A Single-Institution Retrospective Cases Series of Childhood

ORIGINAL ARTICLE

A Single-institution Retrospective Cases Series of Childhood Undifferentiated Embryonal Liver Sarcoma (UELS): Success of Combined Therapy and the Use of Orthotopic Liver Transplant

Ashley S. Plant, MD,* Ronald W. Busuttil, MD,w Abbas Rana, MD,w Scott D. Nelson, MD,z Martin Auerbach, MD,y and Noah C. Federman, MD*8z

in 2 representative cases. Although follow-up is short for some Background/Introduction: Undifferentiated embryonal liver sar- patients, overall survival in these 5 patients was 100% with follow-up coma (UELS) makes up 9% to 15% of all malignant liver tumors ranging from 21 to 68 months. Disease-free survival ranged from 8 to in children. UELS is characteristically diagnosed between the ages 46 months with no patients with residual disease. of 6 and 10 years and presents with abdominal pain, vomiting, and an abdominal mass. There is currently no standardized treatment Conclusions: UELS is an aggressive high-grade primary liver sar- for UELS except attempt at complete surgical resection. There coma with high metastatic potential. This report represents one of have been only about 150 cases of UELS reported in the literature the largest single-institution studies of UELS. Using multimodality all with historically poor overall survival of <37.5% at 5 years. therapy, patients have achieved 100% overall survival even in the This report is one of the largest single-institution reports of UELS setting of extensive disease, metastases, and recurrence. In cases of consisting of 5 patients over 2 decades. The purpose of this study is unresectable primary tumor or recurrent and refractory disease to characterize presentation and to report treatment success in isolated to the liver, OLT is a potential therapeutic option. We UELS in children, adolescents, and young adults and the use of report success with adjuvant chemotherapy and complete surgical liver transplantation and, lastly, to suggest a use of positron resection with OLT as an alternative in unresectable or refractory emission tomography/computed tomography (PET/CT) in mon- cases. We also suggest a possible utility of PET/CT in monitoring itoring of this disease process. treatment response in this disease. Methods: We conducted an Institutional Review Board–approved Key Words: sarcoma, soft tissue, undifferentiated, liver, childhood, retrospective chart review. Data were collected from UELS patients transplant younger than 21 years seen at the University of California Los (J Pediatr Hematol Oncol 2013;35:451–455) Angeles over the past 20 years (January 2001 to September 2011). Descriptive analysis was conducted including multiple parameters of patient demographics, tumor characteristics, treatment modalities, and morbidity and mortality. ndifferentiated embryonal liver sarcoma (UELS) is a Results: Five patients with UELS were identified. Patients initially Urare malignant liver tumor of childhood making up 9% 1 presented with fever, abdominal pain, or nausea. Ages ranged from to 15% of all hepatic malignancies. Diagnosis is usually 10 to 19 years old (median age 13 y old), and there was a 4:1 male-to- made between 6 and 10 years of age and typical presenting female predominance. Tumor size ranged from 6 to 22 cm in largest signs and symptoms include nausea, anorexia, right upper diameter. One patient presented with metastatic disease to the lungs quadrant mass, abdominal pain, and fever. Imaging typi- and heart and 1 patient recurred 2 years from diagnosis with bilateral cally reveals a large hepatic mass in the right lobe more paraspinal masses. Treatment included local control surgery with often than the left lobe, made up of both cystic and solid neoadjuvant and adjuvant chemotherapy with an anthracycline/ components, and occasionally involving the portal system alkylating agent combination. One patient with recurrent and 2 refractory disease achieved local control with an orthotopic liver making them notoriously difficult to resect. Newer studies transplantation (OLT). Metastatic disease was controlled with sur- suggest an older age distribution with average age of pre- 1 gery and radiation therapy. 18-Fluorodeoxyglucose PET/CT was a sentation being at 10.5 years of age. Histology in the useful imaging tool for judging response to therapy with complete majority of cases contains spindle or stellate cells, pleomor- loss of metabolic activity in tumor after neoadjuvant chemotherapy phic and prominent eosinophilia, with variable immunohistochemistry staining.1,3,4 Serum a-fetoprotein is normal. Negative myogenin staining typically differentiates UELS Received for publication May 30, 2012; accepted August 29, 2012. from rhabdomyosarcomas.5 Some have argued that UELS is From the *Department of Pediatrics, Division of Hematology/ on a spectrum with mesenchymal hamartoma.6 There have w Oncology; Department of Surgery, Division of Liver and Pancreas also been reports of association with p53 mutations.7 UELS Transplantation; Departments of zPathology; yMedical and Molecular Pharmacology, Ahmanson Biological Imaging Center/ has high metastatic potential primarily to lung and lymph Nuclear Medicine; 8The UCLA Jonsson Comprehensive Cancer nodes. Recurrences are mostly locoregional in nature, but Center, David Geffen School of Medicine; and zRonald Reagan they have been reported in the lungs, bone, and brain.3 Medical Center, Mattel Children’s Hospital, University of UELS are aggressive sarcomas and historically carried California Los Angeles, Los Angeles, CA. N.C.F. is supported by St. Baldrick’s Career Development Award and a poor prognosis before development of multimodal ther- a STOP Cancer Research Award. apy with reported survival rates of <37.5%.4,8 Previous The authors declare no conflict of interest. studies have shown success with combined surgical and Reprints: Noah C. Federman, MD, Department of Pediatrics, Division adjuvant chemotherapy regimens based on treatment of of Hematology/Oncology, 6223 W 6th St Los Angeles, CA 90048 8–11 (e-mail: [email protected]). other childhood soft tissue and hepatic malignancies. Copyright r 2012 by Lippincott Williams & Wilkins There have been several case reports of success with liver

J Pediatr Hematol Oncol Volume 35, Number 6, August 2013 www.jpho-online.com | 451 Plant et al J Pediatr Hematol Oncol Volume 35, Number 6, August 2013 transplantation in refractory or unresectable cases.12,13 variable a-1 antitrypsin staining. One patient presented However, there is no standard therapeutic approach to with pulmonary metastatic disease and 1 had distant recur- these malignancies. rence of disease with pulmonary and paraspinal metastases We present 5 cases of UELS in one of the largest case at 2 years from completion of therapy. series from a single institution treated successfully with combined surgical and adjuvant chemotherapy protocols. Treatment and Outcome We also report successful outcome of total hepatectomy and Surgical resection and adjuvant chemotherapy formed orthotopic liver transplantation (OLT) in a patient with the basis of treatment for the 5 patients.8–18 Chemotherapy locally recurrent/refractory disease not amenable to surgical regimens for 3 patients consisted of 5 cycles of ifosfamide resection. We report success with adjuvant chemotherapy 3 gm/m2/d3 days and doxorubicin 37.5 mg/m2 on days with an ifosfamide-based and doxorubicin-based regimen 1 and 2. Patient B received 5 cycles of actinomycin-D combined with complete surgical resection as standard of 1.5 mg/m2/d on day 1, ifosfamide 2 gm/m2/d on days 1 to 5 care for treatment of UELS with total hepatectomy and of weeks 1 and 4, doxorubicin 40 mg/m2/d on days 1 and 2 OLT as an alternative in unresectable or refractory cases. of week 4, and vincristine 1.5 mg/m2/d on day 1 of weeks 1, 2, 3, and 4 per Italian Sarcoma Protocol RMS88. Patient C received 5 cycles of cisplatin and doxorubicin (375 mg/m2 METHODS cumulative anthracycline) outside the United States. Four This is an Institutional Review Board (IRB)-approved patients underwent right hepatic lobectomy and patient C [University of California Los Angeles (UCLA) IRB ap- had an extensive hepatic surgical resection after tumoral proval #11-001743] retrospective review of 5 cases of UELS rupture. Patients B and C both received salvage chemo- in patients younger than 21 years of age seen at UCLA therapy. Patient B’s salvage regimen included 7 cycles of identified in the UCLA Sarcoma and Liver Transplant etoposide 100 mg/m2/d and ifosfamide 2800 mg/m2/d5 Databases. Chart review was conducted searching for mul- days followed by weekly paclitaxel 80 mg/m2 on days 1, 8, tiple parameters: age, sex, ethnicity, signs and symptoms at and 15 of 6 cycles of 28 days. Patient C received salvage presentation, date and age of diagnosis, location of tumor, chemotherapy consisting of ifosfamide, etoposide, and car- presence and location of metastases, imaging results, his- boplatin for 2 cycles followed by another 2 cycles adjuvantly tology and pathology reports, size of tumor, chemotherapy after liver transplantation with ifosfamide and carboplatin regimen, use of any salvage chemotherapy, use of surgery, at an outside hospital (dosing information was not avail- liver transplantation, recurrence and site of recurrence, able). Both patients with metastatic disease received local morbidity and mortality, and survival in months from radiation (6000 cGy) to the sites of metastatic disease. diagnosis and months of disease-free survival. Patients were Patient B received 6000 cGy of radiation to pulmonary and assigned letters; medical record numbers, names, and other paraspinal metastases, and patient E received 6000 cGy of identifying data were removed before data analysis. Results radiation to pulmonary metastases. Patient E had extension were documented as a descriptive analysis of a case series. of his tumor into the inferior vena cava but after chemo- Patient C was treated elsewhere but was included in our therapy repeat scans revealed no evidence of further disease study, because he received OLT at our institution and was with minimal scar tissue. He was placed on Arixtra for 4 followed here subsequently. months after chemotherapy. He has now been disease free for 8 months (Table 1). RESULTS Patient B had a regional recurrence in the paraspinal area posterior to the liver, and patient C experienced a local Patient Characteristics recurrence of the tumor at the primary site. Patient C went The age of patients ranged from 10 to 19 years of age, on to receive a total hepatectomy and OLT for refractory median 13 years, an older age range than previously re- disease. Overall, multimodal therapy was well tolerated. ported.2 There was a 4:1 male-to-female ratio. There was no Patient B had a pulmonary embolism after resection of the predominance of ethnicity. The symptoms at presentation paraspinal recurrence. included fever, abdominal pain, abdominal mass, nausea Baseline 18-fluorodeoxyglucose positron emission and vomiting, fatigue, constipation, abdominal asymmetry, tomography/computed tomography (18F-FDG PET/CT) in and acute abdomen. The most common presenting symp- patients D and E showed that UELS is very 18F-FDG avid. tom was right upper quadrant or nonspecific abdominal 18F-FDG PET/CT performed after 2 cycles of neoadjuvant pain. chemotherapy predicted response to chemotherapy with a significant decrease in 18F-FDG uptake (Fig. 1A). SUV Tumor Characteristics max in patient D’s tumor decreased from 9.6 to 1.5 after 2 Tumor size ranged from 6 to 22.6 cm in largest dia- cycles of neoadjuvant chemotherapy. SUV max in patient meter. Four of 5 tumors were located in the right hepatic E’s tumor decreased from 9.9 to 2.9 between February 11, lobe. Patient C presented to UCLA at the time of recur- 2011 and March 24, 2011 after 2 cycles of chemotherapy. rence after being treated in a foreign country, and a primary Lung lesions also demonstrate decrease from an average hepatic lobe site of tumor was not specified. Patient E’s SUV max of 10.3 to 1.3 with complete resolution in 2 primary tumor was located in the right hepatic lobe and lesions. Tumors were highly sensitive to neoadjuvant ifos- extended into the inferior vena cava and right atrium. Two famide/doxorubicin chemotherapy showing both metabolic tumors were noted to be multiloculated and cystic on initial response and response by RECIST criteria on 18F-FDG imaging studies. Patient D had an exophytic mass extend- PET/CT as well as >90% pathologic necrosis on histo- ing from the right lobe of the liver. Histology revealed pathologic analysis after resection. Disease-free survival uniformly pleomorphic spindle and stellate cells with oc- ranged from 8 to 46 months with a mean of 30.2 months. casional bizarre giant cells. Immunohistochemistry revealed Overall survival ranged from 21 to 68 months with a mean universally negative myogenin and desmin staining and of 43 months. As of time of submission, all patients are

452 | www.jpho-online.com r 2012 Lippincott Williams & Wilkins J Pediatr Hematol Oncol Volume 35, Number 6, August 2013 A Single-institution Retrospective Cases Series

TABLE 1. Treatment and Outcome Primary Liver Salvage Site of OS DFS Patients Chemotherapy Surgery Transplantation Chemotherapy Radiation Recurrence Recurrence (mo) (mo) A Ifosfamide, Right No No No No None 24 23 doxorubicin lobectomy (5 cycles) B Vincristine, Right lobe No Ifosfamide/etoposide; 6000 cGy to lung Yes Liver 68 46 dactinomycin, resection gemcitabine/taxotere; and paraspinal ifosfamide paclitaxel metastasis (5 cycles) C Cisplatin, Resection Yes Ifosfamide, etoposide, No Yes Liver 61 37 doxorubicin after and carboplatin (5 cycles) rupture D Ifosfamide, Right lobe No No No No None 41 37 doxorubicin resection (5 cycles) E Ifosfamide, Right lobe No No 6000 cGy to lung No None 21 8 doxorubicin resection metastasis (6 cycles)

DFS indicates disease-free survival; OS, overall survival.

alive, well, and disease free. No patients are currently re- the UELS tumors themselves, supporting a role for p53 in ceiving salvage chemotherapy for recurrent and/or meta- UELS carcinogenesis. static disease. Currently, CT and magnetic resonance imaging are the imaging modalities used to evaluate UELS tumors at presentation and after resection. Increasing evidence in DISCUSSION pediatric and adult bone and soft tissue sarcomas suggests a Malignant liver tumors make up a little over 1% of role for 18F-FDG PET/CT in staging evaluation, response pediatric malignancies, the most common of which is hep- to therapy, and surveillance of recurrence.23–25 Two atoblastoma as opposed to hepatocellular carcinoma seen patients in this study demonstrated the utility of 18F-FDG mostly commonly in adults.19 Two thirds of all liver lesions PET/CT as a modality for monitoring treatment response. are malignant, and overall there are 100 to 150 new cases of Both patients had complete resolution of metabolic activity pediatric liver malignancies per year in the United in the tumor after adjuvant chemotherapy. 18F-FDG PET/ States.20,21 Other less common pediatric liver malignancies CT was very useful for monitoring treatment response in include sarcomas, such as rhabdomyosarcoma and UELSs, these patients and response to therapy by decreased PET/ as well as hepatocellular carcinoma. Neuroblastoma is the CT SUV correlated with response to therapy by pathologic most common malignancy to metastasize to the liver fol- necrosis. However, attention must be paid to the use of lowed by leukemia, lymphoma, and Wilms tumor. pediatric imaging protocols to reduce radiation dosage and The clinical differentiation of rhabdomyosarcoma and to overall cumulative radiation exposure. UELS can be difficult. Rhabdomyosarcoma usually occurs In the treatment of UELS, complete surgical resection in children younger than 5 years and arises from the biliary with negative margins is frequently difficult to achieve when ducts. These tumors account for 0.8% to 1% of pediatric the tumor is situated in close proximity to the major hepatic liver malignancies. In contrast, UELS occurs more com- vessels (portal vein, hepatic vein, and hepatic artery). OLT monly in the 6- to 10-year age group arising within the liver has been successful as a definitive therapy for unresectable itself. Jaundice is not typically present at diagnosis, whereas UELS refractory to chemotherapy or in recurrent cases. In this is a common finding in rhabdomyosarcoma because 1 case of recurrent and refractory UELS, we have shown of the biliary location. UELS accounts for 10% to 15% successful liver transplantation now disease free for 37 of pediatric liver malignancies. Unlike, hepatoblastoma and months with overall survival of 61 months since diagnosis. hepatocellular carcinoma, UELS is not associated with This is important as organ transplantation is not often elevated a-fetoprotein. Also, it confers a much poorer considered as there is theoretical risk of primary malig- prognosis historically than the approximately 85% 5-year nancy recurrence with long-term immunosuppression, and survival rates seen with multimodal therapy for early-stage transplant for salvage therapy is typically frowned upon hepatoblastoma and liver biliary rhabdomyosarcoma. because of inherent morbidity/mortality and the dearth of Although hepatoblastoma and rhabdomyosarcoma this valuable resource. However, for these “unresectable” are associated with heritable factors, such as, Beckwith- cases of UELS, complete hepatectomy and OLT is the only Wiedemann syndrome and familial adenomatous poly- means to achieve successful “local” control, a basic tenet in posis, and predisposing factors of low birth weight, there sarcoma therapy. In adult hepatocellular carcinoma, recent are no predisposing factors for the development of UELS. studies have shown large success with salvage transplan- There are reports of germline p53 mutations in several tation and similar results to primary transplantation.23,24,26 patients; so, a careful genetic and family history should be Although clearly speculative, we suggest that consideration obtained along with counseling for p53 testing.22 Further- for OLT in the UELS salvage setting be given to those more, mutations in the p53 gene have been shown within patients who have disease that is chemoresponsive and do r 2012 Lippincott Williams & Wilkins www.jpho-online.com | 453 Plant et al J Pediatr Hematol Oncol Volume 35, Number 6, August 2013

FIGURE 1. 18-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) images. A, Patient E before adjuvant chemotherapy PET/CT revealed multiple large foci of intense 18F-FDG activity corresponding to the enhancing portions of the large multiseptated masses in the right hepatic lobe, predominantly along the posteromedial margins of the masses. The nonenhancing portions of the masses do not demonstrate significant metabolic activity, suggestive of central necrosis. There are innumerable large and small foci of intense metabolic activity within the bilateral lungs, corresponding to the solid enhancing pulmonary masses seen on CT. Prevascular and subcarinal mediastinal lymph nodes also demonstrate intense metabolic activity. Also, there are a few nonenhancing low-density hilar masses, predominantly on the right showing significant metabolic activity. B, Patient E after adjuvant chemotherapy PET/CT showed that pulmonary nodules within the lungs have dramatically decreased in size, number, and 18F-FDG activity. There is some mild uptake within scattered pulmonary nodules of bilateral lower lobes. No focus of abnormal metabolic activity in the cervical, supraclavicular, mediastinal, axillary, retroperitoneal, or inguinal nodal regions. Hypodense lesions in the liver demonstrate much less 18F-FDG activity than on prior study with only a mild focus of residual activity in the medial aspect of the largest hypodense lesion.

not have evidence for portal vein tumor involvement nor metastatic sites when indicated for patients diagnosed with clinically evident metastatic disease. pediatric UELS, and use of salvage chemotherapy in A recent study demonstrated similar results with 5 refractory or recurrent cases. patients from a single institution treated with a uniform This case series further elicits descriptive data about treatment approach that includes resection with neo- UELS and suggests a model for histology-specific stan- adjuvant chemotherapy and radiation when indicated.24 dardized multimodal therapy. The authors of this study suggest that chemotherapy with vincristine, actinomycin, and cyclophosphamide along with surgical resection are sufficient for high cure rates in UELS CONCLUSIONS without the addition of anthracyclines, topoisomerase in- UELSs are rare and aggressive malignancies of chil- hibitors, or platinum compounds. The authors report a dren, adolescents, and young adults that have no stan- median survival rate of 53 months among their patients dardized therapeutic approach other than achieving local using this uniform approach. Our study differs in the age of control with attempt at complete surgical resection. Treat- patients (range of 4 to 13 y in recent study vs. 10 to 19 y in ment modalities have been based on small case series in the our study). The chemotherapeutic regimen was also differ- literature. Early success has been shown in dual therapy ent as our study used a soft tissue sarcoma anthracycline/ with adjuvant chemotherapy and surgical resection.8–11 alkylating agent backbone regimen of ifosfamide and dox- Chemotherapy regimens are based on known protocols for orubicin. Our study suggests similar findings of successful childhood sarcomas and liver malignancies.8 In cases where use of multimodal therapy including complete resection the tumor is unresectable at diagnosis, prognosis is usually when possible, neoadjuvant chemotherapy and radiation to poor.4,8 Our study adds to the growing body of knowledge

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