyosarcoma also detailed the highly aggressive nature of this disease with most patients developing local recurrence and/ or distant metastasis [3]. However, more recent reports demonstrate improved outcomes for UESL [4-6]. A published case series of 4 long-term survivors of UESL suggested that surgery and chemotherapy demonstrated as effective for soft tissue sarcomas can lead to long-term survival [5]. One of these patients received radiation. Chemotherapy included the use of vincristine, actinomycin,
Liver transplant for undifferentiated embryonal sarcoma
E3
doxorubicin, ifosfamide, and cisplatinum in varying combinations. This report was followed almost 10 years later by 2 case series demonstrating long-term survival of UESL using surgery and chemotherapy [4,6]. Kim et al [6] reported 6 cases of UESL of which 5 were long-term survivors 3 to 10 years after diagnosis. These patients were treated with preoperative and postoperative chemotherapy according to regimens 35 and 38 of the Third Intergroup Rhabdomyosarcoma Study Group. During the same year, the Soft Tissue Sarcoma Italian and German Cooperative Study Groups reported the outcome of 17 patients treated for UESL between 1979 and 1995 [4]. Twelve patients were alive with follow-up ranging from 2.4 to 20 years. Generally, these patients were treated with conservative surgery, followed by 3 to 4 courses of chemotherapy, followed by second-look surgery and subsequent adjuvant chemotherapy. Several different chemotherapy protocols were used, which incorporated vincristine, actinomycin, doxorubicin, epirubicin, cyclophosphamide, ifosfamide, carboplatinum, cisplatinum, and etoposide. The authors concluded that the prognosis of UESL should no longer be considered to be poor [4]. Unfortunately, our patient's treatment options were limited when his disease recurred. He had already received chemotherapy known to be effective against UESL, had failed alternative chemotherapy, and had undergone an initial aggressive surgical resection of his tumor. As the effectiveness of radiation had not been clearly demonstrated, it was not considered an option for cure in this case. Given the overall good state of health of this child, with no evidence of metastatic disease and no evidence of organ impairment from prior treatment, we decided to pursue liver transplant. We know of only 2 other published reports of liver transplantation for children with UESL [7-9]. The first describes a 6-year-old boy who received 2 courses of preoperative chemotherapy before transplant. His postoperative course was complicated by chronic rejection, and he was retransplanted 4 months after his initial transplant. He was alive 6.5 years after his transplant [8]. The second report was a 15-year-old adolescent boy who received a living related donor transplant after he did not tolerate preoperative chemotherapy. He received chemotherapy postoperatively and developed a local recurrence 2 years later. The recurrence was resected, and he had remained disease free 18 months after the second surgery [9]. Currently, our patient remains in continuous clinical remission 5 years after liver transplant and has an excellent quality of life.
With this report, we aim to increase awareness of liver transplantation as a potential treatment option for localized, recurrent UESL. A case series of liver transplants for nonresectable hepatic tumors that did not include patients with UESL reports that liver transplantation should be considered an option in the treatment of all children with unresectable hepatic tumors [10]; it seems reasonable to include patients with UESL in this category and therefore to widen the scope of liver tumors that would benefit from liver transplant. The prognosis of UESL is no longer as dismal as published in early reports from the 1970s and 1980s. Aggressive attempts to cure this disease should include surgical resection, multiagent chemotherapy, and if indicated, liver transplantation. We encourage physicians to consider liver transplantation as a treatment of unresectable or recurrent UESL and to report successful outcomes of transplantation so that the prognosis of UESL in children may continue to improve.
References [1] Mueller B, Lopez-Terrada D, Finegold M. Tumors of the liver. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. Philadelphia, PA: Lipincott Williams &Wilkins; 2006. p. 887-904. [2] Stocker JT, Ishak KG. Undifferentiated (embryonal) sarcoma of the liver: report of 31 cases. Cancer 1978;42:336-48. [3] Horowitz ME, Etcubanas E, Webber BL, et al. Hepatic undifferentiated (embryonal) sarcoma and rhabdomyosarcoma in children. Results of therapy. Cancer 1987;59:396-402. [4] Bisogno G, Pilz T, Perilongo G, et al. Undifferentiated sarcoma of the liver in childhood: a curable disease. Cancer 2002;94:252-7. [5] Urban CE, Mache CJ, Schwinger W, et al. Undifferentiated (embryonal) sarcoma of the liver in childhood. Successful combined-modality therapy in four patients. Cancer 1993;72:2511-6. [6] Kim DY, Kim KH, Jung SE, et al. Undifferentiated (embryonal) sarcoma of the liver: combination treatment by surgery and chemotherapy. J Pediatr Surg 2002;37:1419-23. [7] Dower NA, Smith LJ, Lees G, et al. Experience with aggressive therapy in three children with unresectable malignant liver tumors. Med Pediatr Oncol 2000;34:132-5. [8] Dower NA, Smith LJ. Liver transplantation for malignant liver tumors in children. Med Pediatr Oncol 2000;34:136-40. [9] Okajima H, Ohya Y, Lee KJ, et al. Management of undifferentiated sarcoma of the liver including living donor liver transplantation as a backup procedure. J Pediatr Surg 2009;44:e33-8. [10] Kalicinski P, Ismail H, Broniszczak D, et al. Non-resectable hepatic tumors in children—role of liver transplantation. Ann Transplant 2008;13:37-41.
www.elsevier.com/locate/jpedsurg
Liver transplant for relapsed undifferentiated embryonal sarcoma in a young child Michael J. Kelly a , Laura Martin b , Maria Alonso c , Rachel A. Altura a,⁎ a
Division of Pediatric Hematology-Oncology, Department of Pediatrics, Hasbro Children's Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA b Division of Pediatric Hematology-Oncology, Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH 43205, USA c Departments of Surgery and Pediatrics, Cincinnati Children's Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA Received 10 July 2009; revised 8 September 2009; accepted 10 September 2009
Key words: Liver; Sarcoma; Transplant; Child
Abstract Undifferentiated embryonal sarcoma of the liver is a rare hepatic malignancy of childhood with a historically poor prognosis. Recent improvements in outcomes have been reported in small numbers of cases with the use of combination therapy involving aggressive surgical resection and chemotherapy. Complete surgical resection is frequently difficult to achieve when the location of the tumor is along the margins of the major hepatic vessels (portal vein, hepatic vein, and hepatic artery). Here we report a case of undifferentiated embryonal sarcoma of the liver that recurred along surgical hepatic vein margins in a 9-year-old boy who subsequently underwent orthotopic liver transplantation from a cadaveric donor. The patient has been in continuous clinical remission for the last 5 years. © 2009 Elsevier Inc. All rights reserved.
Undifferentiated embryonal sarcoma of the liver (UESL) is a rare hepatic malignancy in childhood [1]. Early case series in the 1970s and 1980s reported the dismal prognosis of this disease with most patients dying of local recurrence or metastatic disease [2,3]. Steady improvements in outcome have been made by treating UESL with aggressive surgical resection and with chemotherapy known to have activity against sarcomas [4]. We report a case of recurrent UESL that was treated with secondary chemotherapy and total surgical resection with liver transplantation who has been in continuous remission for 5 years.
⁎ Corresponding author. Tel.: +1 401 444 5171; fax: +1 401 444 8845. E-mail address: [email protected] (R.A. Altura). 0022-3468/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2009.09.008
1. Case report A 7-year-old boy presented to the emergency department with acute severe abdominal pain. The pain was preceded by approximately 1 year of right shoulder pain. An enlarged, irregular liver was palpated on physical examination, and a computed tomography (CT) scan revealed a large septated cystic hepatic mass. The patient underwent exploratory laparotomy and biopsy. During exploration, it was discovered that the mass had ruptured preoperatively. On pathologic evaluation, the tumor was moderately cellular with a prominent myxoid background pattern. Frequent mitoses and areas of necrosis were observed. Immunoperoxidase staining was positive for wide spectrum keratin, α-1antitrypsin, vimentin, and poly-specific desmin. Epithelial
E2 membrane antigen (EMA), pan-keratin, actin, S-100, factor VIII antigen, CD31, CD34, α-fetoprotein, monoclonal desmin, myogenin, myoD1, and smooth muscle actin were negative. The mass was diagnosed as UESL. The clinical staging workup consisted of bilateral bone marrow biopsies, a chest CT, and a bone scan, all of which were negative for evidence of metastatic disease. The patient underwent 15 weeks of chemotherapy with vincristine, actinomycin, ifosfamide, and adriamycin (doxorubicin) (VAIA) based on the success achieved using this regimen for UESL by the Italian and German Soft Tissue Sarcoma Cooperative Study Group [4]. A right hepatic trisegmentectomy was performed in attempt to completely resect the tumor. Intraoperatively, the mass measured approximately 8 cm, was encapsulated, and was densely adherent to the right diaphragm. Although he required a diaphragmatic resection, the margins of the diaphragm at the resection site were observed to be free of tumor. The patient then completed an additional 10 weeks of VAIA chemotherapy without complications. After completing therapy, the patient did well. Abdominal CT scans were performed every 3 months to monitor for disease recurrence. Fifteen months after the completion of chemotherapy, the patient developed recurrent right shoulder pain. An abdominal CT scan at that time showed a 4.3-cm lesion abutting the hepatic and portal veins that appeared unresectable by imaging (Fig. 1). A staging workup was again negative for metastatic disease. Chemotherapy was restarted with a combination of etoposide and carboplatinum for 2 cycles. Unfortunately, there was no evidence of response to this chemotherapy regimen by imaging, and subsequently, the patient was restarted on VAIA chemotherapy. He received VAIA for another 15 weeks and was
Fig. 1 Pretransplant abdominal CT scan demonstrating the 4.3-cm mass adjacent to the hepatic and portal veins.
M.J. Kelly et al. then listed for liver transplant with the United Network for Organ Sharing. At the initial listing, a pediatric end-stage liver disease score of 29 was requested, which resulted in an indeterminate vote at the Regional Review Board level. After further review, this was amended to a pediatric end-stage liver disease of 24, and we received approval for transplant. A living related donor transplant was not considered because of the proximity of the recurrence to the inferior vena cava. A split-liver transplant would only have been considered if it were possible to resect and reconstruct the retrohepatic inferior vena cava. Ten weeks later, he successfully underwent orthotopic liver transplant without complications. At the time of transplant, there was an identified backup recipient for the donor organ. The posttransplant immunosuppressive regimen consisted of prednisone, tacrolimus, and mycophenolate mofetil (Cellcept, Roche Pharmaceuticals, Nutley, NJ). The prednisone was weaned off, and he remains on the other medications. He is in good health and disease free 5 years later.
2. Discussion Undifferentiated embryonal sarcoma of the liver is an extremely rare malignancy of childhood. Malignant liver tumors account for approximately 1% of pediatric tumors in the United States [1]. Hepatoblastoma and hepatocelluar carcinoma are by far the most common malignant liver tumors, accounting for approximately 43% and 23%, respectively, of hepatic malignancies in childhood [1]. Undifferentiated embryonal sarcoma of the liver is the third most common malignant liver tumor comprising approximately 6% of hepatic malignancies in childhood [1]. It primarily occurs between the ages of 5 and 10 and does not have a sex predilection [2]. The tumors are usually single, large, and cystic. A pseudocapsule often surrounds the sarcoma and separates it from normal hepatic tissue. Histology shows undifferentiated sarcomatous cells with large areas of necrosis and hemorrhage. The tumor often displays a large number of mitoses along with atypical mitoses [2]. A comprehensive report of 31 cases of UESL described this malignancy as very aggressive. Most of the patients died within a year of diagnosis despite treatment with surgery, chemotherapy, and/or radiation therapy [2]. A case series from St Jude Children's Research Hospital, Memphis, Tennessee of patients with UESL and hepatic rhabdomyosarcoma also detailed the highly aggressive nature of this disease with most patients developing local recurrence and/ or distant metastasis [3]. However, more recent reports demonstrate improved outcomes for UESL [4-6]. A published case series of 4 long-term survivors of UESL suggested that surgery and chemotherapy demonstrated as effective for soft tissue sarcomas can lead to long-term survival [5]. One of these patients received radiation. Chemotherapy included the use of vincristine, actinomycin,
Liver transplant for undifferentiated embryonal sarcoma
E3
doxorubicin, ifosfamide, and cisplatinum in varying combinations. This report was followed almost 10 years later by 2 case series demonstrating long-term survival of UESL using surgery and chemotherapy [4,6]. Kim et al [6] reported 6 cases of UESL of which 5 were long-term survivors 3 to 10 years after diagnosis. These patients were treated with preoperative and postoperative chemotherapy according to regimens 35 and 38 of the Third Intergroup Rhabdomyosarcoma Study Group. During the same year, the Soft Tissue Sarcoma Italian and German Cooperative Study Groups reported the outcome of 17 patients treated for UESL between 1979 and 1995 [4]. Twelve patients were alive with follow-up ranging from 2.4 to 20 years. Generally, these patients were treated with conservative surgery, followed by 3 to 4 courses of chemotherapy, followed by second-look surgery and subsequent adjuvant chemotherapy. Several different chemotherapy protocols were used, which incorporated vincristine, actinomycin, doxorubicin, epirubicin, cyclophosphamide, ifosfamide, carboplatinum, cisplatinum, and etoposide. The authors concluded that the prognosis of UESL should no longer be considered to be poor [4]. Unfortunately, our patient's treatment options were limited when his disease recurred. He had already received chemotherapy known to be effective against UESL, had failed alternative chemotherapy, and had undergone an initial aggressive surgical resection of his tumor. As the effectiveness of radiation had not been clearly demonstrated, it was not considered an option for cure in this case. Given the overall good state of health of this child, with no evidence of metastatic disease and no evidence of organ impairment from prior treatment, we decided to pursue liver transplant. We know of only 2 other published reports of liver transplantation for children with UESL [7-9]. The first describes a 6-year-old boy who received 2 courses of preoperative chemotherapy before transplant. His postoperative course was complicated by chronic rejection, and he was retransplanted 4 months after his initial transplant. He was alive 6.5 years after his transplant [8]. The second report was a 15-year-old adolescent boy who received a living related donor transplant after he did not tolerate preoperative chemotherapy. He received chemotherapy postoperatively and developed a local recurrence 2 years later. The recurrence was resected, and he had remained disease free 18 months after the second surgery [9]. Currently, our patient remains in continuous clinical remission 5 years after liver transplant and has an excellent quality of life.
With this report, we aim to increase awareness of liver transplantation as a potential treatment option for localized, recurrent UESL. A case series of liver transplants for nonresectable hepatic tumors that did not include patients with UESL reports that liver transplantation should be considered an option in the treatment of all children with unresectable hepatic tumors [10]; it seems reasonable to include patients with UESL in this category and therefore to widen the scope of liver tumors that would benefit from liver transplant. The prognosis of UESL is no longer as dismal as published in early reports from the 1970s and 1980s. Aggressive attempts to cure this disease should include surgical resection, multiagent chemotherapy, and if indicated, liver transplantation. We encourage physicians to consider liver transplantation as a treatment of unresectable or recurrent UESL and to report successful outcomes of transplantation so that the prognosis of UESL in children may continue to improve.
References [1] Mueller B, Lopez-Terrada D, Finegold M. Tumors of the liver. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. Philadelphia, PA: Lipincott Williams &Wilkins; 2006. p. 887-904. [2] Stocker JT, Ishak KG. Undifferentiated (embryonal) sarcoma of the liver: report of 31 cases. Cancer 1978;42:336-48. [3] Horowitz ME, Etcubanas E, Webber BL, et al. Hepatic undifferentiated (embryonal) sarcoma and rhabdomyosarcoma in children. Results of therapy. Cancer 1987;59:396-402. [4] Bisogno G, Pilz T, Perilongo G, et al. Undifferentiated sarcoma of the liver in childhood: a curable disease. Cancer 2002;94:252-7. [5] Urban CE, Mache CJ, Schwinger W, et al. Undifferentiated (embryonal) sarcoma of the liver in childhood. Successful combined-modality therapy in four patients. Cancer 1993;72:2511-6. [6] Kim DY, Kim KH, Jung SE, et al. Undifferentiated (embryonal) sarcoma of the liver: combination treatment by surgery and chemotherapy. J Pediatr Surg 2002;37:1419-23. [7] Dower NA, Smith LJ, Lees G, et al. Experience with aggressive therapy in three children with unresectable malignant liver tumors. Med Pediatr Oncol 2000;34:132-5. [8] Dower NA, Smith LJ. Liver transplantation for malignant liver tumors in children. Med Pediatr Oncol 2000;34:136-40. [9] Okajima H, Ohya Y, Lee KJ, et al. Management of undifferentiated sarcoma of the liver including living donor liver transplantation as a backup procedure. J Pediatr Surg 2009;44:e33-8. [10] Kalicinski P, Ismail H, Broniszczak D, et al. Non-resectable hepatic tumors in children—role of liver transplantation. Ann Transplant 2008;13:37-41.