pediatric hepatoblastoma

8/13/2019 Pediatric Hepatoblastoma

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Pediatric Hepatoblastoma Follow-up

Author: Jennifer R Willert, MD; Chief Editor: Max J Coppes, MD, PhD, MBAhttp://emedicine.medscape.com/article/986802-overview Practice EssentialsHepatoblastoma is the most common form of liver cancer in children, although it is a comparatively uncommon

pediatric solid tumor. The disease usually affects children younger than 3 years.Essential update: High-risk hepatoblastoma responds to dose-dense cisplatin therapy

Weekly, dose-dense preoperative administration of cisplatin, in combination with monthly doses of doxorubicinand radical surgery, dramatically improved survival in children with high-risk hepatoblastoma, according to a

prospective, single-arm study. The 62 patients in the report, all of whom were aged 18 years or younger, had a 3-year, event-free survival rate of 76%, with a 77% event-free rate found in a subgroup of 39 patients withmetastasis. The overall 3-year survival rate was 83%, and by the end of the study, 79% of patients were incomplete remission .[1, 2] However, more than 50% of patients suffered significant hearing loss, while 71% of patients had at least 1 episodeof febrile neutropenia. Patient deaths included 1 child with profound neutropenia who died of a fungal infectionand 3 children who died from surgical complications.A previous study, using intensive, multidrug treatment and aggressive surgery but a standard dosing schedule forcisplatin, had 3-year rates of 56% and 62% for event-free and overall survival, respectively.Signs and symptoms

Hepatoblastoma is usually diagnosed as an asymptomatic abdominal mass. Patients may also display thefollowing: Hemihypertrophy: An incidental finding in approximately 10% of patients Isosexual precocity: Penile and testicular enlargement without pubic hair is seen in patients with tumors that

secrete the b subunit of human chorionic gonadotropin (b-hCG). Late features of Beckwith-Wiedemann syndrome (BWS): Rare; include midface hypoplasia and slitlike

indentations of the earlobe

Anorexia: In advanced disease Talipes equinovarus Persistent ductus arteriosus Tetralogy of Fallot Extrahepatic biliary atresia Renal anomalies (dysplastic kidney, horseshoe kidney) Cleft palate Dysplasia of the earlobes Goldenhar syndrome Prader-Willi syndrome Meckel diverticulum Simpson-Golabi-Behmel syndrome Symptoms associated with osteopenia: Severe osteopenia is present in most patients, but, with the exception of

pathologic fracture, symptoms are rare Symptoms of acute abdomen: Rare; occur if the tumor ruptures Severe anemia: Occurs occasionally, as a result of tumor rupture and hemorrhage

See Clinical Presentation for more detail.Diagnosis

Lab studies Complete blood count (CBC) with differential: Normochromic normocytic anemia and thrombocytosis may be

present

Liver enzyme levels: Moderately elevated in 15-30% of patients -fetoprotein (AFP) - levels in hepatoblastoma are often as high as 100,000-300,000 mcg/mL Imaging studies
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Radiography: Reveals mass in the right upper quadrant of the abdomen Ultrasonography: Allows assessment of tumor size and anatomy Computed tomography (CT) scanning: Reveals involvement of nearby structures and whether pulmonary

metastases are present Magnetic resonance imaging (MRI): Believed to be superior to CT scanning but does not necessarily add to

the anatomic detail seen on CT scans Positron emission tomography (PET) scanning: May have a role in diagnosis and follow-up evaluation Radionuclide bone scanning: To evaluate for bone metastases in symptomatic patients

Biopsy Surgical resection is the usual manner in which material for pathologic assessment is obtained. Open biopsy is

performed when complete surgical resection is not possible. Needle biopsy is not recommended, becausehepatoblastomas usually are highly vascular.Staging Stage I: Tumor is completely resectable via wedge resection or lobectomy; tumor has pure fetal histologic

(PFH) results; AFP level is within reference range within 4 weeks of surgery Stage IIA: Tumor is completely resectable; tumor has histologic results other than PFH (unfavorable histology

[UH]) Stage IIB: Tumor is completely resectable; AFP findings are negative at time of diagnosis (ie, no marker to

follow) Stage IIC: Tumor is completely resected or is rendered completely resectable by initial radiotherapy or

chemotherapy or microscopic residual disease is present; AFP level is elevated 4 weeks after resection Stage III (any of the following): Either the tumor is initially unresectable but is confined to 1 lobe of the liver,

gross residual disease is present after surgery, the tumor ruptures or spills preoperatively or intraoperatively, orregional lymph nodes are involved

Stage IV: Distant bone or lung metastasis has occurredSee Workup for more detail.Management

Chemotherapy Cisplatin is the most active single agent used to treat hepatoblastoma The cisplatin/5-fluorouracil (5-FU)/vincristine (VCR) combination is regarded as standard chemotherapeutic

treatment in hepatoblastoma Preoperative chemotherapy can completely eradicate metastatic pulmonary disease and multinodular liver

disease Postoperatively, chemotherapy is usually started approximately 4 weeks after surgery to allow liver

regeneration Radiotherapy

Doses used for treatment of hepatoblastoma are usually 1200-2000 centigray (cGy) Radiotherapy may be used when microscopic disease is seen at the resection margins

Adjuvant radiotherapy may have a role in the treatment of chemoresistant pulmonary metastases Resection and transplantation

Lobectomy: Initial resection of operable primary tumors by lobectomy is the standard of care inhepatoblastoma

Liver transplantation: Has had an increasing role in children with nonresectable tumors or in those who showchemotherapy resistance

Thoracotomy and resection of pulmonary metastases: Some patients have long-term, disease-free survivalwhen aggressive attempts are made to surgically eradicate all areas of disease

See Treatment and Medication for more detail.Image library
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Clear cell hepatoblastoma. Hematoxylin and eosin stain. Image courtesy ofDenise Malicki, MD. BackgroundHepatoblastoma is the most common liver cancer in children, although it is relatively uncommon compared withother solid tumors in the pediatric age group. Over the past several years, pathologic variations of hepatoblastomahave been identified, and techniques for establishing the diagnosis of childhood hepatic tumors have improved.Surgical techniques and adjuvant chemotherapy have markedly improved the prognosis of children withhepatoblastoma. Complete surgical resection of the tumor at diagnosis, followed by adjuvant chemotherapy, isassociated with 100% survival rates, but the outlook remains poor in children with residual disease after initial

resection, even if they receive aggressive adjuvant therapy.Considerable controversy has surrounded the discrepancy between US and international hepatoblastomatherapeutic protocols; surgery and staging are initially advised in the United States, whereas adjuvant therapy isstrongly considered internationally. Significant data now support a role for preoperative neoadjuvant chemotherapyif the tumor is inoperable or if the tumor is unlikely to achieve gross total resection at initial diagnosis . [3] Earlyinvolvement of hepatologists and liver transplant teams is recommended if the tumor may not be completelyresectable even with preoperative adjuvant chemotherapy. Liver transplantation is playing an increasing role incases in which the tumor is deemed nonresectable after chemotherapy is administered or in "rescue"transplantation when initial surgery and chemotherapy are not successful . [4, 5] Finally, reports state that aggressive surgical intervention may be warranted for isolated pulmonary metastases .[3, 6] PathophysiologyHepatoblastomas originate from immature liver precursor cells and present morphologic features that mimicnormal liver development. Hepatoblastomas are usually unifocal and affect the right lobe of the liver more oftenthan the left lobe. Microvascular spread can extend beyond the apparently encapsulated tumor.Grossly, the tumor is a tan bulging mass with a pseudocapsule. Cirrhosis is not associated with this tumor.Metastases affect the lungs and the porta hepatis; bone metastases are very rare. CNS involvement has beenreported at diagnosis and during relapse. The identification of distinct subtypes and further molecular biologicalinformation derived regarding liver ontogenesis and growth regulation of hepatic tumors has recently helped pavethe way for a more comprehensive classification system for this disease.Loss of heterozygosity (LOH) of chromosome arm 11p markers occurs commonly in hepatoblastoma identified inassociation with Beckwith-Wiedemann syndrome (BWS) and hemihypertrophy. Isochromosome 8q is seen inmixed hepatoblastomas, and trisomy 20 is seen in pure epithelial hepatoblastomas (see Histologic Findings).Patients with familial adenomatous polyposis (FAP), a syndrome of early-onset colonic polyps andadenocarcinoma, frequently develop hepatoblastomas. Germline mutations in the APC tumor suppressor geneoccur in patients with FAP, and mutations in the APC tumor suppressor gene are frequently detected in the colonic

polyps and adenocarcinomas associated with FAP. One study estimated that 1 in 20 hepatoblastomas is probablyassociated with FAP .[7] Interestingly, APC mutations, although common in patients with hepatoblastoma and FAP,are rare in patients with sporadic hepatoblastomas. Recently, Sanders and Furman reported 2 brothers withhepatoblastoma who had a significant family history of early onset colon cancer .[8] Testing of the younger brotherrevealed a deletion in exon 15 of the APC gene consistent with a diagnosis of FAP.In a study of 29 tumors from children with sporadic hepatoblastoma, no germline APC mutations werefound .[9] These authors conclude that routine APC screening does not need to be performed in these childrenwithout a family history of colorectal cancer or FAP.Loss of function mutations in APC lead to intracellular accumulation of the protooncogene b-catenin, an effector of

Wnt signal transduction. b-catenin mutations have been shown to be common in sporadic hepatoblastomas,occurring in as many as 67% of patients. Furthermore, a study in a mouse model of hepatoblastomas induced bytoxin exposure detected mutations of the b-catenin protooncogene in 100% of the tumors analyzed (27 of
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27) .[10] This finding suggests that alterations in the Wnt signaling pathway likely contribute to the neoplastic process in this particular tumor.Recent studies on other components of the Wnt signaling pathway have also demonstrated a likely role forconstitutive activation of this pathway in the etiology of hepatoblastoma . [11, 12] Overexpression of human Dickkopf-1, a known antagonist of the Wnt pathway, has been found in hepatoblastoma. The authors postulate that this may

be a direct negative feedback mechanism resulting from increased -catenin commonly found in this tumor .[13]

A mutation in t he axin gene, also a known antagonist of -catenin accumulation, has been found in hepatoblastomaand may contribute to the etiology of the smaller percentage of hepatoblastomas in which -catenin mutations havenot been identified, thus implicating the constitutive activation of the Wnt pathway in a significant fraction ofhepatoblastomas .[14, 15] Kuroda et al demonstrated a potential role for transcriptional targeting of tumors with strong-catenin/T-cell factor activity with oncolytic herpes simplex virus vector .[16] The hedgehog (Hh) pathway has also

been evaluated and has been found to be a potential therapeutic target for hepatoblastomas in which the Hh pathway is overexpressed or reactivated at an inappropriate time . [17] Blocking the Hh pathway with the antagonist cyclonamine has shown a strong inhibitory effect on hepatoblastomacell line proliferation. A high frequency of glioma-associated oncogene homolog 1 ( GLI1 ) and patched homolog 1( PTCH1 ) overexpression and Hh-interacting protein (HHIP) promoter methylation is noted in early childhoodhepatoblastoma, which also supports a key role for Hh signalling activation in malignant transformation of

embryonal liver cells .[18]

Wnt pathway activation appears to be more prevalent in embryonal and mixed subtypes of hepatoblastoma,whereas notch pathway activation is more prevalent with the more differentiated pure fetal hepatoblastomatumors .[19] The relative activation of Hh, Wnt, and notched signaling pathways appears to be useful in stratificationof different subtypes.Increasing evidence suggests that hepatoblastoma is derived from a pluripotent stem cell . [20] This further supportsthe hypothesis that this tumor arises from a developmental error during hepatogenesis and supports the hypothesisthat research particularly focused on these developmental processes governing liver maturation and growth mayultimately lead to more effective targeted therapy for this disease.FrequencyUnited States

Hepatoblastoma accounts for 79% of all liver tumors in children and almost two thirds of primary malignant livertumors in the pediatric age group. Approximately 100 cases of hepatoblastoma are reported per year. The annualincidence of hepatoblastoma in infants younger than 1 year is 11.2 cases per million; in 1990 -1995, the annualincidence in children overall was 1.5 cases per million, which is almost double the incidence from 1975 -1979.A significantly higher rate of hepatoblastomas is observed among low birth weight (LBW) and very low birthweight (VLBW) infants born prematurely .[21] A Childrens Oncology Group (COG) protocol (AEP10 4C1) is currently investigating exogenous and endogenouscauses for the increase in incidence and potential cause of premature births. The study is also exploring potentialeffectors independent of prematurity and LBW or VLBW. All children with hepatoblastoma diagnosed before age6 years from 2000-2005 are eligible for retrospective analysis, and prospective analysis will be performed forchildren diagnosed between June 2005 and December 31, 2008. This is the largest, most comprehensive case-

control study of hepatoblastoma performed thus far.International

In Japan, efforts to improve vaccination rates have led to decreases in hepatocellular carcinoma (HCC) and, to alesser degree, in hepatoblastoma. Carcinogen exposure in some developing countries is linked to hepatoblastomaand HCC.Mortality/MorbidityA large multicenter COG study included 182 children with hepatoblastoma diagnosed between August 1989 andDecember 1992 .[22] Of these, 9 had stage I disease with favorable histology (FH), 43 had stage I with unfavorablehistology (UH), 7 had stage II, 83 had stage III, and 40 had stage IV disease (see Staging).All 9 patients with stage I and FH received treatment with low-dose doxorubicin and were alive and free ofdisease. Overall survival rates for all stages 5 years after treatment were 57-69%. The 5-year event-free survival

(EFS) rates were 91% for patients with stage I with UH, 100% for stage II, 64% for stage III, and 25% for stageIV.


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In general, patients who undergo complete resection of the tumor and adjuvant chemotherapy have a survival rateof 100%. Patients with favorable histology and low mitotic rate with complete resection may not requirechemotherapy; for this reason, US protocols have advocated for formal staging and pathologic diagnosis prior toadministering any adjuvant chemotherapy.More recently, data from the International Childhood Liver Tumour Strategy Group (SIOPEL), which used

preoperative adjuvant chemotherapy, demonstrated overall survival rates as high as 89% and event-free survival

rates as high as 80% .[23]Australian investigators demonstrated that patients treated between 1984 and 2004 also hadexcellent outcomes, provided surgical margins were clear .[3] No correlation between -fetoprotein (AFP) levels andoutcome was reported in the study.Other morbidity can result from precancerous medical conditions, operative complications, or toxic effects ofchemotherapy. Short- and long-term sequelae and toxic effects of surgical management and chemotherapy arediscussed below (see Surgical Care and Medical Care).Race

White children are affected almost 5 times more frequently than black children. Black patients tend to have worseoutcomes.Sex

Males are typically affected more frequently than females; the male-to-female ratio is 1.7:1. Male-to-female ratiosare somewhat higher in Europe (1.6-3.3:1) and Taiwan (2.9:1).Age

Hepatoblastoma usually affects children younger than 3 years, and the median age at diagnosis is 1 year.Hepatoblastoma is very rarely diagnosed in adolescence and is exceedingly rare in adults. Occasionally, nests ofhepatoblastoma cells are found in hepatocellular carcinoma lesions; this is more common in adults than in children.Older children and adults tend to have a worse prognosis.History

Patients with hepatoblastoma are usually asymptomatic at diagnosis. Disease is advanced at diagnosis inapproximately 40% of patients, and 20% have pulmonary metastases.

Children with advanced disease may have anorexia. Severe osteopenia is present in most patients and regresses with resection of the tumor. Symptoms associated with

osteopenia are rare with the exception of pathologic fracture, which is often incidentally identified on routineimaging studies during evaluation of these children.

Rarely, patients in whom the tumor has ruptured present with symptoms consistent with acute abdomen.Occasionally, patients present with severe anemia resulting from tumor rupture and hemorrhage.

Family history of early onset intestinal polyps or adenocarcinoma may reveal familial adenomatous polyposis(FAP). A history of hemihypertrophy or Beckwith-Wiedemann syndrom e (BWS) should prompt screening using -fetoprotein (AFP) as a marker to detect hepatoblastoma in these patients. For such patients, AFP monitoringshould be performed every 3 months until the child is aged at least 4 years. Children who survive hepatoblastomashould be considered for evaluation of FAP, and those patients found to carry an APC mutation need closesurveillance because of their increased risk for colonic polyps and frank progression to adenocarcinoma.

Diagnosing primary malignant liver tumors before clinical signs and symptoms develop is important. Childrenwith a history of chronic hepatitis B infection who have advanced liver disease should be monitored at least every6-12 months with serum AFP levels and abdominal ultrasonography. Many children with hepatitis B infection areimmunotolerant, do not have significant liver abnormalities, and are not at increased risk for liver cancer. Anychild with documented cirrhosis for any reason should be periodically monitored with serum AFP level andultrasonography because of their increased risk of developing a hepatic malignancy associated with advanced liverdisease.Physical

Hepatoblastoma is usually diagnosed as an asymptomatic abdominal mass. Approximately 10% of patients have incidental findings of hemihypertrophy. Hepatoblastoma can be associated with isosexual precocity. Penile and testicular enlargement without pubic hair is

seen in patients with tumors that secrete the b subunit of human chorionic gonadotropin (b-hCG).


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Late features of BWS, such as midface hypoplasia and slitlike indentations of the earlobe, may occur, but this israre.

Patients with BWS and those with hemihypertrophy should be monitored with serial abdominal ultrasonographyand serum AFP level every 3 months until at least age 4 years; some would argue that these patients should bemonitored until age 7 years because of the risk of Wilms tumor as well.

Other associated syndromes and malformations include the following: Talipes equinovarus Persistent ductus arteriosus Tetralogy of Fallot Extrahepatic biliary atresia Renal anomalies (dysplastic kidney, horseshoe kidney) Cleft palate Dysplasia of the earlobes Goldenhar syndrome Prader-Willi syndrome Meckel diverticulum

Hepatoblastoma is also seen in association with Simpson-Golabi-Behmel syndrome. Routine screening with AFPlevel monitoring and abdominal ultrasonography is suggested in these patients, who are also at risk for developingWilms tumor.CausesAs with other pediatric malignancies, the cause of hepatoblastoma is generally unknown. Cancer has been

postulated to arise from unregulated cellular differentiation and proliferation. Similarities between the developingfetal liver and the fetal epithelial-type cells of hepatoblastoma are striking. Developing cells of the early feta l liverand the cells of fetal hepatoblastoma are similar in size and configuration. A developmental disturbance duringliver formation in embryogenesis likely results in aberrant proliferation of these undifferentiated cells.Increasing data support a rol e for aberrant transduction of the Wnt/ -catenin signaling pathway and its moleculartargets in hepatoblastoma tumorigenesis. Research in this area may ultimately contribute not only toward a betterunderstanding of this malignant neoplasm but may also lead to more specific molecular-targeted therapies. Hepatoblastoma, like Wilms tumor, is associated with BWS and hemihypertrophy, suggesting gestational

oncogenic events. Persons with dysplastic kidney or Meckel diverticulum have a higher incidence of this tumor. Hepatoblastoma has also been reported to be associated with maternal oral contraceptive exposure, fetal

alcohol syndrome, and gestational exposure to gonadotropins. Studies performed in Europe suggest an association between low birth weight (LBW), ver y low birth weight

(VLBW), and prematurity and hepatoblastoma. The suspected correlation between LBW, prematurity (< 1000g), and hepatoblastoma has now been confirmed in both the United States and Japan . [24, 25]

Patients with FAP have a significantly increased incidence of hepatoblastoma and should therefore be screenedin early childhood with AFP measurements.

A child with neurofibromatosis type 1 (NF1) who developed hepatoblastoma was reported .[26] Hepatoblastomahas also been reported in association with other cancer predisposition syndromes including FAP, BWS, Li-Fraumeni syndrome , trisomy 18, and glycogen storage disorders.

Premature infants, particularly those with LBW or VLBW, are at significantly increased risk of developinghepatoblastoma. The presence of erythropoietin receptors in hepatoblastomas has been postulated to potentiallycontribute to this increased incidence because many premature infants with LBW or VLBW receive thismedication during their time in neonatal intensive care.

Increasing evidence suggests that exposure to carcinogenic agents such as bromochloroacetic acid may betumorigenic .[27]

Differential Diagnoses Hepatocellular Carcinoma

Laboratory StudiesDiagnostic evaluation of a child in whom a liver tumor is suggested should include the following: CBC count with differential should be obtained.
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o Normochromic normocytic anemia is often present.o Thrombocytosis may be present. In a study by Ortega et al, 60% of patients had platelet counts greater than

500 X 10 9/L, and 12% had platelet counts greater than 1000 X 10 9/L.[22] Liver enzyme levels are moderately elevated in 15-30% of patients. -fetoprotein (AFP) is a major serum protein synthesized by fetal liver cells, yolk sacs, and the GI tract. AFP

is found in high concentrations in fetal serum and in children with hepatoblastoma, hepatocellular carcinoma,germ cell tumors, or teratocarcinoma. The tumor's ability to synthesize AFP reflects its fetal origin. Embryonaltumors produce less AFP than fetal tumors.

o Levels of AFP in hepatoblastoma are often as high as 100,000-300,000 mcg/mL. Ortega et al found AFPlevels elevated for age in 97% of patients .[22]

o The half-life of AFP is 4-9 days, and levels usually fall to within reference range within 4-6 weeksfollowing resection.

o Other causes of elevated AFP levels include viral hepatitis, cirrhosis, inflammatory bowel disease, andyolk sac tumors.

o Although elevated AFP levels are not specific for hepatoblastoma, they provide an excellent marker forresponse to therapy, disease progression, and detection of recurrent disease.

o Rarely, a hepatoblastoma can recur as a non AFP-secreting tumor with metastases, even if the initial

tumor was AFP secreting.o Interpretation of AFP levels can be difficult because hepatoblastoma tends to occur within the first 2 years

of life. Reference range AFP levels are comparatively high at birth and even higher in premature infants,which can complicate interpretation of this value. By age 1 year, adult levels of 3-15 mcg/mL have beenreached.

o Data from the German Cooperative Pediatric Liver Tumor Study showed that both very low (< 100 ng/L)and very high (>1,000,000 ng/L) AFP levels are associated with poorer prognosis than intermediate AFPlevels .[28]

o Laboratory-specific and age-specific AFP values should be used.o Baseline testing of glomerular filtration rate (GFR) or creatinine clearance should be performed before

cisplatin administration; follow-up studies are needed periodically to assess nephrotoxicity.

Imaging Studies Abdominal radiography Plain abdominal films reveal a right upper quadrant abdominal mass. Calcification is seen in approximately 6% of hepatic masses and 12% of hemangiomas.

Ultrasonography Abdominal ultrasonography allows assessment of tumor size and anatomy, which helps in surgical planning. The mass usually appears hyperechoic on abdominal ultrasound images, which is particularly useful in

determining vascular involvement (vessels have lower attenuation than surrounding parenchyma). Baseline echocardiography is needed before anthracycline (doxorubicin) administration; follow-up studies are

needed to assess cardiotoxicity. CT scanning

CT scanning of the abdomen using contrast reveals patchy enhancement. CT scanning reveals involvement of nearby structures. Regional lymph nodes are almost never involved. CT scanning of the chest is warranted to assess for pulmonary metastases.

MRI: This is believed to be superior to CT scanning but does not necessarily add to the anatomic detail seen on CTscans.

Radionuclide bone scanning: This is recommended to evaluate for bone metastases when a patient is symptomatic. Positron emission tomography (PET) scanning: Studies support a potential role for PET scanning at diagnosis and

for follow-up evaluation in hepatoblastoma .[29] Other Tests

A baseline audiology evaluation is needed before cisplatin or carboplatin administration; follow-up studies areneeded to assess ototoxicity.

A baseline cardiology evaluation is needed for any child receiving anthracycline; the child should be monitoredevery 1-2 years thereafter.


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Procedures Pathologic diagnosis: Before commencing therapy, surgical diagnosis must be made. Surgical resection is the usual

manner in which material for pathologic assessment is obtained. Open biopsy is performed when complete surgicalresection is not possible. Needle biopsy is not recommended because these lesions usually are highly vascular.Histologic Findings

Standardizing criteria for histologic classification of hepatoblastoma has been suggested because of the significantvariation in the current medical literature. Particular attention to the subtypes of this tumor and direct correlationwith clinical outcomes is increasingly being incorporated into all major protocols internationally . [30]

Six histologic variants of hepatoblastoma have been described, as follows: Epithelial type

Fetal pattern (fetal components are shown in the image below) Fetalcomponents of hepatoblastoma. Hematoxylin and eosin stain. Image courtesy of Denise Malicki, MD.

Embryonal and fetal pattern (as is shown in the image below)Embryonal hepatoblastoma. Hematoxylin and eosin stain. Image courtesy of Denise Malicki, MD.

Macrotrabecular pattern Small cell undifferentiated pattern

Mixed epithelial and mesenchymal type With teratoid features Without teratoid features

Pure epithelial tumors account for approximately 56% of cases; they contain varying amounts of fetal cells,embryonal cells, or both. Within this group, purely fetal tumors account for 31% of hepatoblastomas; embryonaltumors account for 19% of hepatoblastomas; and macrotrabecular tumors and small cell undifferentiated typeseach account for 3% of hepatoblastomas. The remaining 44% of hepatoblastomas are mixed tumors containing

primitive mesenchymal tissue and specialized derived components, such as myofibroblastic, chondroid, andosteoid tissues in addition to epithelial elements. Mixed tumors may express teratoid features. Teratoidhepatoblastomas are admixed with various heterologous structures of epithelial or mesenchymal origin.

Fetal cells are smaller than normal hepatocytes and have low nuclear-to-cytoplasmic (N/C) ratios and infrequentmitoses; cells form slender cords. Embryonal cells have a higher N/C ratio and more mitoses; they resemble earlyducts of embryonal liver. Extramedullary hematopoiesis can be associated with mixed tumors. In tumors that have

been completely resected, pure fetal histologic (PFH) results (with a 92% rate of disease-free survival) areassociated with better prognosis than other histologic types, which have an overall disease-free survival rate of57%. The absence of mitoses is a good prognostic sign. In advanced disease in which tumors cannot be completelyresected, PFH results do not predict a better outcome.

Special stains, molecular studies, and evaluation of the Wnt, notch and hedgehog (Hh) pathways can also behelpful in differentiating subtypes of hepatoblastoma.

INI1 testing helps differentiate hepatoblastoma from a more aggressive variant that mimics rhabdoid tumor.Staging
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Staging of hepatoblastoma is based on degree of surgical resection, histologic evaluation, and presence ofmetastatic disease. The system cited here is based on the work of von Schweinitz et al . [31] Stage I

o The tumor is completely resectable via wedge resection or lobectomy.o The tumor has PFH results.o The AFP level is within reference range within 4 weeks of surgery.

Stage IIAo The tumor is completely resectable.o The tumor has histologic results other than PFH (UH).

Stage IIBo The tumor is completely resectable.o AFP findings are negative at time of diagnosis (ie, no marker to follow).

Stage IICo The tumor is completely resected or rendered completely resectable by initial radiotherapy or

chemotherapy or microscopic residual disease is present.o The AFP level is elevated 4 weeks after resection.

Stage III (any of the following)o The tumor is initially unresectable but is confined to one lobe of liver.o Gross residual disease is present after surgery.o Tumor ruptures or spills preoperatively or intraoperatively.o Regional lymph nodes are involved.

Stage IV: Distant bone or lung metastasis is present.European groups have also developed a staging system through SIOPEL-1; the system uses the predictive value of

pretreatment extent of disease (PRETEXT) in order to stage patients and determine which therapy is mostappropriate .[23] Using this system, physicians are able to refer higher risk patients for evaluation by liver transplantteams earlier with improved outcomes. These groups also advocate for chemotherapy treatment of lung metastasesfollowed by surgical resection, with attempts for negative surgical margins providing optimal outcomes.Which staging regimen is preferred among the Childrens Cancer Group (CCG) staging, Pediatric Oncology Group

(POG) staging, and the European group staging is still actively discussed. However, for comparability reasons,following one staging regimen has been suggested, and international collaboration with consistency is ideal for thisrare tumor.Medical CareEuropean groups, such as the International Society for Paediatric Oncology (SIOP), and groups in the UnitedKingdom and Australia, have been instrumental in demonstrating a role for preoperative adjuvant chemotherapy inimproving surgical and overall outcomes. The European cooperative groups have also been very influential inencouraging a role for liver transplantation in patients with tumors deemed nonresectable. They have alsodeveloped criteria that can be used to determine which patients will benefit most from preoperative adjuvantchemotherapy as well as which patients should be referred early on for consideration for liver transplantation. Chemotherapy

o The most important advance in the care of children with hepatoblastoma has been the discovery ofeffective chemotherapy. Initial reports showed the efficacy of vincristine (VCR), cyclophosphamide(CPM), and doxorubicin with 5-fluorouracil (5-FU). This regimen was based on reports that suggested theefficacy of these agents in children and adults with liver tumors.

o Cisplatin is the most active single agent used to treat hepatoblastoma. Doxorubicin is active as well. Theseagents are currently being combined in clinical trials. Attempts to reduce the ototoxic effects of cisplatinhave led to the use of carboplatin; however, whether this agent will be as effective as cisplatin againsthepatoblastoma remains to be seen. No direct randomized control trial has addressed this question to date.

o The Intergroup Liver Tumor study showed similar efficacy of the cisplatin/5-FU/VCR regimen and thecisplatin plus doxorubicin regimen .[32] Because the latter regimen was more toxic, the cisplatin/5-FU/VCRcombination is regarded as standard in hepatoblastoma. The Intergroup Liver Tumor study demonstratedthat intensification of therapy by alternating platinum analogs increased the risk of adverse outcome inchildren with unresectable or metastatic hepatoblastoma. The cisplatin/5-FU/VCR regimen was shown to


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be superior in this trial. Early referral for evaluation for liver transplantation is encouraged in these patients.

o Preoperative chemotherapy can completely eradicate metastatic pulmonary disease and multinodular liverdisease. Some authors recommend that all patients undergo preoperative chemotherapy, although patientsmay present in a setting in which resection occurs first.

o Chemotherapy is usually started approximately 4 weeks after surgery to allow liver regeneration. Aminimum of 2 weeks should pass after surgery before administration of cytotoxic agents.

o Recent international data continue to support the role of neoadjuvant preoperative chemotherapy withimprovements in survival. Data from Italy in a cohort of 13 children with hepatoblastoma also support arole for etoposide and epirubicin when combined with cisplatin, with event-free survival (EFS) and overallsurvival rates at 5 years of 84% and 88%, respectively . [33]

o Perilongo et al studied whether preoperative cisplatin alone is as effective as cisplatin plus doxorubicin instandard risk hepatoblastoma .[34] Children younger than 16 years were included in the study (n=126) andrandomly assigned to receive cisplatin alone or cisplatin plus doxorubicin. Three-year EFS was 83% forcisplatin and 85% in the cisplatin/doxorubicin group. Overall survival in the cisplatin alone group was95% compared with 93% in the cisplatin/doxorubicin group. Each treatment arm achieved similar rates ofcompleted resection and survival.

o Treatment usually consists of 6 cycles of chemotherapy administered every 2- 4 weeks; -fetoprotein(AFP) levels are used as a guide to determine response to therapy.

o In addition to the drugs discussed above, carboplatin and etoposide have been used along with livertransplantation for advanced or recurrent disease with some success. Paclitaxel is also used in pat ients withextremely high-risk disease.

o Use of neoadjuvant (preoperative) chemotherapy can often render a previously inoperable tumor moreeasily resectable. Some data from tumor xenografts suggest that these tumors may respond to irinotecan.Irinotecan has indeed shown activity in relapsed or refractory hepatoblastoma but has not yet been used forfront-line therapy.

o Gemcitabine has been used with some partial responses in phase II trials. Combination therapy with otheragents may improve outcomes in patients with relapsed/recurrent disease, perhaps providing decreased

time to progression.o An approach with limited pediatric application is hepatic artery chemoembolization (HACE), which has

been used successfully in some liver tumors in adults.o Promising studies performed in mice suggest a role for antiangiogenic agents, such as vascular endothelial

growth factor (VEGF), in suppressing tumor growth in hepatoblastoma . [35] A considerable amount of preclinical data have also demonstrated a role for multidrug resistance 1 (MDR1) inhibition as potentiallyleading to an improved response to chemotherapy in tumors that have otherwise become refractory totreatment because of a drug resistance mechanism .[36, 37]

o A few isolated studies have reported patients receiving only chemotherapy with survival at greater than 5years .[38]

o New agents such as ixabepilone ,[39] gemcitabine, and bevacizumab (Avastin) have shown efficacy withtolerable side effect and the ability to administer on an outpatient basis. Bevacizumab is associated withside effects such as hypertension, leukoencephalopathy and wound-healing complications that must betaken into consideration .[40]

o Increasingly, "personalized" oncology evaluations that include assays to evaluate which pathways are mostsusceptible for relapsed patients are under investigation.

Radiotherapyo Doses used for treatment of hepatoblastoma are usually 1200-2000 centigray (cGy). These dose limits are

based on the liver's limited ability to regenerate after radiation.o Radiotherapy may be used when microscopic disease is seen at the resection margins; in general,

preoperative chemotherapy should minimize this.o Adjuvant radiotherapy may have a role in the treatment of chemoresistant pulmonary metastases.o Photodynamic diagnostics and therapy in hepatoblastoma cell lines and animal models are under

investigation.Surgical Care


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Because of the rarity of this disease and to optimize results, children with extensive hepatoblastoma should bemanaged and treated in centers affiliated with experienced liver transplant teams and with surgeons familiar withthis diagnosis and familiar with complex decisions regarding planning for resection. These surgical and livertransplant teams work closely with oncologists, pathologists, and radiologists to provide optimal outcomes.

The hepatoblastoma can be completely resected at diagnosis in approximately one third of patients, those who havestage I or II disease. In 60% of patients, hepatoblastomas are localized but are unresectable at diagnosis.Approximately 10% of patients have metastases at diagnosis, most commonly to the lungs. These figures varydepending on the age of the patient at diagnosis, the size of the tumor, and the expertise of the surgical staffavailable for the procedure. Heroic efforts to resect tumors "up front" should be avoided, and adjuvantchemotherapy should be strongly considered when subtotal resection with microscopic margins is possible or whensurgical morbidity is expected to be high.

Initial resection of operable primary tumors by lobectomy is the standard of care. Occasionally, pulmonary lesionsare resected. This can occur after chemotherapy as well, with the ultimate goal for negative surgical margins for alldisease.

The following cases warrant early referral to a transplant surgeon: Multifocal or large solitary lesions Tumors involving all 4 sectors of the liver Unifocal, centrally located tumors that involve the main hilar structures or main hepatic veins

Second-look laparotomy is warranted if AFP levels remain elevated following resection. Local porta hepatis nodalsampling is performed rather than true nodal dissection because nodal involvement is rare.

The most frequent complication of surgery is intraoperative hemorrhage; loss of the entire blood volume is notuncommon.

In cases involving a substantial portion of the liver, particularly when diaphragmatic extension precludes completesurgical resection, liver transplantation has been advocated. Liver transplantation has also been considered in the

presence of unresectable disease following neoadjuvant (preoperative) or adjuvant (postoperative) chemotherapy.Living related-donor transplantation may be considered in some situations as well. Early involvement of the livertransplant team and the hepatology team is essential because delays can adversely affect outcomes.

Results from numerous cooperative international large group studies on hepatoblastoma continue to support a rolefor preoperative adjuvant chemotherapy in those tumors not easily respectable up front .[6, 41, 42, 43, 28] Some authorsadvocate using adjuvant chemotherapy preoperatively, even when resection may be successful up front. Thecontroversy over this is considerable ,[44] but all are in agreement that complete resection with no residual disease isultimately the most important prognostic factor for improved survival results in hepatoblastoma. Hence, anytreatment, medical or surgical, that leads to an improvement in gross total resection is the goal.

Increasing evidence suggests that arterial chemoembolization is feasible in patients with unresectablehepatoblastoma, patients who are not candidates for liver transplant, or both.

Liver transplantation has an increasing role in children with nonresectable tumors or in those who showchemotherapy resistance. Overall 5-year survival is as high as 70-89% in some series. Early referral andcollaboration with liver transplant centers is encouraged. Whether posttransplant chemotherapy is indicated iscontroversial.

Thoracotomy and resection of pulmonary metastases also have a role, with some patients having long-termdisease-free survival when aggressive attempts are made to surgically eradicate all areas of disease.Consultations

A multidisciplinary approach in children with malignancy is necessary to ensure that appropriate care is safelyadministered with minimal toxicity. The team usually consists of specialized pediatric nurses, pediatric surgeons,

pharmacologists with expertise in dealing with chemotherapy in children, nutritionists, social workers, child lifespecialists, and subspecialists in areas such as pediatric gastroenterology, neurology, cardiology, and infectiousdiseases.

Early referral to liver transplant centers is encouraged for nonresectable tumors or those that show chemotherapyresistance.

Referral to a radiation oncologist with pediatric experience may also be indicated.Diet


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Adequate nutrition is necessary for childhood growth and development. Maintaining adequate nutritional status isalso important to maximize response to therapy.

Many of the treatments may result in compromised nutritional status. Children undergoing r adiotherapy orchemotherapy, particularly children younger than 5 years, typically require enteral or parenteral supplementation,often with electrolyte supplementation as well.

Occupational therapists and child life specialists may be consulted to help with behavioral issues related to feeding, particularly in infants and toddlers.Activity

Specific postoperative limitations on activity may be necessary, and, occasionally, some activities are limited because of central line placement or severe immunosuppression and myelosuppression associated with therapy;otherwise, no specific limitations are placed on activity.

Most children are encouraged to attend daycare or school and participate in normal play essential to childhooddevelopment. Contact sports should be avoided during therapy, especially during periods of thrombocytopenia.

Medication Summary All chemotherapy orders are written and countersigned by pediatric oncologists. Most children are treated

according to clinical protocols used in multiple institutions. For patients with refractory disease, a phase Ior II trial is usually considered. Information on clinical trials is usually accessible through the NationalCancer Institute (NCI) Web site and linked sites. The resources presented below should serve asguidelines only.

Antineoplastic agents have a narrow therapeutic index, and effective doses usually cause significant toxiceffects. Any physician or other practitioner caring for children with cancer must be familiar with theindications, appropriate dosages, and toxic effects of the chemotherapy agents prescribed. They must also

be familiar with any special considerations regarding age, weight, pharmacokinetic variations (ie, drugabsorption, distribution, metabolism, excretion), coexisting medical problems, or possible

pharmacokinetic interactions. To minimize risk to the patient, only practitioners familiar with the toxiceffects and potential complications should prescribe antineoplastic agents.

Full discussion of the agents typically used in treating hepatoblastoma is beyond the scope of this article, but brief summaries of the drugs most commonly used are provided below.

Antineoplastic agents, alkylating agents, metal salts Class Summary

The mechanism of action is similar to that of alkylating agents, namely, binding and cross-linking DNAstrands.

View full drug information Carboplatin (Paraplatin)

Similar to cisplatin, produces DNA cross-links that are predominantly interstrand. Effect is cell cycle

nonspecific. View full drug information

Cisplatin (Platinol)

Binds and cross-links DNA strands, disrupting cell function. Usually combined with etoposide or

doxorubicin. View full drug information

Cyclophosphamide (Cytoxan, Neosar)

After metabolism by hepatic microsomal enzymes, produces active alkylating metabolites that probably

damage DNA. Usually administered with doxorubicin and vincristine or doxorubicin and cisplatin. Alsoan immunosuppressant.

Administered with mesna to prevent urotoxicity (ie, hemorrhagic cystitis). Antitumor antibiotics, natural products
http://www.cancer.gov/http://www.cancer.gov/http://www.cancer.gov/http://www.cancer.gov/http://reference.medscape.com/drug/paraplatin-carboplatin-342107#1http://reference.medscape.com/drug/paraplatin-carboplatin-342107#1http://reference.medscape.com/drug/paraplatin-carboplatin-342107#1http://reference.medscape.com/drug/paraplatin-carboplatin-342107#1http://reference.medscape.com/drug/platinol-aq-cisplatin-342108#1http://reference.medscape.com/drug/platinol-aq-cisplatin-342108#1http://reference.medscape.com/drug/platinol-aq-cisplatin-342108#1http://reference.medscape.com/drug/platinol-aq-cisplatin-342108#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/cytoxan-cyclophosphamide-342214#1http://reference.medscape.com/drug/platinol-aq-cisplatin-342108#1http://reference.medscape.com/drug/platinol-aq-cisplatin-342108#1http://reference.medscape.com/drug/paraplatin-carboplatin-342107#1http://reference.medscape.com/drug/paraplatin-carboplatin-342107#1http://www.cancer.gov/http://www.cancer.gov/


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Class Summary

These agents are usually derived from microorganisms and have various antitumor mechanisms. Allinterfere with the DNA structure or the breakage-resealing process.

View full drug information Doxorubicin (Adriamycin)

Causes DNA strand breakage mediated by effects on topoisomerase II. Intercalates into DNA and inhibits

DNA polymerase. Usually combined with vincristine and cyclophosphamide, or with cisplatin. Topoisomerase II inhibitors, natural products Class Summary

These plant alkaloids inhibit the topoisomerases that interfere with the normal DNA breakage-resealingreaction and cause single-strand breaks in DNA.

View full drug information Etoposide (Toposar, VePesid)

Interacts with topoisomerase II and produces single-strand breaks in DNA. Arrests cells in late S phase or

G2 phase. Typically combined with ifosfamide, cisplatin, or carboplatin. Antineoplastic antimetabolites Class Summary

These agents are close structural analogs of vital intermediates in the biosynthetic pathways of nucleicacids and proteins. They either inhibit synthesis of cellular macromolecules and their building blocks orare incorporated into the macromolecules, resulting in a defective product.

View full drug information 5-Fluorouracil (Adrucil)

Prodrug that inhibits thymidine synthesis and is incorporated into RNA and DNA. Specific to the S phase of the cell cycle. Mitotic inhibitors, natural products Class Summary

These plant alkaloids bind to microtubular proteins, inhibiting RNA synthesis by disrupting DNAformation.

View full drug information Vincristine (Oncovin, Vincasar PFS)

Binds tubulin, leading to its depolymerization, which results in mitotic inhibition and metaphase arrest.Specific to S and M phases of the cell cycle. Used in combination with doxorubicin andcyclophosphamide.

Colony-stimulating factors Class Summary

These agents promote growth and differentiation of myeloid progenitor cells. They may improve survivaland function of granulocytes.

View full drug information Filgrastim (Neupogen)

G-CSF Used to combat neutropenia, particularly in patients receiving myelosuppressive therapy.Produced recombinantly in Escherichia coli for clinical use.

Further Inpatient Care
http://reference.medscape.com/drug/doxorubicin-342120#1http://reference.medscape.com/drug/doxorubicin-342120#1http://reference.medscape.com/drug/doxorubicin-342120#1http://reference.medscape.com/drug/doxorubicin-342120#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/adrucil-fluorouracil-342092#1http://reference.medscape.com/drug/adrucil-fluorouracil-342092#1http://reference.medscape.com/drug/adrucil-fluorouracil-342092#1http://reference.medscape.com/drug/adrucil-fluorouracil-342092#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/g-csf-neupogen-filgrastim-342164#1http://reference.medscape.com/drug/g-csf-neupogen-filgrastim-342164#1http://reference.medscape.com/drug/g-csf-neupogen-filgrastim-342164#1http://reference.medscape.com/drug/g-csf-neupogen-filgrastim-342164#1http://reference.medscape.com/drug/g-csf-neupogen-filgrastim-342164#1http://reference.medscape.com/drug/g-csf-neupogen-filgrastim-342164#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#1http://reference.medscape.com/drug/adrucil-fluorouracil-342092#1http://reference.medscape.com/drug/adrucil-fluorouracil-342092#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/vepesid-toposar-etoposide-342098#1http://reference.medscape.com/drug/doxorubicin-342120#1http://reference.medscape.com/drug/doxorubicin-342120#1


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Follow-up care: Children may be admitted to the hospital to expedite the diagnostic workup or when severe signsor symptoms are present. For medically stable patients, the workup can be performed in the outpatient setting. Acentral line is typically placed when the patient is scheduled for biopsy or resection. Double-lumen central lines are

preferred if vessel access is adequate because this allows concurrent administration of multiple parenteralmedications.

Multidisciplinary evaluation: The child is initially evaluated by a pediatric oncologist and surgeons with expertisein childhood malignancies. Evaluation should be performed at a pediatric cancer center. Once the diagnosis isestablished and the staging workup is completed, the patient and family are instructed on the diagnosis andtherapeutic options. Most children and families are offered participation in cooperative group trials. Once thetreatment plan is developed, chemotherapy is most frequently administered in the inpatient setting. However, withimprovements in supportive care, some chemotherapy may be administered in the outpatient setting. Followingcompletion of the treatment cycle, patients are discharged home with detailed instructions for home care andoutpatient follow-up visits.

Liver transplantation: Patients who undergo liver transplantation require a multidisciplinary team with experiencedhepatologist and liver transplant surgeons as well as the team outlined above.Further Outpatient Care

Patients are periodically monitored in the clinic after each course of therapy to assess for complications andresponse to therapy.

Myelosuppression and pancytopenia are common complications, and a CBC count with a platelet count is obtainedonce or twice weekly.

Some drugs, such as cisplatin and carboplatin, affect renal function and require close monitoring of electrolytesand oral or parenteral electrolyte supplementation.

Blood product support is provided when the hemoglobin drops below 8 g/dL, symptoms of anemia are present, the platelet count drops below 10,000 X 10 9/L, or any signs of bleeding are evident.

Fever must be treated as a medical emergency during therapy because the risk of a bacterial or fungal infection ishigh in patients with myelosuppression.

Children with central lines are susceptible to bacteremia and life-threatening sepsis. In addition, all children withcentral lines must receive appropriate antimicrobial prophylaxis against subacute bacterial endocarditis (SBE) for

all procedures, including dental procedures. Close contact with the liver transplant team is required for patients who require this treatment. All medical

decisions for patients with this complex condition should be communicated to all members of the team includingoncologists, primary surgeon, hepatologists, and transplant surgeons.

Late effects clinics are available at most major oncology centers, and children with hepatoblastoma should bereferred to these clinics if they remain disease free for more than 2 years. Even if the risk of recurrence decreaseswith time, these children are still at risk for late effects, which include secondary cancers (etoposide andanthracycline), cardiotoxicity (anthracycline), renal toxicity (platinum agents), ototoxicity (platinum agents), and

potential speech and developmental delays due to therapy administered. Psychosocial team members, child life experts, medical social workers, nutritionists, and all care providers can

help families adjust to life after cancer and can also help encourage a cancer preventive lifestyle for these at-risk

patients.Inpatient & Outpatient Medications

Infection prophylaxis: Chemotherapy agents cause myelosuppression and immunosuppression. Prophylaxisagainst Pneumocystis jiroveci, which causes Pneumocystis carinii pneumonia, is recommended for all patients. Thedrug of choice is trimethoprim-sulfamethoxazole (2.5 mg/kg/dose of trimethoprim administered orally twice daily)administered on 3 consecutive days per week. Prophylaxis is initiated before chemotherapy and is continued for atleast 3 months after completing therapy.

Colony-stimulating factors: Granulocyte colony-stimulating factor (G-CSF) support has become common in pediatric oncology as the intensity of chemotherapy has increased. The doses recommended are 5-10 mcg/kg/d,starting 24-36 hours after the last dose of chemotherapy. G-CSF administration is continued for 10-14 days or untilthe absolute neutrophil count (ANC) is greater than 2,000-10,000/mcL.

Erythropoietin: The use of erythropoietin is discouraged because of reports that hepatoblastoma has receptors forthis agent and may therefore be stimulated to grow from exogenous sources.Transfer


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With supervision by the oncology team, routine care can be performed by the primary care provider for patientconvenience. CBC counts and blood chemistries may be obtained and blood products may be administered by

primary care providers. Some patients may even be evaluated and treated for febrile neutropenia by the primary care provider. However,

the primary care provider must maintain close contact with the subspecialist physicians and transfer the patient tothe pediatric oncology center for any complications that require specialized care.Deterrence/Prevention

The cause of hepatoblastoma is unknown. Because onset of hepatoblastoma is in patients at a young age,investigators have focused on events before conception and during gestation. Factors for which evidence is limitedor inconsistent include medications, hormones, birth characteristics, congenital anomalies, previous spontaneousabortion or fetal death, alcohol consumption, tobacco use, and paternal occupational exposures.

Children with hemihypertrophy or Beckwith-Wiedemann syndrome (BWS) and children born to individualsaffected by familial adenomatous poly posis (FAP) should be screened regularly using blood -fetoprotein (AFP)levels as dictated in current protocols. Children found to harbor a FAP mutation should be periodically monitoredfor the development of polyps by a gastroenterologist as they reach the teenage years.ComplicationsTumor rupture may occur at diagnosis, resulting in acute abdomen or severe hemorrhage, both of which constitute

medical emergencies. Intraoperative and postoperative complications may occur as a result of resection or biopsy procedures.Complications can develop with the administration of chemotherapy. Myelosuppression and immunosuppression

place the patient at risk for bleeding and infection. After several cycles of therapy, organ toxicity may occur; forexample, renal function or hearing may be impaired.Posttransplantion complications can develop and require close long-term follow-up by the liver transplant team.Particular attention must be paid to cardiac, renal, and hearing status to assess for the long-term toxic effects ofanthracyclines, cisplatin, or carboplatin. One of the most important adverse effects of platinum chemotherapy ishearing loss. A Cochrane Database review of 3 studies that evaluated the use of the chemoprotective agentamifostine versus no additional treatment did not come to any definitive conclusions. Further research is neededregarding the usefulness of possible drugs to prevent hearing loss in children treated with platinum

chemotherapy .[45]

Psychosocial effects of frequent painful procedures, hospitalizations, and interference with normal childhoodgrowth and development must be addressed, and children and families must be referred to appropriate specialistswhen needed. The family's psychosocial needs are affected greatly by having a child with cancer.Prognosis

See Mortality/Morbidity.Patient Education

Medications: To ensure compliance and good medical care, patient and family understanding regarding theimportance of treatment and the toxic effects of the medications is critical. In addition, patients and their familiesshould learn to recognize and identify signs and symptoms of complications that require urgent medical care.

Long-term follow-up surveillance: After completion of therapy, patients in whom treatment was successful require

close surveillance for any signs or symptoms of recurrent disease. Follow-up care includes monitoring AFP levels, physical examination, and diagnostic imaging. Because most recurrences occur during the first 2 years followingtreatment, most protocols recommend close follow-up monitoring during this interval. Hepatoblastoma does notusually recur more than 3 years after completion of therapy.

Long-term issues: Growth and development and long-term toxic effects on organs are long-term issues. Patientswho remain free of recurrent disease for 5 years are considered cured; long-term follow-up monitoring to assessthe impact of therapy on growth, development, and organ toxicity is essential. Patients are usually monitored by

pediatric oncologists, but some sequelae may require the involvement of other subspecialist health care providers. Other issues: Most centers have late effects clinics, and all children treated for cancer should continue to see their

oncology providers regularly to monitor for potential long-term complications of therapy. When appropriate, mostcenters help transition to an adult provider, with guidelines on what to watch for and which tests should be

performed to monitor for potential late effects. A cancer-preventive lifestyle is encouraged and includes avoiding passive or primary tobacco exposure, wearing sunscreen, healthy eating habits, maintaining a healthy weight, andan exercise regimen.


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