H e p a t o c e l l u l a r C a rc i n o m a in Children Deirdre Kelly, FRCPCH, FRCP, FRCPI, MDa,*, Khalid Sharif, FRCS Paed, FCPS Paed Surg (Pak)a, Rachel M. Brown, MBChB, FRCPathb, Bruce Morland, MBChB, MRCP, DM, FRCPCHc KEYWORDS Hepatocellular Carcinoma Pediatrics Epidemiology Histopathology Transplant Outcome KEY POINTS The spectrum of background liver disease predisposing to hepatocellular carcinoma (HCC) in children is different from that in adults. In children younger than 5 years the differential diagnosis of hepatoblastoma (HB) should be considered. The fibrolamellar variant preferentially affects teenagers and young adults.
HEPATOCELLULAR CARCINOMA IN CHILDREN
Liver tumors are relatively rare in childhood, but may be associated with a range of diagnostic, genetic, therapeutic, and surgical challenges sufficient to tax even the most experienced clinician. This article outlines the epidemiology, etiology, pathology, initial workup, and management of HCC in children and adolescents. Epidemiology
Primary pediatric liver malignancies comprise 1% to 2% of all pediatric tumors. HB is the commonest primary hepatic malignancy (48%); HCC is the second most common primary liver malignancy of childhood (27%) with vascular tumors and sarcomas making up the rest.1 HCC has an incidence of 0.3 to 0.45 cases per million per year (23%) and represents an increasingly common indication for liver transplant (LT) in children. Although HCC is more common in adolescents (10–14 years), histologically
The authors have nothing to disclose. a The Liver Unit, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK; b Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, UK; c Oncology Department, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK * Corresponding author. E-mail address: [email protected] Clin Liver Dis 19 (2015) 433–447 http://dx.doi.org/10.1016/j.cld.2015.01.010
liver.theclinics.com
1089-3261/15/$ – see front matter Crown Copyright Ó 2015 Published by Elsevier Inc. All rights reserved.
434
Kelly et al
confirmed HCC has been reported in children younger than 5 years. HCC is more common in males than in females with 3:1 preponderance and tends to present with more advanced disease in children than in adults. Childhood HCC incidence increases significantly with age; however, it has remained stable over the past few decades. Data collected from the West Midlands Regional Children’s Tumour Registry2 have indicated the incidence of liver tumors to be 1.2 per million person-years: the incidence of HCC was 0.09, somewhat lower than that reported in published series. Cause
HCC is primarily an adult-onset disease, with only 0.5% to 1% of cases occurring before the age of 20 years. Many etiologic factors worldwide have been linked with the development of HCC including cirrhosis (due to various causes including alcohol intake), hepatitis B and C, and ingestion of aflatoxins in contaminated food. These factors produce significant geographic variation, with HCC being most common in subSaharan Africa and southeast Asia, where its incidence may reach 90 to 100 per 100,000 population largely as a result of hepatitis B virus (HBV) infection. There is a strong link between HCC and infection with the HBV. The incidence of HCC in chronic HBV carriers is approximately100-fold greater than that in the HBV-negative population3 and is commoner in areas with high endemic HBV infection rates. Chen and colleagues4 reported 100% positivity for HBV infection in Taiwan, and Chan and colleagues5 reported 64% positivity in children with HCC in Hong Kong. Although integration of the HBV genome into the HCC genome can be demonstrated at the molecular level,6 this event in itself is not necessarily oncogenic and a secondary, as yet unidentified, promoter is probably necessary for the development of tumor.7 This secondary promoter could be environmental influences or genetic variations. The decrease of HBV because of neonatal vaccination has led to a reduction of cases in childhood, which will, in time, be reflected in the adult population.8 Although hepatitis C is a known risk factor for HCC in adults, it is rare in children and there is only a single case report of this occurrence requiring transplant.9 Tyrosinemia I (fumarylacetoacetate hydrolase deficiency) is an autosomal recessive inborn error of tyrosine metabolism that produces liver failure in infancy or chronic liver disease with cirrhosis. Before therapy, there was a high risk of HCC in childhood or early adolescence. The development of therapy with nitisinone (2-[2-nitro-4-(trifluoromethyl)benzoyl] cyclohexane-1,3-dione), which prevents the production of cytotoxic tyrosine metabolites in combination with a tyrosine- and phenylalanine-restricted diet, has transformed the natural history of tyrosinemia and has reduced, but not eliminated the risk of HCC.10,11 HCC is also associated with glycogen storage disease types 1 and IV.12 The link between cirrhosis and HCC is unclear; however, the association of cirrhosis of any origin and dysplastic regenerating nodules have long been considered as precursors of HCC. Only about 30% of pediatric cases of HCC are associated with cirrhosis or preexisting liver abnormality, in contrast to adult HCC in which cirrhosis is present in 70% to 90%. Similarly, alpha-1-antitrypsin deficiency exhibits a different mechanism for carcinogenesis, where liver injury results from abnormal and chronic regenerative signaling from the sick cells to younger less-sick hepatocytes: chronic regeneration in the presence of tissue injury leading to adenomas and ultimately to carcinomas. It is suggested that the latter mechanism may explain hepatocarcinogenesis in other chronic liver diseases, that is, genetic disorders, viral hepatitis or nonalcoholic steatohepatitis, and glycogen storage disease type III. It has been recently suggested that progressive familial intrahepatic cholestasis type 2 (PFIC 2), associated with a mutation of the ABCB11 gene resulting in deficiency of bile salt
HCC in Children
export pump (BSEP; a membrane canalicular bile acid transporter), represents a specific and previously unrecognized risk for HCC in young children.13 In cases associated with tyrosinemia type I, cirrhosis is an invariable finding. In cases associated with biliary atresia, the development of HCC is not universally associated with cirrhosis, and in cases of Wilson disease or cholestatic syndromes that may not be associated with cirrhosis (eg, Alagille syndrome and PFIC 1 and PFIC 3), there seems to be no predisposition to malignant transformation.14 Thus, while the development of cirrhosis clearly has a part to play in oncogenesis, the exact relationship remains unclear. Clinical Features
The classic symptoms of HCC in noncirrhotic individuals are similar to symptoms of those with other liver tumors, the common presentation being an abdominal mass and pain; in advanced cases children may have cachexia or jaundice. Symptoms and signs of liver insufficiency may be present if the tumor arises in the context of liver disease, and thus signs of underlying liver disease (splenomegaly from portal hypertension, spider nevi, etc.) should be sought as a possible clue to underlying etiologic factors. The rare fibrolamellar type of HCC is usually seen in the older age group (median age 26.4 years) and generally occurs in noncirrhotic livers. The commonest presentation is with an abdominal mass without any other systemic symptoms. These tumors are thought to have a more favorable prognosis because these tend not to spread early. Diagnostic Investigations Laboratory tests
There are no specific diagnostic findings on full blood count associated with HCC; however, liver function tests frequently give abnormal results especially in children in whom HCC has occurred in cirrhotic livers. In children with PFIC 2, gamma glutamyltransferase levels are low. Exclusion of known risk factors, such as serology for hepatitis B and C, plasma and urine amino acid and urinary succinyl acetone for tyrosinemia, as well as level and phenotype for alpha-1 antitrypsin, should be performed. If suspected, genetic confirmation of PFIC 2, tyrosinemia, and Alagille syndrome should be done. Alphafetoprotein
Alphafetoprotein (AFP) is a useful diagnostic and prognostic marker of HCC and its level is elevated in nearly 50% to 70% patients with HCC.15,16 However, it should be noted that cirrhosis may also lead to persistent AFP elevation because of hepatic regeneration. Most investigators agree that AFP levels greater than 400 to 500 ng/mL in a patient with cirrhosis strongly suggest the diagnosis of HCC, whereas some propose an even lower cutoff between 200 and 300 ng/mL. Levels tend to be higher in patients with more bulky disease and with metastases. AFP levels are used as a useful prognostic marker, with return of AFP levels to normal after treatment indicating remission, whereas persistently abnormal results should alert the clinician to the possibility of residual tumor or relapse. Other markers
The fibrolamellar variant of HCC is usually associated with normal values of AFP, but elevation of levels of vitamin-B12-binding proteins, especially transcobalamin I, makes this a useful marker that may also be used to monitor disease response and progression.
435
436
Kelly et al
Radiologic Investigations
The radiologic assessment of HCC aims to determine the site and characteristics of the tumor, establish the presence of any metastases, and help to assess the suitability for surgical resection. In children without cirrhosis, it is difficult to distinguish HCC from HB on imaging grounds alone. Both tumors are typically large (unless detected by screening) and are often multifocal. In both tumors there may be evidence of calcification, venous invasion, and lung metastases. Ultrasonography
The typical sonographic appearance of HCC is of a large, heterogeneous (usually predominantly hyperechoic), and vascular mass. The use of ultrasonographic contrast agents in children is currently experimental, but the results in adults suggest that they may be helpful for identifying and characterizing liver lesions.17 Computed tomography scan
Computed tomographic (CT) scanning gives detailed information on the anatomic limits of liver tumors. Triphasic CT scan, after administration of intravenous contrast typically shows HCCs to be hypervascular in the arterial phase and isodense or hypodense in the portal venous phase. This technique is widely used for the detection of HCC in adults with cirrhosis, but it is relatively insensitive to small tumors, especially when cirrhosis is present, with an overall sensitivity and specificity of about 80% to 85% and 90% to 95%, respectively.18,19 MRI scanning
MRI scanning is now considered as the investigation of choice because it gives good definition of the tumor and surrounding infiltration, enabling accurate assessment of segmental involvement. MRI findings of HCC tend to be of a heterogeneous (but predominantly hypointense) mass on T1-weighted images, and mildly hyperintense in comparison with normal liver on T2-weighted images. Contrast-enhanced T1-weighted images show a pattern similar to CT, with early arterial enhancement and reduced signal intensity in the portal venous phase.20 This observation has important implications for clinical staging and any proposed surgical interventions. The vascular anatomy can also be demonstrated and may avoid the need for hepatic angiography. In the adult with a chronically deranged liver, radiologic staging of HCC is based on conventional criteria endorsed by the European Association for Study of the Liver and the American Association for the Study of Liver Disease.21 While these staging criteria can be adopted for staging of HCC in children, prospective series using these systems have not been validated. PET scan imaging
Areas of high metabolism may help to find extrahepatic sites that may not be detected by other imaging modalities. PET has been proved to be useful for localizing relatively early some metastases or recurrence of disease before any mass effect per se was detectable on routine checks. Biopsy
Although clinical and laboratory clues can lead to a presumptive diagnosis in most children with liver tumors, caution must be exercised at all times. Unless primary surgery is feasible, biopsy is necessary in all patients without cirrhosis. In the setting of cirrhosis, HCC can often be diagnosed by imaging and elevated AFP level; however, biopsy may still be required in equivocal cases, especially with small lesions (
HEPATOCELLULAR CARCINOMA IN CHILDREN
Liver tumors are relatively rare in childhood, but may be associated with a range of diagnostic, genetic, therapeutic, and surgical challenges sufficient to tax even the most experienced clinician. This article outlines the epidemiology, etiology, pathology, initial workup, and management of HCC in children and adolescents. Epidemiology
Primary pediatric liver malignancies comprise 1% to 2% of all pediatric tumors. HB is the commonest primary hepatic malignancy (48%); HCC is the second most common primary liver malignancy of childhood (27%) with vascular tumors and sarcomas making up the rest.1 HCC has an incidence of 0.3 to 0.45 cases per million per year (23%) and represents an increasingly common indication for liver transplant (LT) in children. Although HCC is more common in adolescents (10–14 years), histologically
The authors have nothing to disclose. a The Liver Unit, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK; b Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, UK; c Oncology Department, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK * Corresponding author. E-mail address: [email protected] Clin Liver Dis 19 (2015) 433–447 http://dx.doi.org/10.1016/j.cld.2015.01.010
liver.theclinics.com
1089-3261/15/$ – see front matter Crown Copyright Ó 2015 Published by Elsevier Inc. All rights reserved.
434
Kelly et al
confirmed HCC has been reported in children younger than 5 years. HCC is more common in males than in females with 3:1 preponderance and tends to present with more advanced disease in children than in adults. Childhood HCC incidence increases significantly with age; however, it has remained stable over the past few decades. Data collected from the West Midlands Regional Children’s Tumour Registry2 have indicated the incidence of liver tumors to be 1.2 per million person-years: the incidence of HCC was 0.09, somewhat lower than that reported in published series. Cause
HCC is primarily an adult-onset disease, with only 0.5% to 1% of cases occurring before the age of 20 years. Many etiologic factors worldwide have been linked with the development of HCC including cirrhosis (due to various causes including alcohol intake), hepatitis B and C, and ingestion of aflatoxins in contaminated food. These factors produce significant geographic variation, with HCC being most common in subSaharan Africa and southeast Asia, where its incidence may reach 90 to 100 per 100,000 population largely as a result of hepatitis B virus (HBV) infection. There is a strong link between HCC and infection with the HBV. The incidence of HCC in chronic HBV carriers is approximately100-fold greater than that in the HBV-negative population3 and is commoner in areas with high endemic HBV infection rates. Chen and colleagues4 reported 100% positivity for HBV infection in Taiwan, and Chan and colleagues5 reported 64% positivity in children with HCC in Hong Kong. Although integration of the HBV genome into the HCC genome can be demonstrated at the molecular level,6 this event in itself is not necessarily oncogenic and a secondary, as yet unidentified, promoter is probably necessary for the development of tumor.7 This secondary promoter could be environmental influences or genetic variations. The decrease of HBV because of neonatal vaccination has led to a reduction of cases in childhood, which will, in time, be reflected in the adult population.8 Although hepatitis C is a known risk factor for HCC in adults, it is rare in children and there is only a single case report of this occurrence requiring transplant.9 Tyrosinemia I (fumarylacetoacetate hydrolase deficiency) is an autosomal recessive inborn error of tyrosine metabolism that produces liver failure in infancy or chronic liver disease with cirrhosis. Before therapy, there was a high risk of HCC in childhood or early adolescence. The development of therapy with nitisinone (2-[2-nitro-4-(trifluoromethyl)benzoyl] cyclohexane-1,3-dione), which prevents the production of cytotoxic tyrosine metabolites in combination with a tyrosine- and phenylalanine-restricted diet, has transformed the natural history of tyrosinemia and has reduced, but not eliminated the risk of HCC.10,11 HCC is also associated with glycogen storage disease types 1 and IV.12 The link between cirrhosis and HCC is unclear; however, the association of cirrhosis of any origin and dysplastic regenerating nodules have long been considered as precursors of HCC. Only about 30% of pediatric cases of HCC are associated with cirrhosis or preexisting liver abnormality, in contrast to adult HCC in which cirrhosis is present in 70% to 90%. Similarly, alpha-1-antitrypsin deficiency exhibits a different mechanism for carcinogenesis, where liver injury results from abnormal and chronic regenerative signaling from the sick cells to younger less-sick hepatocytes: chronic regeneration in the presence of tissue injury leading to adenomas and ultimately to carcinomas. It is suggested that the latter mechanism may explain hepatocarcinogenesis in other chronic liver diseases, that is, genetic disorders, viral hepatitis or nonalcoholic steatohepatitis, and glycogen storage disease type III. It has been recently suggested that progressive familial intrahepatic cholestasis type 2 (PFIC 2), associated with a mutation of the ABCB11 gene resulting in deficiency of bile salt
HCC in Children
export pump (BSEP; a membrane canalicular bile acid transporter), represents a specific and previously unrecognized risk for HCC in young children.13 In cases associated with tyrosinemia type I, cirrhosis is an invariable finding. In cases associated with biliary atresia, the development of HCC is not universally associated with cirrhosis, and in cases of Wilson disease or cholestatic syndromes that may not be associated with cirrhosis (eg, Alagille syndrome and PFIC 1 and PFIC 3), there seems to be no predisposition to malignant transformation.14 Thus, while the development of cirrhosis clearly has a part to play in oncogenesis, the exact relationship remains unclear. Clinical Features
The classic symptoms of HCC in noncirrhotic individuals are similar to symptoms of those with other liver tumors, the common presentation being an abdominal mass and pain; in advanced cases children may have cachexia or jaundice. Symptoms and signs of liver insufficiency may be present if the tumor arises in the context of liver disease, and thus signs of underlying liver disease (splenomegaly from portal hypertension, spider nevi, etc.) should be sought as a possible clue to underlying etiologic factors. The rare fibrolamellar type of HCC is usually seen in the older age group (median age 26.4 years) and generally occurs in noncirrhotic livers. The commonest presentation is with an abdominal mass without any other systemic symptoms. These tumors are thought to have a more favorable prognosis because these tend not to spread early. Diagnostic Investigations Laboratory tests
There are no specific diagnostic findings on full blood count associated with HCC; however, liver function tests frequently give abnormal results especially in children in whom HCC has occurred in cirrhotic livers. In children with PFIC 2, gamma glutamyltransferase levels are low. Exclusion of known risk factors, such as serology for hepatitis B and C, plasma and urine amino acid and urinary succinyl acetone for tyrosinemia, as well as level and phenotype for alpha-1 antitrypsin, should be performed. If suspected, genetic confirmation of PFIC 2, tyrosinemia, and Alagille syndrome should be done. Alphafetoprotein
Alphafetoprotein (AFP) is a useful diagnostic and prognostic marker of HCC and its level is elevated in nearly 50% to 70% patients with HCC.15,16 However, it should be noted that cirrhosis may also lead to persistent AFP elevation because of hepatic regeneration. Most investigators agree that AFP levels greater than 400 to 500 ng/mL in a patient with cirrhosis strongly suggest the diagnosis of HCC, whereas some propose an even lower cutoff between 200 and 300 ng/mL. Levels tend to be higher in patients with more bulky disease and with metastases. AFP levels are used as a useful prognostic marker, with return of AFP levels to normal after treatment indicating remission, whereas persistently abnormal results should alert the clinician to the possibility of residual tumor or relapse. Other markers
The fibrolamellar variant of HCC is usually associated with normal values of AFP, but elevation of levels of vitamin-B12-binding proteins, especially transcobalamin I, makes this a useful marker that may also be used to monitor disease response and progression.
435
436
Kelly et al
Radiologic Investigations
The radiologic assessment of HCC aims to determine the site and characteristics of the tumor, establish the presence of any metastases, and help to assess the suitability for surgical resection. In children without cirrhosis, it is difficult to distinguish HCC from HB on imaging grounds alone. Both tumors are typically large (unless detected by screening) and are often multifocal. In both tumors there may be evidence of calcification, venous invasion, and lung metastases. Ultrasonography
The typical sonographic appearance of HCC is of a large, heterogeneous (usually predominantly hyperechoic), and vascular mass. The use of ultrasonographic contrast agents in children is currently experimental, but the results in adults suggest that they may be helpful for identifying and characterizing liver lesions.17 Computed tomography scan
Computed tomographic (CT) scanning gives detailed information on the anatomic limits of liver tumors. Triphasic CT scan, after administration of intravenous contrast typically shows HCCs to be hypervascular in the arterial phase and isodense or hypodense in the portal venous phase. This technique is widely used for the detection of HCC in adults with cirrhosis, but it is relatively insensitive to small tumors, especially when cirrhosis is present, with an overall sensitivity and specificity of about 80% to 85% and 90% to 95%, respectively.18,19 MRI scanning
MRI scanning is now considered as the investigation of choice because it gives good definition of the tumor and surrounding infiltration, enabling accurate assessment of segmental involvement. MRI findings of HCC tend to be of a heterogeneous (but predominantly hypointense) mass on T1-weighted images, and mildly hyperintense in comparison with normal liver on T2-weighted images. Contrast-enhanced T1-weighted images show a pattern similar to CT, with early arterial enhancement and reduced signal intensity in the portal venous phase.20 This observation has important implications for clinical staging and any proposed surgical interventions. The vascular anatomy can also be demonstrated and may avoid the need for hepatic angiography. In the adult with a chronically deranged liver, radiologic staging of HCC is based on conventional criteria endorsed by the European Association for Study of the Liver and the American Association for the Study of Liver Disease.21 While these staging criteria can be adopted for staging of HCC in children, prospective series using these systems have not been validated. PET scan imaging
Areas of high metabolism may help to find extrahepatic sites that may not be detected by other imaging modalities. PET has been proved to be useful for localizing relatively early some metastases or recurrence of disease before any mass effect per se was detectable on routine checks. Biopsy
Although clinical and laboratory clues can lead to a presumptive diagnosis in most children with liver tumors, caution must be exercised at all times. Unless primary surgery is feasible, biopsy is necessary in all patients without cirrhosis. In the setting of cirrhosis, HCC can often be diagnosed by imaging and elevated AFP level; however, biopsy may still be required in equivocal cases, especially with small lesions (
