The focus of this review is primary liver tumors that may necessitate transplantation for cure or prevention of disseminated neoplasia. Almost all liver masses in children are surgically treated, either primarily or following systemic chemotherapy. The extraordinary functional reserve and regenerative capacity of the liver often permits extensive resections, but total extirpation may be required because of intrahepatic dissemination with multilobar masses, a perihilar location, or the involvement of major veins or to prevent the development of new malignancies on a background of underlying inflammatory or metabolic disease. The conditions that eventuate in this choice of therapy, when and how to accomplish it, and the medical and surgical consequences for children of transplantation for tumors are described.
Liver tumors in childhood are rare and are typically not detected clinically until they reach a large size and often spread within the organ or metastasize. This can make surgical resection problematic, and almost all of them require extirpation for cure. With very effective chemotherapy for hepatoblastoma and to some extent for sarcomas, many cancers can be shrunk to permit partial hepatectomy, but for most hepatocarcinomas, some of the other malignancies, and even some benign proliferations, their location at the hilum and multiplicity of masses in multiple lobes make transplantation the treatment of choice. Major advances in diagnostic imaging, especially enhanced computed tomography and magnetic resonance imaging, permit a preoperative choice of resection versus transplantation to be achieved in almost all instances, and for the remainder, intraoperative ultrasonography can further help to determine the most desirable approach. The outcome is very much better in the case of hepatoblastoma when transplantation is a primary modality rather than following unsuccessful attempts at resection. In this review, transplantation for liver tumors in children is considered from all aspects, including the importance of screening for tumors whenever possible to avoid the need for transplantation. Liver Transpl 14:1545–1556, 2008. © 2008 AASLD.
LIVER TUMORS IN CHILDREN
There are several excellent recent reviews of liver tumors in children.1–5 Malignant liver tumors account for approximately 1.1% of all childhood tumors in the United States according to the Surveillance, Epidemiology, and End Results (SEER) program cancer registries, with an annual incidence rate of 1.8 cases per million children younger than 15 years (http://seer.cancer.gov). Approximately two-thirds of all liver masses occurring in children are malignant. Eighty percent of 123 children in the United States registered with malignant liver tumors in 2000 had hepatoblastoma (HB), and they accounted for 91% of primary hepatic malignancies in children less than 5 years of age6 (Fig. 1A). The mean age at diagnosis was 19 months, and the median age was 16 months in the Pediatric Oncology Group series of 106 cases accrued from biological studies.7 Only 5% of cases occurred in children older than 4 years of age. Several sources have shown an increase in the number of cases of HB during the past 2 decades. In the SEER data comparing 1973-1977 with 1993-1997, HB rates increased from 0.6 to 1.2 per million, whereas pediatric hepatocarcinoma rates decreased (from 0.45 to 0.29 per million).6 In the period from 1979 to 1981, liver cancers represented 2% of all cancers in infants younger than 1 year, whereas a decade later, liver cancers increased to 4% of all cancers in infants. Primary liver tumors accounted for 6% to 8% of congenital tumors in Isaacs's review of 265 neoplasms discovered within 30 days of birth.8 Survival is significantly better for patients with HB resectable at diagnosis (stages I and II > 95%) in comparison with patients with unresectable (stage III) or metastatic (stage IV) tumors (69% and 37%, respectively), according to the US Children's Oncology Group.7 For patients with resectable disease, the 5-year event-free survival is 83% versus 41% for those who had residual tumor after surgery. Overall survival rates were similar in the European Pediatric Liver Tumor Group study [Societé Internationale d'Oncologie Pediatrique (SIOPEL) 2], with a 3-year overall survival of 91% for patients with standard-risk tumors and a 3-year overall survival of 53% for patients with high-risk tumors.9
Hepatocellular carcinoma (HCC) is the most common hepatic malignancy of adolescence10 (Fig. 1B). In children between 15 and 19 years of age, HCC accounted for 87% of all malignant liver tumors, but 12.8% occurred in children under the age of 5 years.6 Patients with the fibrolamellar variant of HCC are more likely to be over 10 years of age.11 This form of HCC is not preceded by cirrhosis, chronic inflammation, or metabolic disease, unlike most ordinary HCC. Children with HCC included in the last Children's Oncology Group liver tumor trial showed a 5-year overall survival rate for patients with stage 1 (resectable) tumors of 88% (n = 8), whereas patients with stage 3 and 4 tumors had dismal rates of 23% (n = 25) and 10% (n = 13).10 A SIOPEL (Childhood Liver Tumours Strategy Group) trial showed similar findings.12 Cholangiocarcinoma is very rare in children but has been observed in cases of chronic cholestasis as early as 4 years.13, 14
Sarcomas in children take 1 of 3 forms: (1) rhabdomyosarcoma, which arises in relation to the larger bile ducts, typically in early childhood; (2) embryonal or undifferentiated sarcoma, which is usually detected in children between 6 and 10 years and occasionally is preceded by or occurs simultaneously with the benign mesenchymal hamartoma; and (3) angiosarcoma, which is extremely rare and even more rarely is antedated by a benign hemangioendothelioma in infancy.5 Biliary rhabdomyosarcoma presents a surgical challenge, and in a review of 25 patients over 26 years, gross total resection was achieved in only 6; only 2 of those had negative margins. However, the 5-year survival rate was 75% because of the tumor's sensitivity to chemotherapy and radiation. Therefore, heroic resections or transplants are not generally recommended.15 Undifferentiated sarcoma recently has been successfully treated.16 In a series of 17 patients, 10 were alive in the first complete response after a combination of resection and chemotherapy.17 Angiosarcoma is a very aggressive tumor that often presents in both lobes, typically rendering complete resection highly unlikely. It is generally chemoresistant, but rare successes have been reported.18
Hemangiomas and hemangioendotheliomas are the most common nonmalignant vascular lesions of children. They can range from small incidental findings on scans done for other reasons to giant or multifocal lesions whose clinical manifestations may include congestive heart failure due to arteriovenous shunting, jaundice due to obstruction, consumptive coagulopathy due to Kasabach-Merritt syndrome, and medically resistant hypothyroidism.5 Although not malignant, these lesions have been treated with medical therapy, chemotherapy, surgery, or a combination of these with some success. Therapy used in individual cases includes vincristine, cyclophosphamide, alpha-2 interferon, amino-caproic acid, and low-molecular-weight heparin.19 Transplantation has been used in cases in which medical management has failed and the lesion is too large or multifocal for primary resection20, 21 (Fig. 2).
Adenomas are benign tumors whose incidence has fallen dramatically after peaking in response to high-dose estrogens in oral contraceptives.5 They are still observed de novo or in children of either gender with glycogen storage disease, usually due to glucose 6-phosphatase deficiency (type 1a) or Fanconi anemia. The occasional multiplicity of nodules and the rare examples of transformation to HCC, particularly in males, necessitate life-long screening and promote surgical management and, if necessary, transplantation.
SCREENING FOR POSSIBLE NEOPLASIA
Detection of a liver tumor prior to dissemination and/or massive growth is the single most important management tool for all tumor types at all ages. Transplantation is required only when surgical resection cannot be accomplished. Therefore, awareness of antecedent conditions that permit screening is essential.
There are several conditions for which screening of children for primary liver cancer is recommended by virtue of the attendant risk (Table 1). However, there is no formal guideline for the frequency and manner of screening at this time. Hepatitis B virus can cause HCC as early as age 4 following perinatal transmission from infected carrier mothers.5 Vaccination and perinatal administration of hepatitis B immunoglobulin have already reduced the incidence dramatically.22 In contrast, extraordinary advances in neonatal care in the past 25 years have led to a wholly new population of children, the long-term survivors of birth as early as 22 to 23 weeks of gestation with a weight less than 1000 g.23 In addition to many other chronic problems, they have extraordinary susceptibility to HB. A relative risk for such prematures versus term babies of 16- to 52-fold is recognized around the world.24, 25 HB occurs at the same age as HB in term babies or later.26 It is estimated that 1 of 200 extremely low birth weight prematures will develop HB.27
|Extreme prematurity (especially <1500 g)|
|Hepatitis B virus|
|Familial adenomatosis polyposis|
|Glycogen storage diseases (mainly type I)|
|Progressive familial intrahepatic cholestasis type 2 (ABCB11 disease)|
Screening of infants with hemihypertrophy or hemiaplasia, as part of the Beckwith-Wiedemann overgrowth syndrome, has been carried out for many years via ultrasound to detect intra-abdominal malignancies28 (Fig. 3). These include Wilms' tumor and adrenocortical carcinoma, in addition to the less common HB, which has a relative risk of 2280. HB is not the only proliferative lesion of the Beckwith-Wiedemann syndrome liver, as hemangioendothelioma and mesenchymal hamartoma have also been observed, either concurrently or sequentially.
In familial adenomatous polyposis (FAP), the first manifestation of an autosomal dominant mutation in a family may be HB in a baby, with the colonic polyps detected only afterwards in a parent. The relative risk for children in such cohorts is 800-fold, but many examples are due to new germ-line mutations at 5q21,22 or only in the tumor.29 A series from the Children's Oncology Group focused primarily on known FAP families but raised the issue of de novo cases or the potential for infants of parents too young to be aware of the symptoms of FAP themselves.30 The largest report of sporadic cases looked at 50 patients and found 5 germ-line antigen-presenting cell (APC) mutations. This 10% incidence led the authors to recommend routine screening for APC mutations in all cases of sporadic HB. Screening for APC mutations should include both a screen for APC deletion or duplication and sequencing through the gene itself. In the only prospective screening study to date, 20 children with confirmed or suspected FAP were followed for 10 years by ultrasonography, and no tumors were detected.31 In FAP, other forms of hepatocellular neoplasia are also observed, including adenoma and HCC, as well as biliary adenomas.
The timelines of the development of these various cancers in distinct tissues are not linked, and therefore, surveillance for these cancers needs to continue throughout the patient's life.
Chronic cholestatic syndromes may be the substrate for liver cancers, with HB, cholangiocarcinoma, and HCC having been described in progressive familial intrahepatic cholestasis type 2 or bile-salt excretory protein deficiency due to mutations in ABCB1114, 32 and in the Alagille syndrome of a paucity of intrahepatic bile ducts due to Jagged 1 or NOTCH mutations. HB and HCC have been seen in the explants of infants with cirrhosis due to biliary atresia as early as 1 year.5, 33 Also, we have observed HB in three 2-year olds with congenital hepatic fibrosis and autosomal recessive polycystic disease.
On the basis of the growth rate of HCC and with the aim of detecting tumors when they are <3 cm in diameter, the American Association for the Study of Liver Disease and the European Association for the Study of the Liver recommend screening ultrasound examinations at 6-month intervals, and some institutions shorten this interval to 3 months when the patient is on a transplant waiting list.34 These organizations have also published diagnostic criteria for liver nodules detected during the screening process.35, 36 HCC can be diagnosed noninvasively by computed tomography (CT) or magnetic resonance imaging (MRI) if a lesion >2 cm in diameter within a cirrhotic liver demonstrates rapid contrast enhancement during the arterial phase and washout on the delayed venous phase. These guidelines were developed for cirrhotic adults, and there are no validated evidence-based guidelines for screening for tumors in children and adolescents with chronic liver disease.
The incidence of HCC in children with diffuse liver disease is unknown. According to adult data, ultrasound is insensitive for the diagnosis of HCC in the cirrhotic liver and should not be used for the detection of focal liver lesions in this setting (Fig. 4). MRI is more sensitive than multidetector 3-phase CT for the diagnosis of regenerative and dysplastic nodules and is comparable to CT for the detection of HCC. There is a lower false-positive rate with MRI.37 Interval growth is probably the best indicator of malignancy, and there is a definite need for the establishment of protocols for follow-up imaging in centers that care for children with diffuse liver disease.
In the case of hereditary tyrosinemia type 1 due to fumaryl acetoacetate hydrolase deficiency, prompt medical management, by blocking an enzyme upstream in the tyrosine catabolic pathway, can avert the injury that otherwise leads to HCC more often than any other metabolic defect. However, a low risk of developing HCC remains even with adequate medical management, so these children require life-long surveillance.5
Therefore, for the conditions listed, periodic abdominal ultrasonography and serum alpha fetoprotein measurements, at 3-month intervals in the case of Beckwith-Wiedemann syndrome and similarly for the first 3 years of life for others and then every 6 months thereafter, are advocated. In addition, recognition of the rare sequential occurrences of mesenchymal hamartoma and sarcoma and of hemangioendothelioma with angiosarcoma indicates the need for surveillance ultrasonography whenever a complete resection or transplant has not taken place.
ALGORITHM FOR TREATMENT
For HB, HCC, and most sarcomas, complete surgical resection is the goal of therapy and a necessity for cure. If detection is early and the anatomical conditions permit it, primary excision is preferred for all tumor types.5 The introduction of cisplatin to HB chemotherapy in the early 1980s significantly improved the outcomes for patients overall, particularly those with initially unresectable disease.38 HCC is a much more chemoresistant tumor, so surgical removal, by either resection or transplant, remains the most important factor in survival.
HB treatment plans differ between the United States–based Children's Oncology Group and the European-based Childhood Liver Tumor Strategy Group of the International Society of Pediatric Oncology (SIOPEL). In the United States, the staging system is based on the resectability of the tumor at diagnosis (Table 2).39
|Stage I||Complete resection|
|Favorable histology||Purely fetal histology with a low mitotic index|
|Other histology||All other stage I tumors|
|Stage II||Gross total resection with microscopic residuals or total resection with preoperative or intraoperative rupture|
|Stage III||Unresectable tumors as determined by the attending surgeon, partially resected tumors with macroscopic residual, or any tumor with lymph node involvement|
|Stage IV||Measurable metastatic disease to lungs or other organs|
Assessment of tumor extent is of crucial importance in determining whether or not resection or transplantation should be pursued, and a high-quality contrast-enhanced CT and/or MRI examination is imperative and should be supplemented as needed with sonography of the hepatic vessels.40 Sonography can be valuable in detecting uninvolved hepatic veins that are displaced by the tumor and not visualized on CT because of suboptimal contrast enhancement. Sonography can also detect early tumor invasion of the portal venous system by revealing disruption of the normally hyperechoic vessel wall and depicting vascularized tissue in the vessel lumen. Pedunculated tumors are considered confined to their section of origin and are not regarded as extrahepatic disease. Lymph node metastases are very uncommon in HB, and enlarged lymph nodes found on imaging are not considered involved unless this is confirmed by biopsy. Lymph node metastases are not uncommon in HCC and fibrolamellar carcinoma, and biopsy confirmation is not required if lymphadenopathy is unequivocal on imaging.
Chest CT is used for evaluation of pulmonary metastases and may be performed without contrast if it is not obtained concurrently with the abdominal CT examination. CT should be performed with the goal of keeping the radiation dose as low as reasonably achievable (the ALARA principle). The acquired and reconstructed slice thickness for CT and MRI should not exceed 5 mm so that the minimum size threshold for a measurable lesion is no greater than 1 cm. To assist in comparison, the same modalities used in initial staging and risk stratification are recommended for assessment of response to chemotherapy.40 The Response Evaluation Criteria in Solid Tumor schema from the National Cancer Institute is used to measure response.
The International Childhood Liver Tumour Strategy Group of SIOPEL adopted a preoperative staging system called PRETEXT (Pretreatment Extent of Disease) that uses the number of involved liver sections on imaging for staging; it was most recently revised in 200541 (Fig. 5). In addition to describing the intrahepatic tumor extent, the 2005 revision of the PRETEXT system includes additional criteria determined by imaging findings.42 These detail involvement of the inferior vena cava or hepatic veins, involvement of the portal veins, involvement of the caudate lobe, tumor focality, intraperitoneal tumor rupture or hemorrhage, extrahepatic abdominal disease, lymph node metastases, and distant metastases. Involvement of a vein is defined as the presence of intravascular invasion, occlusion, or complete encasement of the vessel by tumor. It is not sufficient for the tumor to abut or extrinsically compress the vein.
Bone scintigraphy is recommended for staging in children with HCC but not HB because of the rarity of bone metastases. There is a high frequency of abnormal calcium metabolism with HB that may cause false-positive uptake on bone scintigraphy.40, 43 The role of 2-fluoro-2-deoxy-D-glucose positron emission tomography and positron emission tomography/CT is undefined at present.
In the United States, surgeons are urged to perform primary resections whenever the imaging studies indicate the potential for complete excision without endangering the patient. This avoids the toxicity of chemotherapy, including marrow suppression, mucositis, gastrointestinal dysfunction, and nutritional consequences, and the deafness caused by cisplatinum.39 A completely resected tumor, without the presence of metastatic disease, is deemed stage I (Table 2). If after resection pathology shows pure fetal histology, close observation ensues. Currently, in the United States, 25% to 30% of HBs are amenable to primary resection,39 and all 17 stage I patients with pure fetal histology have been cured without adjuvant chemotherapy.44 For all other histologies and for stage 2 disease (microscopic residual after surgery: 3%), 4 cycles of a combination of cisplatin, 5-fluorouracil, and vincristine (C5V) are given. Patients with residual tumor after resection have decreased survival rates.45, 46 Therefore, heroic resections should not be attempted. Instead, the patient should receive neoadjuvant chemotherapy as described later and be evaluated for transplantation.19, 47, 48 For a tumor deemed unresectable at diagnosis (stage III: 52%) or a patient with metastatic disease (stage IV: 20%), current therapy in the United States consists of 4 cycles of chemotherapy, with either resection or liver transplantation after cycle 4, followed by 2 more cycles. The current recommendations of the Children's Oncology Group are to start with C5V for 2 cycles. If there is poor response (little or no tumor shrinkage or an inadequate drop in serum alpha-fetoprotein), doxorubicin should be added to the regimen. Recently, a recommendation was made to add doxorubicin to C5V at the initiation of chemotherapy for stage IV patients and to consider it with stage III.49
The SIOPEL treatment protocols are based on the PRETEXT classification system, as described previously (Fig. 5). SIOPEL recommends that all patients get at least 2 courses of chemotherapy prior to surgery. Chemotherapy generally includes cisplatin alone or in combination with doxorubicin for standard-risk tumors and cisplatin, doxorubicin, and carboplatin for high-risk tumors.9, 50 Patients are reevaluated after 2 cycles for surgical planning, with resection or transplantation occurring after cycle 4 if possible. Postoperative chemotherapy is dependent on the number of cycles given prior to the surgery. Liver transplantation is recommended when complete tumor excision by partial hepatectomy is unlikely, such as cases involving PRETEXT IV tumors (unless clear downstaging of a unifocal tumor to PRETEXT III is shown after preoperative chemotherapy), multifocal PRETEXT III, and central tumors involving the inferior vena cava, all 3 hepatic veins, or the main portal vein or both its right left and right branches (Fig. 3). Involvement of the major liver vessels does not contraindicate transplantation if all tumors can be excised at the time of hepatectomy. As a caveat, it should be noted that even with contemporary imaging techniques, PRETEXT staging is not highly accurate because of the difficulty in distinguishing parenchymal compression of a liver section from true parenchymal ingrowth of a tumor. For example, in the SIOPEL-1 study, preoperative PRETEXT staging compared with pathology was correct in 51%, overstaged in 37%, and understaged in 12% of patients.42 In certain cases, especially multifocal HB, intraoperative ultrasound can improve the depiction of tumor extent and assist with the planning of the most appropriate surgical strategy.51, 52 Liver transplantation is a viable option for children with lung metastases that clear with preoperative chemotherapy or surgical resection by the time of transplantation.53, 54
At relapse, doxorubicin (for those who have not been previously exposed), irinotecan, and ifosfamide have been used most commonly.55 Another therapy being used with variable success in children whose tumors are unresponsive to systemic chemotherapy is direct arterial chemotherapy and/or chemoembolization.56–58
Analysis of the United Network for Organ Sharing (UNOS) database in 2006 has revealed that since 1987, 237 patients have undergone orthotopic liver transplantation (OLT) for HB in the United States.3 The majority of the patients were male (62%), and 60% were under 2 years of age at diagnosis, with the median age at transplant being 2.9 years. Seventy-five percent of the patients received a whole organ, 8% received a split cadaveric graft, and 16% received a graft from a living donor. The overall 1-, 5-, and 10-year patient survival rates were 80%, 69%, and 66%, respectively, versus patient survival rates of 90%, 85%, and 81% for patients transplanted for other indications (Fig. 6). Age, race, sex, bilirubin, creatinine, albumin, and allograft type did not affect patient outcome in this patient population. Recurrence of disease was the primary cause of death in over half of the patients. In a recent study, Otte et al.59 reviewed 147 patients from 24 centers that underwent OLT for HB. One hundred six of these patients underwent OLT as the primary surgical therapy, whereas 41 received a rescue transplant after either incomplete resection or recurrence of disease. The patients who underwent rescue OLT did significantly worse, with only a 30% rate of overall disease-free survival versus 82% in the primary OLT group. This result was confirmed by several single-center studies.2, 60, 61
Complete surgical resection offers the only chance for a cure for HCC, as the tumor is chemoresistant.10, 12 Consultation with a liver transplant center at the time of diagnosis of HCC is an important part of the patient's care plan. Among cirrhotic adults with HCC, those fulfilling the Milan criteria (a single tumor 5 cm or less in diameter or up to 3 tumors, each 3 cm or less in diameter; absence of macroscopic portal vein invasion; and absence of recognizable extrahepatic disease) have improved survival after liver transplantation.62 The Milan criteria have served as a basis for selecting candidates for liver transplantation and prioritization of organ allocation, but they can be challenged on the basis of being too restrictive for children at low risk of recurrence after liver transplantation.34 Most children present with large tumors arising de novo in the absence of underlying liver disease, and the outcomes of pediatric patients undergoing liver transplantation for HCC are similar to the outcomes of those undergoing transplantation for HB or end-stage liver disease. Liver transplantation should be considered an option for children with unresectable HCC confined to the liver, with contraindications including the presence of macroscopic vascular invasion or extrahepatic spread, even if cleared by preoperative chemotherapy.4, 63, 64
As with HB, intra-arterial chemotherapy and chemoembolization have been used in HCC. The numbers are small, 3 patients in 1 study and 7 in another; however, rare instances of responses that enabled resection or transplantation have been reported.56, 57 The 2006 review of the UNOS database revealed that since 1987 only 41 pediatric patients have undergone OLT for HCC.3 The majority of the patients were male (59%), with a median age of 10 years. Seventy-eight percent received a whole organ, 18% received a cadaveric split graft, and 4% received a graft from a living donor. The overall actuarial 1-, 5-, and 10-year patient survival rates were 86%, 63%, and 58%, respectively (Fig. 6). The primary cause of death was recurrence of HCC in 86% of the patients. This study was limited by the fact that tumor staging, chemotherapy regimens, and pre-OLT surgery or other local therapy were not known. A single-center study in 2000 analyzed a total of 19 patients who underwent OLT for HCC.61 Fifteen of the 19 patients had underlying liver disease that put them at risk for HCC, which included tyrosinemia, diverse chronic cholestatic conditions, Wilson's disease, and hepatitis B. The majority of the patients had stage IV disease (11/19) at the time of OLT. This group reported a similar 5-year disease-free survival of 68%, with the majority of deaths due to recurrence of disease. Risk factors for recurrence identified in this patient population were macrovascular invasion and nodal disease.
Other Liver Tumors
The UNOS database reveals that between 1987 and 2007, 35 pediatric patients underwent OLT for hemangioendothelioma (HE).3 The median age at transplant was 20 months (3 months to 15 years). The overall 1-year survival was 78%, and the 5-year survival was 61%. As demonstrated in Fig. 6, these results are similar to the overall survival of pediatric patients transplanted for HCC (79% at 1 year and 59% at 5 years) and significantly worse than that of pediatric patients transplanted for nontumor indications.21
Since 1987, 33 pediatric patients underwent OLT for other primary hepatic tumors: 11 for sarcoma, 7 for adenomas, 4 for hemangiomas, 3 for inflammatory pseudotumors, 2 for arterial venous malformations, 2 for hamartomas, 1 for insulinoma, 1 for carcinoid, 1 for gastrinoma, and 1 for cholangiocarcinoma.
MEDICAL MANAGEMENT ISSUES
The pretransplant and peritransplant care of children listed for transplantation for liver cancer is generally similar to that for other children listed for other indications.65 As for other indications for transplantation, children listed for liver tumors require attention to maintain adequate nutrition and vigilance for serious infections.66 The current health of the child versus the risk of tumor dissemination from prolonged waiting necessarily influence decisions about proceeding to transplantation.
Serial surveillance for tumor spread may change the categorization of a child from being a suitable candidate to one that may not be suitable. This is always a difficult consideration and requires teaching the family that a child's suitability as a liver transplant candidate may change after listing because of the progression of disease. With prioritization for HB (discussed later), this situation should occur infrequently, but it is a major concern and should be discussed with the family at the time of listing.
Other care issues that affect these patients more than other pediatric transplant candidates, both before and after transplantation, are cardiac and renal dysfunction due to either the original disease (eg, certain glycogen storage diseases and hereditary tyrosinemia) or chemotherapy. Management includes serial echocardiograms, particularly in those patients who received anthracyclines as part of their chemotherapy regimen, and close attention to serum creatinine and the glomerular filtration rate when cisplatin is used.39, 65
These have been thoroughly reviewed by Busuttil and Klintmalm.67 The advent of liver transplantation has led to a durable treatment option capable of curing patients with unresectable liver tumors. Since the late 1960s, over 11,000 pediatric liver transplants have been performed in the United States, with 1-year survival rates currently surpassing 90%.68 Since 1987, the UNOS database reveals that 363 of these have been for tumors, including both malignancies and a small number of hemangiomatous lesions unresponsive to medical management or partial hepatectomy (Fig. 6). The Pediatric End-Stage Liver Disease (PELD) and the Model for End-Stage Liver Disease (MELD) were developed to create a more accurate and less subjective measurement of liver disease severity in order to prioritize patients for transplant.69, 70 Unfortunately, the PELD/MELD scoring systems are accurate only in patients with chronic liver disease and not in patients with tumors.70 Patients whose disease severity is not accurately assessed by the PELD/MELD score can be granted exceptions. Over 25% of all pediatric patients transplanted since the inception of the PELD/MELD system were transplanted with an exception score.34 Patients with HB are granted a PELD/MELD score equivalent to a 60% risk of mortality in 3 months. If they are not transplanted in 30 days, these patients are eligible to be upgraded to status 1B. Patients with HCC who meet the Milan criteria are eligible for a PELD/MELD score equivalent to a 20% 3-month mortality and are eligible for an upgrade every 90 days. Currently, there are no standard PELD/MELD exceptions for patients with hemangioendothelioma or other pediatric liver tumors.
Early consultation with a transplant surgeon is recommended prior to extensive hepatic resection for HB. General guidelines include the following:
- 1Multifocal, bilobar HB is a definite indication for primary transplantation. Extensive medical therapy in an attempt to make the patient a resection candidate should be avoided because microscopic disease will inevitably persist in the remaining liver.
- 2Unifocal, centrally located tumors involving the main portal structures or all 3 of the hepatic veins should be considered for primary OLT because these structures would most likely not be rendered tumor-free by chemotherapy.
- 3Macroscopic venous invasion is not a contraindication to OLT if complete resection can occur with the hepatectomy. Although it is associated with a higher recurrence rate, 70% of patients with macrovascular invasion have demonstrated disease-free survival after 5 years.
- 4Patients with pulmonary metastases at presentation are still candidates for OLT if the metastases can be completely eradicated by chemotherapy or surgery prior to transplantation. A 60% to 80% long-term disease-free survival rate has been demonstrated in this subgroup of patients.53, 54, 71
CT and MRI are helpful in determining the amount of liver that will remain after the hepatectomy. Because the liver has excellent regenerative capacity, up to 80% of the liver can be resected. Children generally lack other serious comorbidities, usually have an otherwise normal liver, and are therefore able to tolerate larger resections than adults. Although CT and MRI are very helpful in determining resectability, in many cases the final determination is made in the operating room. At exploration, complete mobilization of the liver is first performed to carefully examine for extrahepatic spread and multifocal disease. Intraoperative ultrasound can help delineate the extent of disease and assess tumor proximity to major hepatic vessels.51, 52 Although a parenchymal margin greater than 1 cm is recommended, it is often difficult, if not impossible, to achieve this large a portal venous or hepatic venous margin. A close margin on either the portal vein or hepatic vein should not be considered a contraindication for resection. If it appears as though any of the margins will be grossly positive, the resection should be aborted, and the patient should be evaluated for transplantation.
POSTTRANSPLANT MANAGEMENT PECULIAR TO PEDIATRICS AND TUMORS
The risk of hepatic artery thrombosis is 3 to 4 times greater in children than in the adult population.72 The incidence of hepatic artery thrombosis in pediatric patients is reportedly between 12% and 25% overall and as high as 30% in children younger than 1 year of age.73 Portal vein thrombosis after pediatric OLT has been shown to occur in 5% to 25%, whereas hepatic vein occlusion/stenosis rates are reported to be between 5% and 10%.74 Biliary complications, including leaks and strictures, occur in 10% of pediatric liver transplant recipients and are usually associated with hepatic artery thrombosis or prolonged donor ischemia.75
Although other diseases treated by liver transplantation may recur in children, such as sclerosing cholangitis, malignancies raise special concerns for disease recurrence that can directly impact posttransplant survival. In the Children's Oncology Group protocol for HB, 2 cycles of the same chemotherapy that permitted transplantation are given for a total of 6 cycles.39, 55 For patients with metastatic disease, this is extended to 8 to 10 cycles of the modified regimen, depending on the responsivity. A metastatic or recurrent tumor is the primary cause of death in children with liver transplants for hepatic malignancies, accounting for 54% of the deaths in those transplanted for HB and 86% of the deaths in those transplanted for HCC.3 The lung is the most common site of metastasis, and other common sites are the brain and bone.43 Minimizing immunosuppression at the earliest possible time is intended to encourage patient-specific immune surveillance against residual tumor cells,76 although this has not been studied systematically. Because immunosuppression levels are generally highest in the first 6 to 12 months after transplantation, serum alpha-fetoprotein levels are obtained approximately every 3 months during that time.
It is recommended that contrast-enhanced abdominal CT or MRI be performed 1 month after primary tumor resection and then every 3 months for 30 months and that chest CT [if the initial CT showed pulmonary metastases or a chest X-ray (CXR) is suspicious for pulmonary recurrence] or CXR (if the initial CT was negative for pulmonary metastases) be performed every 3 months for 30 months. The incidence of HB recurrence is low beyond 30 months after initial diagnosis, and it is recommended that children without evidence of recurrent disease undergo surveillance abdominal sonography and CXR every 6 months to 5 years, rather than CT or MRI, beginning at 30 months after diagnosis.40
Less than 5% of all deaths of pediatric OLT recipients can be attributed to rejection, and only a small number of patients are retransplanted for rejection (15%).77 Overall, there is a 10 times greater risk of mortality from infection than rejection after OLT in the pediatric population.78 Management is the same for other transplanted children.66
Posttransplantation susceptibility to infection is a general problem because of immunosuppression, but this is compounded by the need for additional cycles of chemotherapy afterwards. In a recent analysis of the Studies of Pediatric Liver Transplantation database, 70% of all deaths post-OLT were attributed to infection.78 Data on the incidence in children with tumors are not available. The incidence of Epstein-Barr virus–induced posttransplant lymphoproliferative disease following any form of liver cancer is not known to be increased.
Other issues that are particularly important to children following liver transplantation, such as overall growth and development, achievement of sexual maturity, and compliance with medical therapy during adolescence, are discussed by Killenberg and Clavien,65 Tiao et al.,66 and Kerkar and Emre.77
CURRENT OUTCOMES AND FUTURE PROSPECTS
The 2 major pediatric liver tumor groups in the United States and Europe have agreed to register all patients for transplantation in a common database, the Pediatric Liver Unresectable Tumor Observatory (http://pluto.cineca.org).19 In the United States, it is anticipated that approximately 8 to 12 patients with HB will be transplanted per year. Patients with HCC will not be included in this study. As current chemotherapy has not been successful, a new direction is needed for this tumor. A list of 6 active US National Institutes of Health trials specific for pediatric liver tumors is shown in Table 3. None of them involves transplantation, but the latter will be part of a forthcoming Children's Oncology Group protocol. Biliary rhabdomyosarcoma will continue to be treated as part of the Children's Oncology Group rhabdomyosarcoma protocols. Undifferentiated sarcoma and angiosarcoma are included in a larger ongoing Children's Oncology Group trial (“ARST0332: Risk-Based Treatment for Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas”}.
|1||Cisplatin with or without sodium thiosulfate in treating young patients with stage I, stage II, or stage III childhood liver cancer|
|2||Combination chemotherapy and thalidomide in treating younger patients undergoing surgery for newly diagnosed liver cancer|
|3||Irinotecan in treating young patients with refractory or recurrent hepatoblastoma|
|4||Intensive neoadjuvant chemotherapy in treating young patients undergoing surgical resection for high-risk hepatoblastoma|
|5||Withdrawal of immunosuppression in pediatric liver transplant recipients|
|6||Hepatoblastoma biology study and tissue bank|
This trial is using a combination of therapies, either alone or combined, including surgery, radiation, and chemotherapy with ifosfamide and doxorubicin on the basis of the stage and grade of the tumor.
A team effort with contributions from oncologists, hepatologists, pathologists, surgeons, and transplant surgeons provides the greatest chance of curing children with liver cancers. Much remains to be standardized, although with screening, prompt referral, and recognition of the resectability of the presenting lesions, outcomes are likely to be improved, whether or not transplantation is required.