REVIEW URRENT C OPINION
Management of hepatoblastoma: an update Nathalie Kremer , Ashley E. Walther , and Gregory M. Tiao
Purpose of review To summarize the current standards and guidelines for the diagnosis and management of hepatoblastoma, a rare pediatric liver tumor. Recent findings Hepatoblastoma is the most common malignant liver tumor in childhood. International collaborative efforts have led to uniform implementation of the pretreatment extent of disease (PRETEXT) staging system as a means to establish consensus classification and assess upfront resectability. Additionally, current histopathological classification, in light of more advanced molecular profiling and immunohistochemical techniques and integration of tumor biomarkers into risk stratification, is reviewed. Multimodal therapy is composed of chemotherapy and surgical intervention. Achievement of complete surgical resection plays a key role in successful treatment for hepatoblastoma. Overall, outcomes have greatly improved over the past four decades because of advances in chemotherapeutic agents and administration protocols as well as innovations of surgical approach, including the use of vascular exclusion, ultrasonic dissection techniques, and liver transplantation. Challenges remain in management of high-risk patients as well as patients with recurrent or metastatic disease. Summary Eventually, a more individualized approach to treating the different types of the heterogeneous spectrum of hepatoblastoma, in terms of different chemotherapeutic protocols and timing as well as type and extent of surgery, may become the basis of successful treatment in the more complex or advanced types of hepatoblastoma. Keywords hepatoblastoma, liver resection, liver transplantation, pretreatment extent of disease staging
INTRODUCTION Although rare, with a yearly incidence of five cases per million in children under the age of 4 years, hepatoblastoma is the most common malignant liver tumor in the pediatric population [1]. Incidence nearly doubled between 1975 and 2009 [2] and has increased over the past two decades by roughly 4% per year between 1992 and 2004 [3]. Staging is currently based on computed tomography (CT) or MRI using the pretreatment extent of disease (PRETEXT) system and reassessment after neoadjuvant chemotherapy, termed the posttreatment extent of disease (POSTTEXT) [4]. The PRETEXT system is being used in all four pediatric liver study groups: Children’s Oncology Group (COG), International Childhood Liver Tumor Strategy Group (SIOPEL), German Society of Pediatric Oncology and Hematology (GPOH), and Japanese Study Group for Pediatric Liver Tumor (JPLT). Surgical resection remains the cornerstone of cure in all groups; however, recommended timing of chemotherapy varies. The evolution of chemotherapeutic www.co-pediatrics.com
agents, predominantly cisplatin-based treatments used in neoadjuvant and adjuvant protocols, contributed largely to the decrease in mortality among hepatoblastoma patients over the past several decades [5,6 ]. The overall 5-year-survival rate based on current treatment regimens is 70% [7]. Technical challenges remain in extensive hepatoblastoma with vascular invasion, multifocality, and metastatic disease. In advanced disease, data are lacking in regards to the use of primary transplant versus complex resection as the most appropriate &&
Department of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA Correspondence to Gregory M. Tiao, MD, Department of Pediatric Surgery, Cincinnati Children’s Hospital and Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. Tel: +1 513 636 3334; e-mail: [email protected] Nathalie Kremer and Ashley E. Walther contributed equally to the writing of the article.
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Management of hepatoblastoma: an update Kremer et al.
KEY POINTS PRETEXT staging is internationally used to assess for degree of anatomic involvement and resectability of hepatoblastoma. Patients stages PRETEXT I and II can be primarily resected after chemotherapy. Patients stages PRETEXT III and IV with vascular involvement should be considered candidates for primary liver transplant.
surgical approach. These challenges are of pressing importance, as survival rates for patients with advanced hepatoblastoma are still relatively low [6 ,8 ]. An international consensus classification system that would allow more standardized consistent care is the next step in addressing many of these challenges. &&
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best prognosis has been demonstrated in pure fetal type epithelial hepatoblastoma with low mitotic activity, which occurs in fewer than 7% of patients [14] but may be resected without the need for chemotherapy [16]. The SCUD variant of epithelial hepatoblastoma occurs in about 5% of all cases and has the worst prognosis [14]. An overview of the current hepatoblastoma classification according to the Los Angeles COG liver tumors symposium is outlined in Table 1 [17 ]. Current immunohistochemistry stains utilized in the workup and diagnosis of hepatoblastoma include pancytokeratin, vimentin, glypican 3, a-fetoprotein (AFP), b-catenin, glutamine synthetase, Hep-Par1, and integrase interactor 1 (INI1) [18 ]. In addition, karyotypic and molecular profiling of these tumors has allowed for additional subgrouping. Pathways identified to be involved in hepatoblastoma growth include Wnt (CTNNB1 and APC genes), Sonic Hedgehog, NotchSignaling, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), mitogen activated protein kinase, and insulin-like growth factor [19 ]. The implications for tumor behavior and subsequent impact on risk stratification and treatment recommendations are not identified yet. For example, ongoing discussion exists about INI 1-negative SCUD epithelial hepatoblastoma that shows rhabdoid features and low AFP expression, as these tumors may require an alternative chemotherapy regimen [20]. To ensure optimal treatment of hepatoblastoma, with the ultimate goal to individualize treatment, it is currently recommended that all patients with a liver mass undergo biopsy. Adequate tissue samples may come from percutaneous needle biopsy, laparoscopic core needle or wedge biopsy, or open core needle or wedge biopsy. Fine needle aspiration should be avoided, as insufficient tissue is obtained using this methodology. Close cooperation between the radiologist and the surgeon is necessary to achieve a quality sample and to avoid seeding of the track. Samples should be sent fresh to pathology whenever possible. The specifics on biopsy technique, amount, and sample size have been described previously, but a minimum of 5–10 cores measuring 1 x 0.3 cm in size is required to make the diagnosis [18 ]. A detailed description of the biopsy location is mandatory. However, given the characteristic microscopic heterogeneity of hepatoblastoma, a biopsy that samples approximately 3/100 000 of the entire tumor (an estimated 15 mg versus 500 g before treatment, on average) is only rarely (8–10%) representative of the rest of the tumor, and therefore biopsy before chemotherapy will most likely not implement immediate changes in the international protocols that recommend chemotherapy before surgery for all hepatoblastoma &&
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Epidemiology Approximately 150 children in the United States are diagnosed with hepatoblastoma each year, most of them under the age of 5 years, with the mean age at diagnosis being 19 months [9 ]. There is a slight male predominance. An increased risk of hepatoblastoma is associated with Beckwith–Wiedemann Syndrome [10] and Familial Adenomatous Polyposis [11]. Additionally, a total of 12 cases of hepatoblastoma occurring in children with trisomy 18 have been reported in the literature [12 ]. Association with other inherited disorders is based only on isolated case reports. As medical care of premature infants has improved, a strong association of hepatoblastoma with very low birth weight has emerged, which may contribute to the overall increase in hepatoblastoma incidence [13 ]. Other risk factors include infertility treatment, preeclampsia, high maternal prepregnancy weight, oligohydramnios and polyhydramnios, parental tobacco use, and parental occupational exposure to metals [3]. &
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Tumor biology Hepatoblastoma is an embryonal tumor that usually displays morphologic features of many cell types. Two histologic types are predominant: epithelial and mixed (epithelial and mesenchymal). Early studies report that a majority of hepatoblastoma tumors are epithelial (56–67%) [14]. These epithelial tumors are further subdivided into pure fetal (31%), embryonal (19%), macrotrabecular (3%), and small-cell undifferentiated (SCUD) (3%) [15]. The
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Surgery Table 1. Hepatoblastoma histologic subtypes with associated significance and clinical markers Hepatoblastoma histological subtypes
Potential clinically significant markers
Clinical significance
Epithelial Fetal Pure fetal with low mitotic activity
Requires complete surgical resection only, favorable prognosis
Fetal, mitotically active
Mixed cell types, often transition to embryonal and SCUD
Pleomorphic, poorly differentiated
Uncommon, often found in metastases, relapse tumor and postchemotherapy specimen, also known as transitional, anaplastic or HCC-like, unfavorable prognosis
Embryonal macrotrabecular
Rare ( 3 years and upfront resection not feasible
SIOPEL/GPOH
Recommended at diagnosis
JPLT-2
Recommended at diagnosis in PRETEXT II–IV
Recommended in all liver tumors
X X
PRETEXT II–IV Biopsy
Biopsy
X
SIOPEL/GPOH Standard risk
PRETEXT I
Neoadjuvant followed by resection and then adjuvant chemotherapy
Recommended if patient is: < 6 months; > 3 years and if no upfront resection feasible
Intermediate risk
Study group
High risk
PRETEXT I–III; serum AFP > 100 ng/ml
Low risk
JPLT-2
Intermediate risk
X
Recommended Neoadjuvant chemotherapy resection
Resection
Resection
No chemotherapy
Adjuvant chemotherapy
Adjuvant chemotherapy
Very low risk
Low risk
Intermediate and high risk
Standard and high risk PRETEXT I
PRETEXT II–IV
AFP, a-fetoprotein; COG, Children’s Oncology Group; JPLT-2, Japanese Study Group for Pediatric Liver Tumor; PRETEXT, pretreatment extent of disease; SCUD, small-cell undifferentiated; SIOPEL/GPOH, International Childhood Liver Tumor Strategy Group/German Society of Pediatric Oncology and Hematology.
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reviewed in previous publications. In brief, PRETEXT describes tumor extent prior to treatment based on Couinaud’s system of segmentation, vascular involvement, extrahepatic disease, and metastases as seen on CT or MRI [4]. Staging is assigned using the number of sections affected by tumor growth, with further criteria, including involvement of the caudate lobe (C), extrahepatic abdominal disease (E), multifocal tumor (F), tumor rupture or intraperitoneal hemorrhage (H), distant metastasis (M), lymph node involvement (N), involvement of the portal vein (P), and venous involvement of the inferior vena cava or intrahepatic veins (V) [4]. Although PRETEXT has been demonstrated to have prognostic value [30], the ability of this system to predict resectability has not been shown and is one of the secondary outcomes being studied in an ongoing COG clinical trial, AHEP0731 (ClinicalTrials.gov identifier NCT0098046). Moreover, improved understanding of hepatoblastoma tumor biology suggests that these factors will at some point also have to be included in the future risk stratification systems. If neoadjuvant therapy is administered, POSTTEXT staging should be performed prior to surgical resection [4].
Chemotherapy The introduction of the platinum-based chemotherapeutic agent cisplatin was instrumental in improving the survival of children with hepatoblastoma, including the induction of tumor regression to allow surgical resection in patients initially deemed unresectable [31]. Cisplatin remains the core chemotherapeutic agent in all four liver study group treatment protocols. The COG standard regimen consists of cisplatin, 5-fluorouracil, and vincristine (C5V) [32 ]. The guidelines for the current COG trial, AHEP0731, recommend C5V for low-risk or C5V and doxorubicin for intermediate-risk and high-risk patients [33 ]. SIOPEL and GPOH currently recommend preoperative chemotherapy for every patient. Previous SIOPEL studies have supported neoadjuvant chemotherapy with cisplatin as a monotherapeutic agent for standard risk [5] or the use of a novel protocol incorporating dosedense cisplatin given weekly to patients with highrisk hepatoblastoma [34 ]. JPLT protocols depend on PRETEXT staging and utilize cisplatin and pirarubicin in the postoperative period for PRETEXT I or in the neoadjuvant and adjuvant setting for PRETEXT II–IV [35]. Chemotherapy is not indicated in patients with a tumor of pure fetal histology, as surgical resection alone is curative [16]. Chemotherapy cycles may be repeated for further downstaging of very large or multifocal tumors; however, there is &&
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a limit to the amount of chemotherapy that can be administered before toxicity issues become significant. Side-effects of current chemotherapy regimens include hematologic toxicity, including neutropenia, and ototoxicity. With better diagnosis, treatment, and survival of patients with hepatoblastoma, more advanced or relapsed disease is becoming more common. Hepatoblastoma can develop drug resistance after four cycles of chemotherapy and should be resected prior to this occurrence [36]. A poor response or relapse may partially reflect a still unsatisfactory understanding of the heterogeneous tumor biology of hepatoblastoma.
Surgery Although the treatment approach to hepatoblastoma is multimodal, complete surgical resection is required to achieve a definitive cure. In patients who present with advanced disease and an unfavorable prognosis, chemotherapy is administered with the ultimate goal to achieve resectability. To establish consistency and assess for resectability, the four aforementioned liver study group protocols have adopted the PRETEXT staging system to achieve an international standard. The understanding of liver anatomy and extensive hepatic operative experience is mandatory in the treatment of hepatoblastoma, as the ability to maintain appropriate blood inflow and outflow of the remaining liver at all times is crucial in tumor resection. The Brisbane classification standardized terminology defines liver resection based on two hemilivers, four sections, and eight segments (as defined by Couinaud). The terminology differentiates between trisectionectomy (extended resection of three sections), right or left (hemi) hepatectomy, sectionectomy, and segmentectomy (Fig. 1) [37 ]. The Brisbane classification has become the most common nomenclature used to describe liver resections. Surgical resection to achieve extirpation of a hepatoblastoma includes segmentectomy, sectionectomy, and/or hemihepatectomy for PRETEXT I and II, trisectionectomy for PRETEXT III and IV or transplantation for tumors with bilobar portal vein or hepatic vein and inferior vena cava invasion or extensive loss of normal parenchyma [38 ,39]. Technical challenges encountered in hepatoblastoma resection include bleeding, wound infection, liver failure, postoperative bile leak, biliary stricture, and sequelae of intraoperative inflow and outflow obstruction. Improvements in surgical technique, such as vascular inflow occlusion with the Pringle maneuver, outflow obstruction with a suprahepatic clamp, adherence to strict anatomic resection, and the use of specialized equipment, &&
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Right/left trisectionectomy or extended right/left (hemi) hepatectomy
Right/left (hemi) hepatectomy
Sectionectomy (right posterior, right anterior, left medial and left lateral sections)
Segmentectomy (according to Couinaud segments)
FIGURE 1. Resectional terminology for extended resection, excision of a hemiliver, excision of a segment, or excision of a section (adapted from [37 ]). &&
including ultrasonic dissection devices (CUSA) (Integra, Painsboro, New Jersey), Ligasure, Harmonic scalpel, and argon beam coagulator, are utilized to perform a safe resection. Vascular occlusion to reduce blood loss has not shown any adverse effect on liver function, and a total exclusion time of 30–60 min in pediatric patients is considered safe and effective [40]. The current recommendations of all four study group protocols are summarized in Table 2. Per COG protocol, PRETEXT I and II lesions should be resected at the time of diagnosis and followed with adjuvant chemotherapy. Tumors with pure fetal histology and low mitotic activity require only surgical resection, as this intervention provides adequate treatment [16]. PRETEXT III and
IV lesions should undergo neoadjuvant chemotherapy. POSTTEXT I, II, and III tumors without venous (V) and portal vein (P) involvement also undergo resection. Multifocal or Vþ/Pþ PRETEXT III lesions and PRETEXT IV should be referred to a facility with the ability for complex hepatic resection or liver transplant, if possible before or during neoadjuvant chemotherapy [38 ]. Adjuvant chemotherapy is also administered after resection of more advanced tumors. The European protocols (SIOPEL 3 and HB99) recommend neoadjuvant chemotherapy, regardless of PRETEXT staging, followed by restaging and tumor resection based on POSTTEXT assessment [28,41]. The HB99 trial makes an exception for
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small, nonmetastatic liver tumors (usually PRETEXT I) and recommends primary resection without neoadjuvant chemotherapy [28]. Similarly, the JPLT protocol recommends that nonmetastatic PRETEXT I tumors are resected upfront, whereas PRETEXT II–IV lesions are treated first with neoadjuvant chemotherapy [35]. Chemotherapy is also given postoperatively in these liver study group protocols. In a large retrospective study of the SIOPEL group, recurrent disease was reported in fewer than 12% of all patients who achieved a complete response, with a median time to relapse of 12 months after initial diagnosis. Half of the relapses were staged either PRETEXT III or IV at initial diagnosis [42 ]. In any protocol, if a tumor is deemed unresectable on initial workup and chemotherapy is administered preoperatively, restaging should occur no earlier than during the second cycle of chemotherapy [43 ]. Also, it is important that the tumor response and behavior be assessed by AFP levels and reimaging throughout chemotherapy administration, as these may indicate tumors with poor prognosis. When a patient presents with primary tumor rupture, initial control of hemorrhage followed by a staged hepatectomy after chemotherapy allows effective management through reduction of tumor volume in the liver as well as possible seeding of the peritoneum at time of rupture [44]. Pediatric patients with unresectable hepatoblastoma are candidates for liver transplantation. These include patients with disease involvement of the entire liver, extensive multifocal disease, or vascular invasion. Children undergoing transplant should receive neoadjuvant and adjuvant chemotherapy. Transplantation is indicated in the setting of chemotherapy responsive multifocal disease, as radiographic imaging cannot ensure complete resolution of microscopic foci. Patients with metastases at the time of diagnosis are still eligible for transplantation if these lesions regress with preoperative chemotherapy or undergo surgical resection [45,46]. It is also useful in the setting of intrahepatic recurrence or residual tumor after attempt at partial hepatectomy. Primary liver transplant, however, has a superior survival rate (approximately 80%) in advanced hepatoblastoma versus a lower survival rate (30%) in children who underwent rescue transplant when conventional surgical resection failed [47]. In a retrospective review of the Surveillance, Epidemiology, and End Results database, 318 pediatric hepatoblastoma patients underwent complex resection or liver transplantation with no difference in survival [8 ]. A randomized trial comparing complex resection and primary transplant for advanced hepatoblastoma has not yet been performed; the decision for the best approach lies in
the hands of the surgical team. Unresectable or progressive extrahepatic metastatic disease, including persistent pulmonary lesions that do not respond to chemotherapy, is an absolute contraindication to transplant. The most common complication after liver transplantation is vascular thrombosis, followed by local recurrence, pulmonary metastatic disease, and bile leak. Preexisting pulmonary metastatic disease before liver transplant may be missed using conventional CT imaging, so that PET-CT imaging is recommended [48 ]. Postoperative management of these children, including immunosuppression regimens, requires further investigation. &
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CONCLUSION Hepatoblastoma is a rare pediatric malignancy. However, as it is the most common liver tumor in children, further understanding of the diagnosis and optimal treatment is necessary for the management of these cases. Appreciation of tumor biology, including histologic type and molecular pathways involved, may provide opportunities for individualized treatment plans. One approach to optimizing care is through collaboration of the four liver study groups as well as standardization of staging through the use of PRETEXT. The role of neoadjuvant chemotherapy, specific chemotherapeutic regimens, surgical approach to resection, and the use of liver transplantation are areas requiring further study. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Darbari A, Sabin KM, Shapiro CN, Schwarz KB. Epidemiology of primary hepatic malignancies in U.S. children. Hepatology 2003; 38:560–566. 2. Howlander N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2010. Bethesda, Maryland: National Cancer Institute; 2013 ; http:// seer.cancer.gov/csr/1975_2010/. [Accessed 18 December 2013] 3. Linabery AM, Ross JA. Trends in childhood cancer incidence in the U.S. (1992-2004). Cancer 2008; 112:416–432. 4. Roebuck DJ, Aronson D, Clapuyt P, et al. 2005 PRETEXT: a revised staging system for primary malignant liver tumours of childhood developed by the SIOPEL group. Pediatr Radiol 2007; 37:123–132; quiz 249–250. 5. Perilongo G, Maibach R, Shafford E, et al. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 2009; 361: 1662–1670. 6. Allan BJ, Parikh PP, Diaz S, et al. Predictors of survival and incidence of && hepatoblastoma in the paediatric population. HPB 2013; 15:741–746. Review of a total of 606 patients who were diagnosed with hepatoblastoma in the last 40 years and outlines the developments in incidence, risk factors, and outcomes, showing that survival significantly improved.
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Management of hepatoblastoma: an update Kremer et al. 7. Ortega JA, Douglass EC, Feusner JH, et al. Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: a report from the Children’s Cancer Group and the Pediatric Oncology Group. J Clin Oncol 2000; 18:2665–2675. 8. McAteer JP, Goldin AB, Healey PJ, Gow KW. Surgical treatment of primary & liver tumors in children: outcomes analysis of resection and transplantation in the SEER database. Pediatr Transplant 2013; 17:744–750. The first comparative study evaluating outcomes after hepatic resection versus liver transplant in the pediatric population. 9. Rodriguez-Galindo C, Krailo M, Frazier L, et al. Children’s Oncology Group’s & 2013 blueprint for research: rare tumors. Pediatr Blood Cancer 2013; 60: 1016–1021. A review of completed clinical studies and the development of large international collaborations for rare tumors, including hepatoblastoma. 10. DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 1998; 132 (3 Pt 1):398–400. 11. Giardiello FM, Offerhaus GJ, Krush AJ, et al. Risk of hepatoblastoma in familial adenomatous polyposis. J Pediatr 1991; 119:766–768. 12. Tan ZH, Lai A, Chen CK, et al. Association of trisomy 18 with hepatoblastoma & and its implications. Eur J Pediatr 2013. [Epub ahead of print] Case report reviewing the occurrence of trisomy 18 in association with hepatoblastoma and presents the two most recent patients. 13. Spector LG, Birch J. The epidemiology of hepatoblastoma. Pediatr Blood && Cancer 2012; 59:776–779. Overview of the most recent developments in the epidemiology of hepatoblastoma, including risk factors, such as very low birth weight, paternal smoking, and diagnosis of Beckwith–Wiedemann Syndrome. 14. Weinberg AG, Finegold MJ. Primary hepatic tumors of childhood. Hum Pathol 1983; 14:512–537. 15. Herzog CE, Andrassy RJ, Eftekhari F. Childhood cancers: hepatoblastoma. Oncologist 2000; 5:445–453. 16. Malogolowkin MH, Katzenstein HM, Meyers RL, et al. Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children’s Oncology Group. J Clin Oncol 2011; 29:3301– 3306. 17. Lopez-Terrada D, Alaggio R, de Davila MT, et al. Towards an international && pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Modern Pathol 2013; 27 (3):472–491. Summary of the most recent developments in identification of different subtypes of hepatoblastoma, including clinical implications and molecular markers, currently under investigation. 18. Tanaka Y, Inoue T, Horie H. International pediatric liver cancer pathological & classification: current trend. Int J Clin Oncol 2013; 18:946–954. Summarizes the current terminology of the different subtypes of hepatoblastoma. 19. Purcell R, Childs M, Maibach R, et al. Potential biomarkers for hepatoblas& toma: results from the SIOPEL-3 study. Eur J Cancer 2012; 48:1853–1859. Overview of the most recent molecular markers currently being investigated for further classification and risk stratification of hepatoblastoma, including b-catenin, E-cadherin, Cyclin D1, and Ki-67. 20. Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, et al. Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr Blood Cancer 2009; 52:328–334. 21. Maibach R, Roebuck D, Brugieres L, et al. Prognostic stratification for children & with hepatoblastoma: the SIOPEL experience. Eur J Cancer 2012; 48:1543– 1549. Examination of PRETEXT staging, metastatic disease, AFP, and histology as outcome predictors for hepatoblastoma as used during the most recent SIOPEL trials. 22. Fukuzawa H, Urushihara N, Fukumoto K, et al. Can we predict the prognosis of & resectable hepatoblastoma from serum alpha-fetoprotein response during preoperative chemotherapy? Pediatr Surg Int 2012; 28:887–891. Study evaluating AFP levels of 14 hepatoblastoma patients and monitored them throughout the treatment course, showing that a large, early decrease of AFP levels is a strong indicator of good prognosis. 23. McCarville MB, Roebuck DJ. Diagnosis and staging of hepatoblastoma: imaging aspects. Pediatr Blood Cancer 2012; 59:793–799. 24. Meyers AB, Towbin AJ, Serai S, et al. Characterization of pediatric liver lesions with gadoxetate disodium. Pediatr Radiol 2011; 41:1183–1197. 25. Meyers AB, Towbin AJ, Geller JI, Podberesky DJ. Hepatoblastoma imaging with gadoxetate disodium-enhanced MRI: typical, atypical, pre and posttreatment evaluation. Pediatr Radiol 2012; 42:859–866. 26. Cistaro A, Treglia G, Pagano M, et al. A comparison between (1)(8)F-FDG & PET/CT imaging and biological and radiological findings in restaging of hepatoblastoma patients. BioMed Res Int 2013; 2013:709037. Study comparing imaging for restaging of hepatoblastoma patients suggesting that PET-CT may be more sensitive in identifying metastatic disease or recurrence. 27. Hishiki T. Current therapeutic strategies for childhood hepatic tumors: surgi& cal and interventional treatments for hepatoblastoma. Int J Clin Oncol 2013; 18:962–968. Review of current standards and developments in hepatoblastoma treatment according to the Japanese study protocol.
28. Haeberle B, Schweinitz D. Treatment of hepatoblastoma in the German cooperative pediatric liver tumor studies. Front Biosci 2012; 4:493–498. 29. Malogolowkin MH, Katzenstein HM, Krailo M, Meyers RL. Treatment of hepatoblastoma: the North American cooperative group experience. Front Biosci 2012; 4:1717–1723. 30. Meyers RL, Rowland JR, Krailo M, et al. Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2009; 53:1016–1022. 31. Ortega JA, Krailo MD, Haas JE, et al. Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol 1991; 9:2167–2176. 32. Watanabe K. Current chemotherapeutic approaches for hepatoblastoma. Int J && Clin Oncol 2013; 18:955–961. A comparison and review of the current chemotherapeutic regimen by study group and risk stratification. 33. Czauderna P, Lopez-Terrada D, Hiyama E, et al. Hepatoblastoma state of the && art: pathology, genetics, risk stratification, and chemotherapy. Curr Opin Pediatr 2013; 26:19–28. Summary of the results of hepatoblastoma cooperative trials since 1989 and overview of changes in outcomes and chemotherapy protocols. 34. Zsiros J, Brugieres L, Brock P, et al. Dose-dense cisplatin-based chemo& therapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 2013; 14:834–842. The result of the SIOPEL-4 study shows improved outcomes for 61 high-risk hepatoblastoma patients after treatment with an adjusted dose-dense cisplatinbased chemotherapy and radical surgery. 35. Hishiki T, Matsunaga T, Sasaki F, et al. Outcome of hepatoblastomas treated using the Japanese Study Group for Pediatric Liver Tumor (JPLT) protocol-2: report from the JPLT. Pediatr Surg Int 2011; 27:1–8. 36. von Schweinitz D, Hecker H, Harms D, et al. Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB-89. J Pediatr Surg 1995; 30:845–852. 37. Strasberg SM, Phillips C. Use and dissemination of the Brisbane 2000 && nomenclature of liver anatomy and resections. Ann Surg 2013; 257:377– 382. An overview of the terminology used to describe liver resection for hepatoblastoma and review of the development and use of the Brisbane nomenclature for standardized description of hepatic resection. 38. Meyers RL, Tiao GM, Dunn SP, Langham MR Jr. Liver transplantation in the & management of unresectable hepatoblastoma in children. Front Biosci 2012; 4:1293–1302. The article addresses current controversies in the decision process for liver transplant in advanced hepatoblastoma. 39. Czauderna P, Otte JB, Aronson DC, et al. Guidelines for surgical treatment of hepatoblastoma in the modern era: recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer 2005; 41:1031–1036. 40. Szavay PO, Luithle T, Warmann SW, et al. Impact of pedicle clamping in pediatric liver resection. Surg Oncol 2008; 17:17–22. 41. Czauderna P. Hepatoblastoma throughout SIOPEL trials: clinical lessons learnt. Front Biosci (Elite Ed) 2012; 4:470–479. 42. Semeraro M, Branchereau S, Maibach R, et al. Relapses in hepatoblastoma & patients: clinical characteristics and outcome – experience of the International Childhood Liver Tumour Strategy Group (SIOPEL). Eur J Cancer 2013; 49:915–922. Review of the 59 patients who relapsed after having received treatment for hepatoblastoma during SIOPEL trials 1–3, with an overall relapse rate of 12%. 43. Tajiri T, Kimura O, Fumino S, et al. Surgical strategies for unresectable & hepatoblastomas. J Pediatr Surg 2012; 47:2194–2198. Summary of the application of PRETEXT staging according to the JPLT protocol and respective recommendation for timing and extent of resection. 44. Madanur MA, Battula N, Davenport M, et al. Staged resection for a ruptured hepatoblastoma: a 6-year follow-up. Pediatr Surg Int 2007; 23:609–611. 45. Otte JB, de Ville de Goyet J, Reding R. Liver transplantation for hepatoblastoma: indications and contraindications in the modern era. Pediatr Transplant 2005; 9:557–565. 46. Meyers RL, Katzenstein HM, Krailo M, et al. Surgical resection of pulmonary metastatic lesions in children with hepatoblastoma. J Pediatr Surg 2007; 42:2050–2056. 47. Otte JB, Pritchard J, Aronson DC, et al. Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 2004; 42:74–83. 48. Ruth ND, Kelly D, Sharif K, et al. Rejection is less common in children & undergoing liver transplantation for hepatoblastoma. Pediatr Transplant 2013; 18:52–57. Review of 20 patients who underwent liver transplant for biliary atresia or hepatoblastoma indicating that outcomes for children undergoing primary liver transplant for hepatoblastoma are favorable, with an acute rejection rate of 50%.
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Management of hepatoblastoma: an update Nathalie Kremer , Ashley E. Walther , and Gregory M. Tiao
Purpose of review To summarize the current standards and guidelines for the diagnosis and management of hepatoblastoma, a rare pediatric liver tumor. Recent findings Hepatoblastoma is the most common malignant liver tumor in childhood. International collaborative efforts have led to uniform implementation of the pretreatment extent of disease (PRETEXT) staging system as a means to establish consensus classification and assess upfront resectability. Additionally, current histopathological classification, in light of more advanced molecular profiling and immunohistochemical techniques and integration of tumor biomarkers into risk stratification, is reviewed. Multimodal therapy is composed of chemotherapy and surgical intervention. Achievement of complete surgical resection plays a key role in successful treatment for hepatoblastoma. Overall, outcomes have greatly improved over the past four decades because of advances in chemotherapeutic agents and administration protocols as well as innovations of surgical approach, including the use of vascular exclusion, ultrasonic dissection techniques, and liver transplantation. Challenges remain in management of high-risk patients as well as patients with recurrent or metastatic disease. Summary Eventually, a more individualized approach to treating the different types of the heterogeneous spectrum of hepatoblastoma, in terms of different chemotherapeutic protocols and timing as well as type and extent of surgery, may become the basis of successful treatment in the more complex or advanced types of hepatoblastoma. Keywords hepatoblastoma, liver resection, liver transplantation, pretreatment extent of disease staging
INTRODUCTION Although rare, with a yearly incidence of five cases per million in children under the age of 4 years, hepatoblastoma is the most common malignant liver tumor in the pediatric population [1]. Incidence nearly doubled between 1975 and 2009 [2] and has increased over the past two decades by roughly 4% per year between 1992 and 2004 [3]. Staging is currently based on computed tomography (CT) or MRI using the pretreatment extent of disease (PRETEXT) system and reassessment after neoadjuvant chemotherapy, termed the posttreatment extent of disease (POSTTEXT) [4]. The PRETEXT system is being used in all four pediatric liver study groups: Children’s Oncology Group (COG), International Childhood Liver Tumor Strategy Group (SIOPEL), German Society of Pediatric Oncology and Hematology (GPOH), and Japanese Study Group for Pediatric Liver Tumor (JPLT). Surgical resection remains the cornerstone of cure in all groups; however, recommended timing of chemotherapy varies. The evolution of chemotherapeutic www.co-pediatrics.com
agents, predominantly cisplatin-based treatments used in neoadjuvant and adjuvant protocols, contributed largely to the decrease in mortality among hepatoblastoma patients over the past several decades [5,6 ]. The overall 5-year-survival rate based on current treatment regimens is 70% [7]. Technical challenges remain in extensive hepatoblastoma with vascular invasion, multifocality, and metastatic disease. In advanced disease, data are lacking in regards to the use of primary transplant versus complex resection as the most appropriate &&
Department of Pediatric Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA Correspondence to Gregory M. Tiao, MD, Department of Pediatric Surgery, Cincinnati Children’s Hospital and Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. Tel: +1 513 636 3334; e-mail: [email protected] Nathalie Kremer and Ashley E. Walther contributed equally to the writing of the article.
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Management of hepatoblastoma: an update Kremer et al.
KEY POINTS PRETEXT staging is internationally used to assess for degree of anatomic involvement and resectability of hepatoblastoma. Patients stages PRETEXT I and II can be primarily resected after chemotherapy. Patients stages PRETEXT III and IV with vascular involvement should be considered candidates for primary liver transplant.
surgical approach. These challenges are of pressing importance, as survival rates for patients with advanced hepatoblastoma are still relatively low [6 ,8 ]. An international consensus classification system that would allow more standardized consistent care is the next step in addressing many of these challenges. &&
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best prognosis has been demonstrated in pure fetal type epithelial hepatoblastoma with low mitotic activity, which occurs in fewer than 7% of patients [14] but may be resected without the need for chemotherapy [16]. The SCUD variant of epithelial hepatoblastoma occurs in about 5% of all cases and has the worst prognosis [14]. An overview of the current hepatoblastoma classification according to the Los Angeles COG liver tumors symposium is outlined in Table 1 [17 ]. Current immunohistochemistry stains utilized in the workup and diagnosis of hepatoblastoma include pancytokeratin, vimentin, glypican 3, a-fetoprotein (AFP), b-catenin, glutamine synthetase, Hep-Par1, and integrase interactor 1 (INI1) [18 ]. In addition, karyotypic and molecular profiling of these tumors has allowed for additional subgrouping. Pathways identified to be involved in hepatoblastoma growth include Wnt (CTNNB1 and APC genes), Sonic Hedgehog, NotchSignaling, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), mitogen activated protein kinase, and insulin-like growth factor [19 ]. The implications for tumor behavior and subsequent impact on risk stratification and treatment recommendations are not identified yet. For example, ongoing discussion exists about INI 1-negative SCUD epithelial hepatoblastoma that shows rhabdoid features and low AFP expression, as these tumors may require an alternative chemotherapy regimen [20]. To ensure optimal treatment of hepatoblastoma, with the ultimate goal to individualize treatment, it is currently recommended that all patients with a liver mass undergo biopsy. Adequate tissue samples may come from percutaneous needle biopsy, laparoscopic core needle or wedge biopsy, or open core needle or wedge biopsy. Fine needle aspiration should be avoided, as insufficient tissue is obtained using this methodology. Close cooperation between the radiologist and the surgeon is necessary to achieve a quality sample and to avoid seeding of the track. Samples should be sent fresh to pathology whenever possible. The specifics on biopsy technique, amount, and sample size have been described previously, but a minimum of 5–10 cores measuring 1 x 0.3 cm in size is required to make the diagnosis [18 ]. A detailed description of the biopsy location is mandatory. However, given the characteristic microscopic heterogeneity of hepatoblastoma, a biopsy that samples approximately 3/100 000 of the entire tumor (an estimated 15 mg versus 500 g before treatment, on average) is only rarely (8–10%) representative of the rest of the tumor, and therefore biopsy before chemotherapy will most likely not implement immediate changes in the international protocols that recommend chemotherapy before surgery for all hepatoblastoma &&
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Epidemiology Approximately 150 children in the United States are diagnosed with hepatoblastoma each year, most of them under the age of 5 years, with the mean age at diagnosis being 19 months [9 ]. There is a slight male predominance. An increased risk of hepatoblastoma is associated with Beckwith–Wiedemann Syndrome [10] and Familial Adenomatous Polyposis [11]. Additionally, a total of 12 cases of hepatoblastoma occurring in children with trisomy 18 have been reported in the literature [12 ]. Association with other inherited disorders is based only on isolated case reports. As medical care of premature infants has improved, a strong association of hepatoblastoma with very low birth weight has emerged, which may contribute to the overall increase in hepatoblastoma incidence [13 ]. Other risk factors include infertility treatment, preeclampsia, high maternal prepregnancy weight, oligohydramnios and polyhydramnios, parental tobacco use, and parental occupational exposure to metals [3]. &
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Tumor biology Hepatoblastoma is an embryonal tumor that usually displays morphologic features of many cell types. Two histologic types are predominant: epithelial and mixed (epithelial and mesenchymal). Early studies report that a majority of hepatoblastoma tumors are epithelial (56–67%) [14]. These epithelial tumors are further subdivided into pure fetal (31%), embryonal (19%), macrotrabecular (3%), and small-cell undifferentiated (SCUD) (3%) [15]. The
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Surgery Table 1. Hepatoblastoma histologic subtypes with associated significance and clinical markers Hepatoblastoma histological subtypes
Potential clinically significant markers
Clinical significance
Epithelial Fetal Pure fetal with low mitotic activity
Requires complete surgical resection only, favorable prognosis
Fetal, mitotically active
Mixed cell types, often transition to embryonal and SCUD
Pleomorphic, poorly differentiated
Uncommon, often found in metastases, relapse tumor and postchemotherapy specimen, also known as transitional, anaplastic or HCC-like, unfavorable prognosis
Embryonal macrotrabecular
Rare ( 3 years and upfront resection not feasible
SIOPEL/GPOH
Recommended at diagnosis
JPLT-2
Recommended at diagnosis in PRETEXT II–IV
Recommended in all liver tumors
X X
PRETEXT II–IV Biopsy
Biopsy
X
SIOPEL/GPOH Standard risk
PRETEXT I
Neoadjuvant followed by resection and then adjuvant chemotherapy
Recommended if patient is: < 6 months; > 3 years and if no upfront resection feasible
Intermediate risk
Study group
High risk
PRETEXT I–III; serum AFP > 100 ng/ml
Low risk
JPLT-2
Intermediate risk
X
Recommended Neoadjuvant chemotherapy resection
Resection
Resection
No chemotherapy
Adjuvant chemotherapy
Adjuvant chemotherapy
Very low risk
Low risk
Intermediate and high risk
Standard and high risk PRETEXT I
PRETEXT II–IV
AFP, a-fetoprotein; COG, Children’s Oncology Group; JPLT-2, Japanese Study Group for Pediatric Liver Tumor; PRETEXT, pretreatment extent of disease; SCUD, small-cell undifferentiated; SIOPEL/GPOH, International Childhood Liver Tumor Strategy Group/German Society of Pediatric Oncology and Hematology.
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reviewed in previous publications. In brief, PRETEXT describes tumor extent prior to treatment based on Couinaud’s system of segmentation, vascular involvement, extrahepatic disease, and metastases as seen on CT or MRI [4]. Staging is assigned using the number of sections affected by tumor growth, with further criteria, including involvement of the caudate lobe (C), extrahepatic abdominal disease (E), multifocal tumor (F), tumor rupture or intraperitoneal hemorrhage (H), distant metastasis (M), lymph node involvement (N), involvement of the portal vein (P), and venous involvement of the inferior vena cava or intrahepatic veins (V) [4]. Although PRETEXT has been demonstrated to have prognostic value [30], the ability of this system to predict resectability has not been shown and is one of the secondary outcomes being studied in an ongoing COG clinical trial, AHEP0731 (ClinicalTrials.gov identifier NCT0098046). Moreover, improved understanding of hepatoblastoma tumor biology suggests that these factors will at some point also have to be included in the future risk stratification systems. If neoadjuvant therapy is administered, POSTTEXT staging should be performed prior to surgical resection [4].
Chemotherapy The introduction of the platinum-based chemotherapeutic agent cisplatin was instrumental in improving the survival of children with hepatoblastoma, including the induction of tumor regression to allow surgical resection in patients initially deemed unresectable [31]. Cisplatin remains the core chemotherapeutic agent in all four liver study group treatment protocols. The COG standard regimen consists of cisplatin, 5-fluorouracil, and vincristine (C5V) [32 ]. The guidelines for the current COG trial, AHEP0731, recommend C5V for low-risk or C5V and doxorubicin for intermediate-risk and high-risk patients [33 ]. SIOPEL and GPOH currently recommend preoperative chemotherapy for every patient. Previous SIOPEL studies have supported neoadjuvant chemotherapy with cisplatin as a monotherapeutic agent for standard risk [5] or the use of a novel protocol incorporating dosedense cisplatin given weekly to patients with highrisk hepatoblastoma [34 ]. JPLT protocols depend on PRETEXT staging and utilize cisplatin and pirarubicin in the postoperative period for PRETEXT I or in the neoadjuvant and adjuvant setting for PRETEXT II–IV [35]. Chemotherapy is not indicated in patients with a tumor of pure fetal histology, as surgical resection alone is curative [16]. Chemotherapy cycles may be repeated for further downstaging of very large or multifocal tumors; however, there is &&
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a limit to the amount of chemotherapy that can be administered before toxicity issues become significant. Side-effects of current chemotherapy regimens include hematologic toxicity, including neutropenia, and ototoxicity. With better diagnosis, treatment, and survival of patients with hepatoblastoma, more advanced or relapsed disease is becoming more common. Hepatoblastoma can develop drug resistance after four cycles of chemotherapy and should be resected prior to this occurrence [36]. A poor response or relapse may partially reflect a still unsatisfactory understanding of the heterogeneous tumor biology of hepatoblastoma.
Surgery Although the treatment approach to hepatoblastoma is multimodal, complete surgical resection is required to achieve a definitive cure. In patients who present with advanced disease and an unfavorable prognosis, chemotherapy is administered with the ultimate goal to achieve resectability. To establish consistency and assess for resectability, the four aforementioned liver study group protocols have adopted the PRETEXT staging system to achieve an international standard. The understanding of liver anatomy and extensive hepatic operative experience is mandatory in the treatment of hepatoblastoma, as the ability to maintain appropriate blood inflow and outflow of the remaining liver at all times is crucial in tumor resection. The Brisbane classification standardized terminology defines liver resection based on two hemilivers, four sections, and eight segments (as defined by Couinaud). The terminology differentiates between trisectionectomy (extended resection of three sections), right or left (hemi) hepatectomy, sectionectomy, and segmentectomy (Fig. 1) [37 ]. The Brisbane classification has become the most common nomenclature used to describe liver resections. Surgical resection to achieve extirpation of a hepatoblastoma includes segmentectomy, sectionectomy, and/or hemihepatectomy for PRETEXT I and II, trisectionectomy for PRETEXT III and IV or transplantation for tumors with bilobar portal vein or hepatic vein and inferior vena cava invasion or extensive loss of normal parenchyma [38 ,39]. Technical challenges encountered in hepatoblastoma resection include bleeding, wound infection, liver failure, postoperative bile leak, biliary stricture, and sequelae of intraoperative inflow and outflow obstruction. Improvements in surgical technique, such as vascular inflow occlusion with the Pringle maneuver, outflow obstruction with a suprahepatic clamp, adherence to strict anatomic resection, and the use of specialized equipment, &&
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Right/left trisectionectomy or extended right/left (hemi) hepatectomy
Right/left (hemi) hepatectomy
Sectionectomy (right posterior, right anterior, left medial and left lateral sections)
Segmentectomy (according to Couinaud segments)
FIGURE 1. Resectional terminology for extended resection, excision of a hemiliver, excision of a segment, or excision of a section (adapted from [37 ]). &&
including ultrasonic dissection devices (CUSA) (Integra, Painsboro, New Jersey), Ligasure, Harmonic scalpel, and argon beam coagulator, are utilized to perform a safe resection. Vascular occlusion to reduce blood loss has not shown any adverse effect on liver function, and a total exclusion time of 30–60 min in pediatric patients is considered safe and effective [40]. The current recommendations of all four study group protocols are summarized in Table 2. Per COG protocol, PRETEXT I and II lesions should be resected at the time of diagnosis and followed with adjuvant chemotherapy. Tumors with pure fetal histology and low mitotic activity require only surgical resection, as this intervention provides adequate treatment [16]. PRETEXT III and
IV lesions should undergo neoadjuvant chemotherapy. POSTTEXT I, II, and III tumors without venous (V) and portal vein (P) involvement also undergo resection. Multifocal or Vþ/Pþ PRETEXT III lesions and PRETEXT IV should be referred to a facility with the ability for complex hepatic resection or liver transplant, if possible before or during neoadjuvant chemotherapy [38 ]. Adjuvant chemotherapy is also administered after resection of more advanced tumors. The European protocols (SIOPEL 3 and HB99) recommend neoadjuvant chemotherapy, regardless of PRETEXT staging, followed by restaging and tumor resection based on POSTTEXT assessment [28,41]. The HB99 trial makes an exception for
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small, nonmetastatic liver tumors (usually PRETEXT I) and recommends primary resection without neoadjuvant chemotherapy [28]. Similarly, the JPLT protocol recommends that nonmetastatic PRETEXT I tumors are resected upfront, whereas PRETEXT II–IV lesions are treated first with neoadjuvant chemotherapy [35]. Chemotherapy is also given postoperatively in these liver study group protocols. In a large retrospective study of the SIOPEL group, recurrent disease was reported in fewer than 12% of all patients who achieved a complete response, with a median time to relapse of 12 months after initial diagnosis. Half of the relapses were staged either PRETEXT III or IV at initial diagnosis [42 ]. In any protocol, if a tumor is deemed unresectable on initial workup and chemotherapy is administered preoperatively, restaging should occur no earlier than during the second cycle of chemotherapy [43 ]. Also, it is important that the tumor response and behavior be assessed by AFP levels and reimaging throughout chemotherapy administration, as these may indicate tumors with poor prognosis. When a patient presents with primary tumor rupture, initial control of hemorrhage followed by a staged hepatectomy after chemotherapy allows effective management through reduction of tumor volume in the liver as well as possible seeding of the peritoneum at time of rupture [44]. Pediatric patients with unresectable hepatoblastoma are candidates for liver transplantation. These include patients with disease involvement of the entire liver, extensive multifocal disease, or vascular invasion. Children undergoing transplant should receive neoadjuvant and adjuvant chemotherapy. Transplantation is indicated in the setting of chemotherapy responsive multifocal disease, as radiographic imaging cannot ensure complete resolution of microscopic foci. Patients with metastases at the time of diagnosis are still eligible for transplantation if these lesions regress with preoperative chemotherapy or undergo surgical resection [45,46]. It is also useful in the setting of intrahepatic recurrence or residual tumor after attempt at partial hepatectomy. Primary liver transplant, however, has a superior survival rate (approximately 80%) in advanced hepatoblastoma versus a lower survival rate (30%) in children who underwent rescue transplant when conventional surgical resection failed [47]. In a retrospective review of the Surveillance, Epidemiology, and End Results database, 318 pediatric hepatoblastoma patients underwent complex resection or liver transplantation with no difference in survival [8 ]. A randomized trial comparing complex resection and primary transplant for advanced hepatoblastoma has not yet been performed; the decision for the best approach lies in
the hands of the surgical team. Unresectable or progressive extrahepatic metastatic disease, including persistent pulmonary lesions that do not respond to chemotherapy, is an absolute contraindication to transplant. The most common complication after liver transplantation is vascular thrombosis, followed by local recurrence, pulmonary metastatic disease, and bile leak. Preexisting pulmonary metastatic disease before liver transplant may be missed using conventional CT imaging, so that PET-CT imaging is recommended [48 ]. Postoperative management of these children, including immunosuppression regimens, requires further investigation. &
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CONCLUSION Hepatoblastoma is a rare pediatric malignancy. However, as it is the most common liver tumor in children, further understanding of the diagnosis and optimal treatment is necessary for the management of these cases. Appreciation of tumor biology, including histologic type and molecular pathways involved, may provide opportunities for individualized treatment plans. One approach to optimizing care is through collaboration of the four liver study groups as well as standardization of staging through the use of PRETEXT. The role of neoadjuvant chemotherapy, specific chemotherapeutic regimens, surgical approach to resection, and the use of liver transplantation are areas requiring further study. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Darbari A, Sabin KM, Shapiro CN, Schwarz KB. Epidemiology of primary hepatic malignancies in U.S. children. Hepatology 2003; 38:560–566. 2. Howlander N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2010. Bethesda, Maryland: National Cancer Institute; 2013 ; http:// seer.cancer.gov/csr/1975_2010/. [Accessed 18 December 2013] 3. Linabery AM, Ross JA. Trends in childhood cancer incidence in the U.S. (1992-2004). Cancer 2008; 112:416–432. 4. Roebuck DJ, Aronson D, Clapuyt P, et al. 2005 PRETEXT: a revised staging system for primary malignant liver tumours of childhood developed by the SIOPEL group. Pediatr Radiol 2007; 37:123–132; quiz 249–250. 5. Perilongo G, Maibach R, Shafford E, et al. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 2009; 361: 1662–1670. 6. Allan BJ, Parikh PP, Diaz S, et al. Predictors of survival and incidence of && hepatoblastoma in the paediatric population. HPB 2013; 15:741–746. Review of a total of 606 patients who were diagnosed with hepatoblastoma in the last 40 years and outlines the developments in incidence, risk factors, and outcomes, showing that survival significantly improved.
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Management of hepatoblastoma: an update Kremer et al. 7. Ortega JA, Douglass EC, Feusner JH, et al. Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: a report from the Children’s Cancer Group and the Pediatric Oncology Group. J Clin Oncol 2000; 18:2665–2675. 8. McAteer JP, Goldin AB, Healey PJ, Gow KW. Surgical treatment of primary & liver tumors in children: outcomes analysis of resection and transplantation in the SEER database. Pediatr Transplant 2013; 17:744–750. The first comparative study evaluating outcomes after hepatic resection versus liver transplant in the pediatric population. 9. Rodriguez-Galindo C, Krailo M, Frazier L, et al. Children’s Oncology Group’s & 2013 blueprint for research: rare tumors. Pediatr Blood Cancer 2013; 60: 1016–1021. A review of completed clinical studies and the development of large international collaborations for rare tumors, including hepatoblastoma. 10. DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 1998; 132 (3 Pt 1):398–400. 11. Giardiello FM, Offerhaus GJ, Krush AJ, et al. Risk of hepatoblastoma in familial adenomatous polyposis. J Pediatr 1991; 119:766–768. 12. Tan ZH, Lai A, Chen CK, et al. Association of trisomy 18 with hepatoblastoma & and its implications. Eur J Pediatr 2013. [Epub ahead of print] Case report reviewing the occurrence of trisomy 18 in association with hepatoblastoma and presents the two most recent patients. 13. Spector LG, Birch J. The epidemiology of hepatoblastoma. Pediatr Blood && Cancer 2012; 59:776–779. Overview of the most recent developments in the epidemiology of hepatoblastoma, including risk factors, such as very low birth weight, paternal smoking, and diagnosis of Beckwith–Wiedemann Syndrome. 14. Weinberg AG, Finegold MJ. Primary hepatic tumors of childhood. Hum Pathol 1983; 14:512–537. 15. Herzog CE, Andrassy RJ, Eftekhari F. Childhood cancers: hepatoblastoma. Oncologist 2000; 5:445–453. 16. Malogolowkin MH, Katzenstein HM, Meyers RL, et al. Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children’s Oncology Group. J Clin Oncol 2011; 29:3301– 3306. 17. Lopez-Terrada D, Alaggio R, de Davila MT, et al. Towards an international && pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Modern Pathol 2013; 27 (3):472–491. Summary of the most recent developments in identification of different subtypes of hepatoblastoma, including clinical implications and molecular markers, currently under investigation. 18. Tanaka Y, Inoue T, Horie H. International pediatric liver cancer pathological & classification: current trend. Int J Clin Oncol 2013; 18:946–954. Summarizes the current terminology of the different subtypes of hepatoblastoma. 19. Purcell R, Childs M, Maibach R, et al. Potential biomarkers for hepatoblas& toma: results from the SIOPEL-3 study. Eur J Cancer 2012; 48:1853–1859. Overview of the most recent molecular markers currently being investigated for further classification and risk stratification of hepatoblastoma, including b-catenin, E-cadherin, Cyclin D1, and Ki-67. 20. Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, et al. Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr Blood Cancer 2009; 52:328–334. 21. Maibach R, Roebuck D, Brugieres L, et al. Prognostic stratification for children & with hepatoblastoma: the SIOPEL experience. Eur J Cancer 2012; 48:1543– 1549. Examination of PRETEXT staging, metastatic disease, AFP, and histology as outcome predictors for hepatoblastoma as used during the most recent SIOPEL trials. 22. Fukuzawa H, Urushihara N, Fukumoto K, et al. Can we predict the prognosis of & resectable hepatoblastoma from serum alpha-fetoprotein response during preoperative chemotherapy? Pediatr Surg Int 2012; 28:887–891. Study evaluating AFP levels of 14 hepatoblastoma patients and monitored them throughout the treatment course, showing that a large, early decrease of AFP levels is a strong indicator of good prognosis. 23. McCarville MB, Roebuck DJ. Diagnosis and staging of hepatoblastoma: imaging aspects. Pediatr Blood Cancer 2012; 59:793–799. 24. Meyers AB, Towbin AJ, Serai S, et al. Characterization of pediatric liver lesions with gadoxetate disodium. Pediatr Radiol 2011; 41:1183–1197. 25. Meyers AB, Towbin AJ, Geller JI, Podberesky DJ. Hepatoblastoma imaging with gadoxetate disodium-enhanced MRI: typical, atypical, pre and posttreatment evaluation. Pediatr Radiol 2012; 42:859–866. 26. Cistaro A, Treglia G, Pagano M, et al. A comparison between (1)(8)F-FDG & PET/CT imaging and biological and radiological findings in restaging of hepatoblastoma patients. BioMed Res Int 2013; 2013:709037. Study comparing imaging for restaging of hepatoblastoma patients suggesting that PET-CT may be more sensitive in identifying metastatic disease or recurrence. 27. Hishiki T. Current therapeutic strategies for childhood hepatic tumors: surgi& cal and interventional treatments for hepatoblastoma. Int J Clin Oncol 2013; 18:962–968. Review of current standards and developments in hepatoblastoma treatment according to the Japanese study protocol.
28. Haeberle B, Schweinitz D. Treatment of hepatoblastoma in the German cooperative pediatric liver tumor studies. Front Biosci 2012; 4:493–498. 29. Malogolowkin MH, Katzenstein HM, Krailo M, Meyers RL. Treatment of hepatoblastoma: the North American cooperative group experience. Front Biosci 2012; 4:1717–1723. 30. Meyers RL, Rowland JR, Krailo M, et al. Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2009; 53:1016–1022. 31. Ortega JA, Krailo MD, Haas JE, et al. Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol 1991; 9:2167–2176. 32. Watanabe K. Current chemotherapeutic approaches for hepatoblastoma. Int J && Clin Oncol 2013; 18:955–961. A comparison and review of the current chemotherapeutic regimen by study group and risk stratification. 33. Czauderna P, Lopez-Terrada D, Hiyama E, et al. Hepatoblastoma state of the && art: pathology, genetics, risk stratification, and chemotherapy. Curr Opin Pediatr 2013; 26:19–28. Summary of the results of hepatoblastoma cooperative trials since 1989 and overview of changes in outcomes and chemotherapy protocols. 34. Zsiros J, Brugieres L, Brock P, et al. Dose-dense cisplatin-based chemo& therapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 2013; 14:834–842. The result of the SIOPEL-4 study shows improved outcomes for 61 high-risk hepatoblastoma patients after treatment with an adjusted dose-dense cisplatinbased chemotherapy and radical surgery. 35. Hishiki T, Matsunaga T, Sasaki F, et al. Outcome of hepatoblastomas treated using the Japanese Study Group for Pediatric Liver Tumor (JPLT) protocol-2: report from the JPLT. Pediatr Surg Int 2011; 27:1–8. 36. von Schweinitz D, Hecker H, Harms D, et al. Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB-89. J Pediatr Surg 1995; 30:845–852. 37. Strasberg SM, Phillips C. Use and dissemination of the Brisbane 2000 && nomenclature of liver anatomy and resections. Ann Surg 2013; 257:377– 382. An overview of the terminology used to describe liver resection for hepatoblastoma and review of the development and use of the Brisbane nomenclature for standardized description of hepatic resection. 38. Meyers RL, Tiao GM, Dunn SP, Langham MR Jr. Liver transplantation in the & management of unresectable hepatoblastoma in children. Front Biosci 2012; 4:1293–1302. The article addresses current controversies in the decision process for liver transplant in advanced hepatoblastoma. 39. Czauderna P, Otte JB, Aronson DC, et al. Guidelines for surgical treatment of hepatoblastoma in the modern era: recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL). Eur J Cancer 2005; 41:1031–1036. 40. Szavay PO, Luithle T, Warmann SW, et al. Impact of pedicle clamping in pediatric liver resection. Surg Oncol 2008; 17:17–22. 41. Czauderna P. Hepatoblastoma throughout SIOPEL trials: clinical lessons learnt. Front Biosci (Elite Ed) 2012; 4:470–479. 42. Semeraro M, Branchereau S, Maibach R, et al. Relapses in hepatoblastoma & patients: clinical characteristics and outcome – experience of the International Childhood Liver Tumour Strategy Group (SIOPEL). Eur J Cancer 2013; 49:915–922. Review of the 59 patients who relapsed after having received treatment for hepatoblastoma during SIOPEL trials 1–3, with an overall relapse rate of 12%. 43. Tajiri T, Kimura O, Fumino S, et al. Surgical strategies for unresectable & hepatoblastomas. J Pediatr Surg 2012; 47:2194–2198. Summary of the application of PRETEXT staging according to the JPLT protocol and respective recommendation for timing and extent of resection. 44. Madanur MA, Battula N, Davenport M, et al. Staged resection for a ruptured hepatoblastoma: a 6-year follow-up. Pediatr Surg Int 2007; 23:609–611. 45. Otte JB, de Ville de Goyet J, Reding R. Liver transplantation for hepatoblastoma: indications and contraindications in the modern era. Pediatr Transplant 2005; 9:557–565. 46. Meyers RL, Katzenstein HM, Krailo M, et al. Surgical resection of pulmonary metastatic lesions in children with hepatoblastoma. J Pediatr Surg 2007; 42:2050–2056. 47. Otte JB, Pritchard J, Aronson DC, et al. Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 2004; 42:74–83. 48. Ruth ND, Kelly D, Sharif K, et al. Rejection is less common in children & undergoing liver transplantation for hepatoblastoma. Pediatr Transplant 2013; 18:52–57. Review of 20 patients who underwent liver transplant for biliary atresia or hepatoblastoma indicating that outcomes for children undergoing primary liver transplant for hepatoblastoma are favorable, with an acute rejection rate of 50%.
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