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Epidemiology of primary hepatic malignancies in U.S. children
LIVER FAILURE AND LIVER DISEASE
Epidemiology of Primary Hepatic Malignancies in U.S. Children Anil Darbari,1 Keith M. Sabin,2 Craig N. Shapiro,2 and Kathleen B. Schwarz1 The epidemiology of primary hepatic malignancies in U.S. children is poorly characterized. We analyzed the incidence, mortality, and characteristics of primary hepatic malignancies in U.S. residents less than 20 years of age. Fatal primary hepatic malignancies in persons less than 20 years of age, between 1979 and 1996, were identified using the multiple-cause-ofdeath database (National Center for Health Statistics). Histologically confirmed primary hepatic malignancies occurring between 1973 and 1997 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Between 1979 and 1996, 918 primary hepatic malignancy deaths (average, 0.7/1,000,000/year) were reported nationally among persons less than 20 years of age; rates were higher among Asians and among foreignborn children. Between 1973 and 1997, 271 primary hepatic malignancy cases were reported to SEER among persons less than 20 years of age, of which 184 (67%) and 83 (31%) were hepatoblastoma and hepatocellular carcinoma, respectively. Among children less than 5 years of age, hepatoblastoma accounted for 91% of primary hepatic malignancy cases, whereas among those 15 to 19 years of age, hepatocellular carcinoma accounted for 87% of cases. Five-year survival for hepatoblastoma was 52%, compared with 18% for hepatocellular carcinoma. In the SEER sites, between 1973 and 1977 and 1993 and 1997, hepatoblastoma rates increased (0.6 to 1.2/1,000,000, respectively), while hepatocellular carcinoma rates decreased (0.45 to 0.29/1,000,000, respectively). In conclusion, histologically confirmed hepatocellular carcinoma was reported in children less than 5 years of age, also, where hepatoblastoma is the predominant primary hepatic malignancy. Hepatocellular carcinoma has worse survival rates than hepatoblastoma, and its incidence has not increased. Better maintenance of databases may provide information about associated factors behind this unexpected occurrence. (HEPATOLOGY 2003;38:560-566.)
P
rimary hepatic malignancies are rare in children.1 Malignant neoplasm of the liver is more frequent in adults, is predominantly hepatocellular carcinoma, and is usually secondary to decades of liver injury from hepatitis B virus and/or hepatitis C virus infection,1-3 alcoholic liver disease,4-6 or both. In contrast, pri-
Abbreviations: NCHS, National Center for Health Statistics; SEER, Surveillance, Epidemiology, and End Results; ICD-O, International Classification of Disease for Oncology; ICCC, International Classification for Childhood Cancers. From the 1Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; and 2Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA. Received February 13, 2003; accepted June 15, 2003. K.M.S. is currently with the Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA. Address reprint requests to: Anil Darbari, M.D., Assist. Prof., Division of Pediatric Gastroenterology and Nutrition, Brady 320, Johns Hopkins University School of Medicine, 600 North Wolfe St., Baltimore, MD 21287. E-mail: [email protected]; fax: 410-955-1464. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3803-0006$30.00/0 doi:10.1053/jhep.2003.50375 560
mary hepatic malignancies in children are most commonly either hepatoblastoma or hepatocellular carcinoma. Hepatocellular carcinoma has been observed in young children with tyrosinemia and other inherited metabolic disorders7 and in older children with hepatitis B virus infection acquired perinatally.8-10 However, the epidemiology of primary hepatic malignancies in U.S. children is not well characterized. Most available information is from institution-based case series; since a 1975 national survey of U.S. pediatric surgeons,11 no population-based evaluation of primary liver cancer in U.S. children has been published. In recent decades, the advent of pediatric liver transplantation and other developments has brought increased attention to a number of potentially fatal childhood liver diseases, including primary hepatic malignancy. Pediatric hepatocellular carcinoma is of special interest because its rates in children decreased in Taiwan after introduction of routine infant hepatitis B vaccination.12,13 To improve the medical and surgical management of primary hepatic malignancies and to develop and evaluate prevention
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strategies, more data on the epidemiology of the disease among U.S. children are needed. The purpose of the present study was to describe the epidemiology of primary hepatic malignancies in U.S. children under twenty years of age from 1973 to 1997.
Materials and Methods Mortality Data. Data from the National Center for Health Statistics (NCHS) multiple-cause-of-death database from 1979 to 1996 were obtained for persons less than 20 years of age.14 From death certificates on which “primary malignant neoplasm of liver” (ICD-9 CM code 155.0; hepatoblastoma and hepatocellular carcinoma do not have separate ICD-9 codes)15 was listed as a primary cause of death, information was obtained on each death, including age at death, race/ethnic origin, sex, geographic area of residence, place of birth, and underlying and contributing causes of death. Surveillance, Epidemiology, and End Results Data. The Surveillance, Epidemiology, and End Results (SEER) program collects cancer data from designated population-based cancer registries representing approximately 14% of the U.S. population. It codes histology and cancer site by the International Classification of Disease for Oncology, second edition (ICD-O-2), and by the International Classification for Childhood Cancers (ICCC) systems.16,17 Histologically confirmed cases of hepatocellular carcinoma (ICD-O-2 code 8170) and hepatoblastoma (ICD-O-2 code 8970) among persons less than 20 years of age reported in the period from 1973 to 1997 were included in this study. Other information collected included duration of survival after diagnosis and population characteristics. Population Data. Population estimates were obtained from the U.S. Census Bureau. Statistical Analysis. Data analyses were performed using SPSS and Sigmastat (SPSS, Inc., Chicago, IL) statistical packages. Rates were calculated using population data and adjusted to the 1990 U.S. standard population using the direct method. Differences in age-specific incidence of hepatoblastoma and hepatocellular carcinoma (SEER database) for 5-year periods from 1973 to 1997 and differences in gender-specific incidence were analyzed by the 2 test. Trends in annual incidence rates were analyzed using standard linear regression methods.
Results Multiple-Cause-of-Death Data. In the multiplecause-of-death database, 918 children aged less than 20 years were reported with the primary cause of death listed
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as “primary malignant neoplasm of liver” between 1979 and 1996. The mean age was 8.2 years (median, 6 years). Of these, 59.6% were male, 80.5% were white, 14.4% were black, 2.2% were Asian-Pacific Islander, and 1% were American Indian/native Alaskan. Overall, the annualized age-adjusted rate between 1979 and 1996 was 0.7/ 1,000,000. Age-adjusted rates were higher in males versus females (0.22/1,000,000 vs. 0.16/1,000,000) and higher among Asians and others (1.02/1,000,000 and 1.06/ 1,000,000, respectively) versus whites and blacks (0.93/ 1,000,000 and 0.98/1,000,000). Age-specific incidence was 1.5/1,000,000 in the 0- to 4-year-old age group, 0.3/1,000,000 in the 5- to 9-year-old age group, 0.4/ 1,000,000 in the 10- to 14-year-old age group, and 0.6/ 1,000,000 in the 15- to 19-year-old age group. Although 94% of cases of fatal primary hepatic malignancies were reported in U.S.-born children, the incidence of fatal primary hepatic malignancy was higher among foreign-born children (1/1,000,000) compared with U.S.-born children (0.6/1,000,000). On death certificates, up to 20 contributory causes can be listed by the reporting physician. Although hepatorenal tyrosinemia is known to be associated with childhood hepatocellular carcinoma, tyrosinemia does not have a separate ICD-9 code. Instead, we examined ICD-9 code 270.2, which could include any one of albinism, alkaptonuria, alkaptonuric ochronosis, disturbances of tyrosine and tryptophan metabolism, homogentisic acid defects, hydroxykynureninuria, hypertyrosinemia, indicanuria, kynureninase defects, oasthouse urine disease, ochronosis, tyrosinosis, tyrosinuria, and Waardenburg syndrome. Among the reports of deaths from primary hepatic malignancies in children between 1979 and 1996, 94.4% did not have a contributory cause mentioned. The most common contributory conditions listed were aromatic amino acid disorder (ICD-9 270.2) in 17 (1.9%) of cases, nonalcoholic cirrhosis (ICD-9 571.5) in 1.8% of cases, chronic liver disease (ICD-9 571.9) in 1.4% of cases, and hepatitis B (ICD-9 070.20) in 1.4% of cases. The database is not constructed to determine whether overlap exists between associated conditions such as hepatitis B and chronic liver disease. Neither is it possible to determine whether the associated conditions were associated with hepatoblastoma or hepatocellular carcinoma. Hepatitis B was listed as contributory condition in 7.3% of death certificates among foreign-born children, compared with 1.3% among U.S.-born children. In examining rates over time, the annual age-adjusted rate of reported deaths from primary hepatic malignancies ranged between 0.5 and 1/1,000,000 between 1979 and 1996, and remained relatively stable for all years (Fig. 1)
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Fig. 1. Age-adjusted incidence rates of primary hepatic malignancies for persons less than 20 years of age, United States, 1979-1996 (multiple-cause-of-death, NCHS).
and for different racial/ethnic groups and persons born outside the United States (data not shown). SEER Data. In the SEER database, 303 cases of hepatic malignancies in children less than 20 years of age were reported between 1973 and 1997, representing 1.1% of all pediatric malignancies diagnosed during this time period. Of the 303 cases, 271 (89%) were primary hepatic malignancies, and 32 (11%) were secondary (extrahepatic malignancies metastatic to the liver). Based on the ICCC site code, of the 271 cases of primary hepatic malignancies, 184 (67%) were diagnosed as hepatoblastoma, 83 (31%) were diagnosed as hepatocellular carcinoma, and 4 (1.5%) were unspecified. The overall age-adjusted rates (95% confidence intervals) of hepatoblastoma were 1.09 (0.89-1.37) per 1,000,000 and of hepatocellular carcinoma were 0.41 (0.24-0.65) per 1,000,000. Of the 184 histologically confirmed hepatoblastoma cases among children less than 20 years of age, 168 (91.3%) were among children less than 5 years of age: 57% were male, 79% were white, 10% were black, 10% were other, and 1% were unknown. Age-adjusted rates (95% confidence intervals) of hepatoblastoma were 1.22 (0.94-1.65) and 0.96 (0.68-1.38) per 1,000,000 for males and females, respectively, and 1.11 (0.87-1.4), 0.88 (0.47-1.95), and 1.16 (0.68-2.59) per 1,000,000 for whites, blacks, and others, respectively. Of the 70 histologically confirmed hepatocellular carcinoma cases reported to SEER among children less than 20 years of age between 1973 and 1997, 12.86% were among children less than 5 years of age, whereas 34% were among children 15 to 19 years old. Of these, 56% were male, 73% were white, 11% were black, and 16% were other races. Age-adjusted rates (95% confidence intervals) of hepatocellular carcinoma for males and females were 0.45 (0.21-0.83) and 0.37 (0.17-0.72) per
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1,000,000, respectively, and were 0.37 (0.20-0.65), 0.38 (0.08-1.32), and 0.75 (0.08-1.32) per 1,000,000 for whites, blacks, and others, respectively. The age-adjusted rates for the various age groups differed substantially for the 2 types of primary hepatic malignancies. For hepatoblastoma, the rate was substantially higher for children less than 5 years of age and was relatively lower for older age groups (Fig. 2). The age-adjusted incidence rates (95% confidence intervals) per million were 4.0 (3.42-4.65) for hepatoblastoma and 0.21 (0.07-0.41) for hepatocellular carcinoma in the less than 5 years age group; after this age, rates of hepatoblastoma fall dramatically, and primary hepatic malignancies were largely hepatocellular carcinoma. The rate of hepatocellular carcinoma was relatively low for all age groups (Fig. 2). Between 1973-1977 and 1993-1997, the rate of hepatoblastoma increased 93% (0.61 vs. 1.18 per 1,000,000, respectively, P ⬍ .0001) (Fig. 3). In comparison, the incidence of hepatocellular carcinoma in children showed a tendency to decrease during the same time period (Fig. 3), although the rates in 1973-1977 vs. 1993-1997 were not significantly different (0.45 vs. 0.29 per 1,000,000, P ⫽ .17). The overall 5-year survival for children less than 20 years of age diagnosed with hepatoblastoma was 52.4% and, for children less than 20 years of age diagnosed with hepatocellular carcinoma, 18.0% (Table 1). For hepatocellular carcinoma, the survival was significantly lower in the third, fourth, and fifth years following the diagnosis as compared with the first year (P ⬍ .001). There were no statistically significant differences in the survival by age, sex, or race, although the numbers of persons within each subcategory were small (data not shown).
Fig. 2. Age-adjusted incidence rates of fatal primary hepatic malignancies (NCHS, 1979-1996) and histologically confirmed hepatoblastoma and hepatocellular carcinoma (SEER, 1973-1997) among persons less than 20 years of age, by age group.
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Fig. 3. Age-adjusted incidence rates of histologically confirmed hepatoblastoma and hepatocellular carcinoma among persons less than 20 years of age, by year, SEER, 1973-1977.
Discussion Primary hepatic malignancies in children are relatively rare. Based on SEER data, primary hepatic malignancies make up approximately 1% of all malignant neoplasms among children less than 20 years of age. Previously published reviews of hepatoblastoma and hepatocellular carcinoma have been generally institution-based case series, and the clinical reports on hepatocellular carcinoma in U.S. children since 1905 are scarce. Most of the reports from the United States are case series or questionnaires of physicians.11,18-21 There are hospital-based case series9,22,23 and epidemiologic analysis of hepatocellular carcinoma from the cancer registry24 of China. The data presented here, which are based on nationwide death certificate data (NCHS) and population-based registries (SEER), provide a more complete and representative overview than can be obtained from case series.
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Annually, 36 to 69 deaths from primary malignant neoplasms of the liver among children less than 20 years of age were reported in the multiple-cause-of-death database. From the SEER database, 67% and 31% of primary hepatic malignancies were histologically confirmed as hepatoblastoma and hepatocellular carcinoma, respectively. Applying these percentages to the multiple-causeof-death database, an estimated 615 children (average, 34 per year) and 284 children (average, 16 per year) would have died of hepatoblastoma and hepatocellular carcinoma, respectively, between 1979 and 1996. As reflected in the SEER data, hepatoblastoma is generally a disease of children less than 5 years of age. Rates of hepatoblastoma are 20-fold higher than rates of hepatocellular carcinoma for children under 5 years of age. Based on SEER data, the rates among boys and girls did not differ significantly (M/F ratio was 1.32 for hepatoblastoma and 1.27 for hepatocellular carcinoma). This contrasts with previous reports, in which a stronger male predominance for both hepatoblastoma and hepatocellular carcinoma has been observed.11,18-21,23,24 Risk factors for hepatoblastoma are not well characterized. Hepatoblastoma has been shown to be associated with Beckwith-Weidmann syndrome25,26 hemihypertrophy, and familial adenomatous polyposis, none of which have unique ICD-9 codes.27 The relatively low incidence of these conditions did not allow us to examine their association with hepatoblastoma in the multiple cause of death database. Recent reports from the United States and Japan have suggested an increased incidence of hepatoblastoma in extremely low birth weight infants.28-31 Because birth weight is not collected in the SEER database, we could not analyze this association.
Table 1. Five-Year Observed Survival Rates for Childhood Hepatoblastoma and Hepatocellular Carcinoma, SEER, 1973-1996 Years of Survival Following Diagnosis (%) Age Group
Hepatoblastoma survival rates 0-4 y 5-9 y 10-14 y 15-19 y Total Hepatocellular carcinoma survival rates 0-4 y 5-9 y 10-14 y 15-19 y Total
No. of Patients
1y
2y
3y
4y
5y
162 9 3 4 178
73.9 76.5 100 75.0 81.3
60.8 62.6 66.7 25.0 53.8
57.8 62.6 66.7 25.0 53.0
56.9 62.6 66.7 25.0 52.8
55.2 62.6 66.7 25.0 52.4
9 15 22 22 68
33.6 44.8 59.1 52.4 47.4
22.4 37.4* 39.4* 31.4* 32.6*
22.4 22.4* 22.5* 15.8* 20.7*
22.4 22.4* 16.9* 10.5* 18.0*
22.4 22.4* 16.9* 10.5* 18.0*
NOTE. For hepatoblastoma, 6 patients were excluded from the analysis because they were autopsy or death certificate case (2), because race values were not provided (2), and because they were alive with no survival time (2). For hepatocellular carcinoma, 2 patients were excluded from the survival analysis because of development of a second malignancy (1), and because they were autopsy or death certificate cases (1). Data are age adjusted to the 1970 U.S. standard population. *Denotes P ⬍ .001 compared with percentage surviving 1 year following diagnosis.
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Risk factors for hepatocellular carcinoma in children are also not well characterized. Between 1970 and 1992, hepatocellular carcinoma was the third most frequently seen pediatric liver tumor at the Armed Forces Institute of Pathology.18 Associated conditions were seen in less than 25% of cases, including biliary atresia, congenital hepatic fibrosis, Byler disease, and Wilson disease. Hepatorenal tyrosinemia is associated with an early age of onset of hepatocellular carcinoma.32 This condition could not be examined specifically in the multiple-cause-of-death database; aromatic amino acid disorders in general were reported in less than 2% of hepatocellular carcinoma deaths. Hepatocellular carcinoma is strongly associated with hepatitis B virus infection in adults.33 In young children with hepatitis B virus infection, hepatocellular carcinoma has been reported from Southeast Asia and Europe.8-10,34 Of all 918 deaths reported in the multiplecause-of-death database, less than 6% had any associated liver disease coded, e.g., chronic liver disease, hepatitis B, and others. The relative absence of contributory conditions reported with hepatocellular carcinoma in the multiple-cause-of-death database suggests that these conditions may have been underdiagnosed or unrecognized. However, the higher proportion of foreign-born children with hepatitis B listed as a contributory cause of death compared with U.S.-born children highlights an important feature of the epidemiology of hepatitis B virus infection in the United States. Although prevalence of hepatitis B virus infection is relatively low in the United States, where, overall, only 5% of the general population has serologic evidence of past infection and less than 1% are chronically infected,35 the extent to which children acquire hepatitis B virus infection in the United States has not been appreciated, primarily because most infections in this age group are asymptomatic. Not including perinatal infections, recent estimates indicate that 16,000 children less than 10 years old were being infected annually in the United States prior to implementation of routine infant hepatitis B immunization in 1992.36 However, by 2000, 90% of 19- to 36-month-old children had been fully immunized with 3 doses of hepatitis B vaccine,37 and the incidence of acute hepatitis B among children less than 15 years old had decreased by 75%.38 Because the risk of developing chronic infection and its sequelae such as hepatocellular carcinoma is inversely related to age, routine childhood hepatitis B immunization will eventually have a major impact on hepatitis B-related chronic liver disease deaths among both children and adults. The success of routine childhood hepatitis B immunization in interrupting hepatitis B virus transmission and preventing chronic infection has been demonstrated in developing countries where most infections are acquired
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in infancy and early childhood. During the 15 years after routine childhood hepatitis B immunization was implemented in Taiwan, chronic hepatitis B virus prevalence among children less than 15 years old declined 93%, and hepatocellular carcinoma rates among 6- to 14-year-old children declined 50%.12,13,39 Given the absence of alcoholic liver disease in children and the association of some inborn errors of metabolism with hepatocellular carcinoma in childhood, we expected that the epidemiology of hepatocellular carcinoma in U.S. children might differ from that for adults. For childhood hepatocellular carcinoma, we observed (1) no increase in the annual incidence over the last 2 decades compared with the rate for adults, which increased from 1.4/100,000 during 1976-1980 to 2.4/100,000 during 1991-199540; (2) an underlying liver disease was less often a contributing cause in children than adults; (3) lack of male predominance compared with adults among whom incidence is 3-fold higher in men versus women40; (4) no difference in incidence in whites versus blacks compared with a 2-fold higher incidence in blacks compared with whites in adults40; and (5) poorer 5-year survival rates compared with those in adults.40 The 5-year survival rate for children with hepatoblastoma was 52%. An improvement in surgical techniques and improved chemotherapy along with selective use of transplantation could account for these survival rates.41-43 However, hepatocellular carcinoma survival rates continue to be poor. The 18% overall 5-year survival rate in the U.S. children with hepatocellular carcinoma in this study is similar to that reported from previous studies.18,20 In contrast, the 5-year survival rate in adults from an International Registry of Hepatic Tumors in Liver Transplantation has been shown to be 44.4%.43 Survival rates are better with surgical resection plus transplantation in selected groups of individuals41-43 compared with resection alone and better for resection compared with no resection both in adults41 and in children.41,44 Newer techniques such as intrahepatic chemoembolization have been shown to be promising in children with unresectable tumors.45 The United Network for Organ Sharing (UNOS) has operated the Organ Procurement and Transplantation Network (OPTN) under contract with the Health Resources and Services Administration of the U.S. Department of Health and Human Services since 1986.46 To review whether liver transplantation had any effect on primary hepatic malignancies, we reviewed the OPTN data from 1988 to 1996, corresponding to the period studied in SEER and NCHS databases. Viewed ecologically, liver transplantation appears to have minimal affect on liver cancer mortality. Between 1988 and 1996, 72
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of hepatocellular carcinoma have been relatively stable. Survival rates for hepatoblastoma are substantially higher than for hepatocellular carcinoma. Finally, the epidemiology of hepatocellular carcinoma in children appears to differ from that in adults. Risk factors and conditions contributing to both hepatoblastoma and hepatocellular carcinoma need to be better characterized to optimize the medical and surgical management and to improve the survival of children with such highly fatal malignancies.
References Fig. 4. Liver transplantation for primary hepatic malignancies by age groups for persons less than 18 years of age, United States, 1988-1996 (Organ Procurement and Transplantation Network Data, United Network for Organ Sharing).
patients younger than 18 years of age (4-9 patients annually, with the exception of 18 transplantations performed during 1993) were listed as having received liver transplantation for hepatoblastoma, hepatoma (hepatocellular carcinoma) and cirrhosis, or hepatoma (hepatocellular carcinoma).46 Furthermore, the majority of liver transplantations performed among children under 5 years of age were for hepatoblastoma, whereas those for children over 10 years of age were for hepatocellular carcinoma (Fig. 4), similar to the findings in our study. A lack of awareness for this highly fatal malignancy among physicians caring for children could result in a delay in the diagnosis in children. This could result in vascular invasion and be considered a factor for worse survival in adults, even with resection.41,43 We hope to improve the awareness of childhood hepatocellular carcinoma among physicians caring for children so that these children are diagnosed earlier and their survival is improved. This study has several limitations. Autopsies are not routinely performed to verify cause of death; therefore, diagnoses may not be accurate. Lack of differentiation between hepatoblastoma and hepatocellular carcinoma based on ICD-9 CM codes in the multiple-cause-of-death database makes finer analyses impossible. The SEER database is representative of 14% of the U.S. population and should not be extrapolated to the entire United States. Our study highlights the need for inclusion of contributing causes of death in these databases. Primary hepatic malignancies in children are predominantly hepatoblastoma in children less than 5 years of age and hepatocellular carcinoma in children older than 5 years. Over the last 2 decades, rates of hepatoblastoma in children less than 20 years of age have increased, but rates
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35. McQuillan GM, Coleman PJ, Kruszon-Moran D, Moyer LA, Lambert SB, Margolis HS. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination Surveys 1976-1994. Am J Pub Health 1991;89:14-18. 36. Armstrong GL, Mast EE, Wojczynski M, Margolis HS. Childhood hepatitis B virus infections in the United States before hepatitis B immunization. Pediatrics 2001;108:1123-1128. 37. National, state and urban area vaccination coverage levels among children aged 19-35 months, United States, 2000. MMWR 2001;50:637-641. 38. Goldstein ST, Alter MJ, Williams IT, Moyer LA, Judson FN, Mottram K, Fleenor M, et al. Incidence and risk factors for acute hepatitis B in the United States, 1982-1998: implications for vaccination programs. J Infect Dis 2002;185:713-719. 39. Ni Y-H, Change M-H, Huang L-M, Chen HL, Hsu HY, Chiu TY, Tsai KS, et al. Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination. Ann Intern Med 2001;135:796-800. 40. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745-750. 41. Tagge EP, Ragge DU, Reyes J, Tzakis A, Iwatsuki S, Starzl TE, Wiener ES. Resection, including transplantation, for hepatoblastoma and hepatocellular carcinoma: impact on survival. J Pediatr Surg 1992;27: 292-297. 42. Rose AT, Rose M, Pinson W, Wright JK, Blair T, Blanke C, Delbeke D, et al. Hepatocellular carcinoma outcomes based on indicated treatment strategy. Am Surg 1998;64:1128-1134. 43. Klitmalm GB. Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg 1998;228:479-488. 44. Chen JC, Chen CC, Chen WJ, Lai HS, Hung WT, Lee PH. Hepatocellular carcinoma in children: clinical review and comparison with adult cases. J Pediatr Surg 1998;33:1350-1354. 45. Arcement CM, Towbin RB, Meza MP, Gerber DA, Kaye RD, Mazariegos GV, Carr BI, et al. Intrahepatic chemoembolization in unresectable pediatric liver malignancies. Pediatr Radiol 2000;30:779-785. 46. OPTN Data. United Network for Organ Sharing. Available at: www. unos.org. Accessed: March 7, 2003.
Epidemiology of Primary Hepatic Malignancies in U.S. Children Anil Darbari,1 Keith M. Sabin,2 Craig N. Shapiro,2 and Kathleen B. Schwarz1 The epidemiology of primary hepatic malignancies in U.S. children is poorly characterized. We analyzed the incidence, mortality, and characteristics of primary hepatic malignancies in U.S. residents less than 20 years of age. Fatal primary hepatic malignancies in persons less than 20 years of age, between 1979 and 1996, were identified using the multiple-cause-ofdeath database (National Center for Health Statistics). Histologically confirmed primary hepatic malignancies occurring between 1973 and 1997 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Between 1979 and 1996, 918 primary hepatic malignancy deaths (average, 0.7/1,000,000/year) were reported nationally among persons less than 20 years of age; rates were higher among Asians and among foreignborn children. Between 1973 and 1997, 271 primary hepatic malignancy cases were reported to SEER among persons less than 20 years of age, of which 184 (67%) and 83 (31%) were hepatoblastoma and hepatocellular carcinoma, respectively. Among children less than 5 years of age, hepatoblastoma accounted for 91% of primary hepatic malignancy cases, whereas among those 15 to 19 years of age, hepatocellular carcinoma accounted for 87% of cases. Five-year survival for hepatoblastoma was 52%, compared with 18% for hepatocellular carcinoma. In the SEER sites, between 1973 and 1977 and 1993 and 1997, hepatoblastoma rates increased (0.6 to 1.2/1,000,000, respectively), while hepatocellular carcinoma rates decreased (0.45 to 0.29/1,000,000, respectively). In conclusion, histologically confirmed hepatocellular carcinoma was reported in children less than 5 years of age, also, where hepatoblastoma is the predominant primary hepatic malignancy. Hepatocellular carcinoma has worse survival rates than hepatoblastoma, and its incidence has not increased. Better maintenance of databases may provide information about associated factors behind this unexpected occurrence. (HEPATOLOGY 2003;38:560-566.)
P
rimary hepatic malignancies are rare in children.1 Malignant neoplasm of the liver is more frequent in adults, is predominantly hepatocellular carcinoma, and is usually secondary to decades of liver injury from hepatitis B virus and/or hepatitis C virus infection,1-3 alcoholic liver disease,4-6 or both. In contrast, pri-
Abbreviations: NCHS, National Center for Health Statistics; SEER, Surveillance, Epidemiology, and End Results; ICD-O, International Classification of Disease for Oncology; ICCC, International Classification for Childhood Cancers. From the 1Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; and 2Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA. Received February 13, 2003; accepted June 15, 2003. K.M.S. is currently with the Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA. Address reprint requests to: Anil Darbari, M.D., Assist. Prof., Division of Pediatric Gastroenterology and Nutrition, Brady 320, Johns Hopkins University School of Medicine, 600 North Wolfe St., Baltimore, MD 21287. E-mail: [email protected]; fax: 410-955-1464. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3803-0006$30.00/0 doi:10.1053/jhep.2003.50375 560
mary hepatic malignancies in children are most commonly either hepatoblastoma or hepatocellular carcinoma. Hepatocellular carcinoma has been observed in young children with tyrosinemia and other inherited metabolic disorders7 and in older children with hepatitis B virus infection acquired perinatally.8-10 However, the epidemiology of primary hepatic malignancies in U.S. children is not well characterized. Most available information is from institution-based case series; since a 1975 national survey of U.S. pediatric surgeons,11 no population-based evaluation of primary liver cancer in U.S. children has been published. In recent decades, the advent of pediatric liver transplantation and other developments has brought increased attention to a number of potentially fatal childhood liver diseases, including primary hepatic malignancy. Pediatric hepatocellular carcinoma is of special interest because its rates in children decreased in Taiwan after introduction of routine infant hepatitis B vaccination.12,13 To improve the medical and surgical management of primary hepatic malignancies and to develop and evaluate prevention
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strategies, more data on the epidemiology of the disease among U.S. children are needed. The purpose of the present study was to describe the epidemiology of primary hepatic malignancies in U.S. children under twenty years of age from 1973 to 1997.
Materials and Methods Mortality Data. Data from the National Center for Health Statistics (NCHS) multiple-cause-of-death database from 1979 to 1996 were obtained for persons less than 20 years of age.14 From death certificates on which “primary malignant neoplasm of liver” (ICD-9 CM code 155.0; hepatoblastoma and hepatocellular carcinoma do not have separate ICD-9 codes)15 was listed as a primary cause of death, information was obtained on each death, including age at death, race/ethnic origin, sex, geographic area of residence, place of birth, and underlying and contributing causes of death. Surveillance, Epidemiology, and End Results Data. The Surveillance, Epidemiology, and End Results (SEER) program collects cancer data from designated population-based cancer registries representing approximately 14% of the U.S. population. It codes histology and cancer site by the International Classification of Disease for Oncology, second edition (ICD-O-2), and by the International Classification for Childhood Cancers (ICCC) systems.16,17 Histologically confirmed cases of hepatocellular carcinoma (ICD-O-2 code 8170) and hepatoblastoma (ICD-O-2 code 8970) among persons less than 20 years of age reported in the period from 1973 to 1997 were included in this study. Other information collected included duration of survival after diagnosis and population characteristics. Population Data. Population estimates were obtained from the U.S. Census Bureau. Statistical Analysis. Data analyses were performed using SPSS and Sigmastat (SPSS, Inc., Chicago, IL) statistical packages. Rates were calculated using population data and adjusted to the 1990 U.S. standard population using the direct method. Differences in age-specific incidence of hepatoblastoma and hepatocellular carcinoma (SEER database) for 5-year periods from 1973 to 1997 and differences in gender-specific incidence were analyzed by the 2 test. Trends in annual incidence rates were analyzed using standard linear regression methods.
Results Multiple-Cause-of-Death Data. In the multiplecause-of-death database, 918 children aged less than 20 years were reported with the primary cause of death listed
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as “primary malignant neoplasm of liver” between 1979 and 1996. The mean age was 8.2 years (median, 6 years). Of these, 59.6% were male, 80.5% were white, 14.4% were black, 2.2% were Asian-Pacific Islander, and 1% were American Indian/native Alaskan. Overall, the annualized age-adjusted rate between 1979 and 1996 was 0.7/ 1,000,000. Age-adjusted rates were higher in males versus females (0.22/1,000,000 vs. 0.16/1,000,000) and higher among Asians and others (1.02/1,000,000 and 1.06/ 1,000,000, respectively) versus whites and blacks (0.93/ 1,000,000 and 0.98/1,000,000). Age-specific incidence was 1.5/1,000,000 in the 0- to 4-year-old age group, 0.3/1,000,000 in the 5- to 9-year-old age group, 0.4/ 1,000,000 in the 10- to 14-year-old age group, and 0.6/ 1,000,000 in the 15- to 19-year-old age group. Although 94% of cases of fatal primary hepatic malignancies were reported in U.S.-born children, the incidence of fatal primary hepatic malignancy was higher among foreign-born children (1/1,000,000) compared with U.S.-born children (0.6/1,000,000). On death certificates, up to 20 contributory causes can be listed by the reporting physician. Although hepatorenal tyrosinemia is known to be associated with childhood hepatocellular carcinoma, tyrosinemia does not have a separate ICD-9 code. Instead, we examined ICD-9 code 270.2, which could include any one of albinism, alkaptonuria, alkaptonuric ochronosis, disturbances of tyrosine and tryptophan metabolism, homogentisic acid defects, hydroxykynureninuria, hypertyrosinemia, indicanuria, kynureninase defects, oasthouse urine disease, ochronosis, tyrosinosis, tyrosinuria, and Waardenburg syndrome. Among the reports of deaths from primary hepatic malignancies in children between 1979 and 1996, 94.4% did not have a contributory cause mentioned. The most common contributory conditions listed were aromatic amino acid disorder (ICD-9 270.2) in 17 (1.9%) of cases, nonalcoholic cirrhosis (ICD-9 571.5) in 1.8% of cases, chronic liver disease (ICD-9 571.9) in 1.4% of cases, and hepatitis B (ICD-9 070.20) in 1.4% of cases. The database is not constructed to determine whether overlap exists between associated conditions such as hepatitis B and chronic liver disease. Neither is it possible to determine whether the associated conditions were associated with hepatoblastoma or hepatocellular carcinoma. Hepatitis B was listed as contributory condition in 7.3% of death certificates among foreign-born children, compared with 1.3% among U.S.-born children. In examining rates over time, the annual age-adjusted rate of reported deaths from primary hepatic malignancies ranged between 0.5 and 1/1,000,000 between 1979 and 1996, and remained relatively stable for all years (Fig. 1)
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Fig. 1. Age-adjusted incidence rates of primary hepatic malignancies for persons less than 20 years of age, United States, 1979-1996 (multiple-cause-of-death, NCHS).
and for different racial/ethnic groups and persons born outside the United States (data not shown). SEER Data. In the SEER database, 303 cases of hepatic malignancies in children less than 20 years of age were reported between 1973 and 1997, representing 1.1% of all pediatric malignancies diagnosed during this time period. Of the 303 cases, 271 (89%) were primary hepatic malignancies, and 32 (11%) were secondary (extrahepatic malignancies metastatic to the liver). Based on the ICCC site code, of the 271 cases of primary hepatic malignancies, 184 (67%) were diagnosed as hepatoblastoma, 83 (31%) were diagnosed as hepatocellular carcinoma, and 4 (1.5%) were unspecified. The overall age-adjusted rates (95% confidence intervals) of hepatoblastoma were 1.09 (0.89-1.37) per 1,000,000 and of hepatocellular carcinoma were 0.41 (0.24-0.65) per 1,000,000. Of the 184 histologically confirmed hepatoblastoma cases among children less than 20 years of age, 168 (91.3%) were among children less than 5 years of age: 57% were male, 79% were white, 10% were black, 10% were other, and 1% were unknown. Age-adjusted rates (95% confidence intervals) of hepatoblastoma were 1.22 (0.94-1.65) and 0.96 (0.68-1.38) per 1,000,000 for males and females, respectively, and 1.11 (0.87-1.4), 0.88 (0.47-1.95), and 1.16 (0.68-2.59) per 1,000,000 for whites, blacks, and others, respectively. Of the 70 histologically confirmed hepatocellular carcinoma cases reported to SEER among children less than 20 years of age between 1973 and 1997, 12.86% were among children less than 5 years of age, whereas 34% were among children 15 to 19 years old. Of these, 56% were male, 73% were white, 11% were black, and 16% were other races. Age-adjusted rates (95% confidence intervals) of hepatocellular carcinoma for males and females were 0.45 (0.21-0.83) and 0.37 (0.17-0.72) per
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1,000,000, respectively, and were 0.37 (0.20-0.65), 0.38 (0.08-1.32), and 0.75 (0.08-1.32) per 1,000,000 for whites, blacks, and others, respectively. The age-adjusted rates for the various age groups differed substantially for the 2 types of primary hepatic malignancies. For hepatoblastoma, the rate was substantially higher for children less than 5 years of age and was relatively lower for older age groups (Fig. 2). The age-adjusted incidence rates (95% confidence intervals) per million were 4.0 (3.42-4.65) for hepatoblastoma and 0.21 (0.07-0.41) for hepatocellular carcinoma in the less than 5 years age group; after this age, rates of hepatoblastoma fall dramatically, and primary hepatic malignancies were largely hepatocellular carcinoma. The rate of hepatocellular carcinoma was relatively low for all age groups (Fig. 2). Between 1973-1977 and 1993-1997, the rate of hepatoblastoma increased 93% (0.61 vs. 1.18 per 1,000,000, respectively, P ⬍ .0001) (Fig. 3). In comparison, the incidence of hepatocellular carcinoma in children showed a tendency to decrease during the same time period (Fig. 3), although the rates in 1973-1977 vs. 1993-1997 were not significantly different (0.45 vs. 0.29 per 1,000,000, P ⫽ .17). The overall 5-year survival for children less than 20 years of age diagnosed with hepatoblastoma was 52.4% and, for children less than 20 years of age diagnosed with hepatocellular carcinoma, 18.0% (Table 1). For hepatocellular carcinoma, the survival was significantly lower in the third, fourth, and fifth years following the diagnosis as compared with the first year (P ⬍ .001). There were no statistically significant differences in the survival by age, sex, or race, although the numbers of persons within each subcategory were small (data not shown).
Fig. 2. Age-adjusted incidence rates of fatal primary hepatic malignancies (NCHS, 1979-1996) and histologically confirmed hepatoblastoma and hepatocellular carcinoma (SEER, 1973-1997) among persons less than 20 years of age, by age group.
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Fig. 3. Age-adjusted incidence rates of histologically confirmed hepatoblastoma and hepatocellular carcinoma among persons less than 20 years of age, by year, SEER, 1973-1977.
Discussion Primary hepatic malignancies in children are relatively rare. Based on SEER data, primary hepatic malignancies make up approximately 1% of all malignant neoplasms among children less than 20 years of age. Previously published reviews of hepatoblastoma and hepatocellular carcinoma have been generally institution-based case series, and the clinical reports on hepatocellular carcinoma in U.S. children since 1905 are scarce. Most of the reports from the United States are case series or questionnaires of physicians.11,18-21 There are hospital-based case series9,22,23 and epidemiologic analysis of hepatocellular carcinoma from the cancer registry24 of China. The data presented here, which are based on nationwide death certificate data (NCHS) and population-based registries (SEER), provide a more complete and representative overview than can be obtained from case series.
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Annually, 36 to 69 deaths from primary malignant neoplasms of the liver among children less than 20 years of age were reported in the multiple-cause-of-death database. From the SEER database, 67% and 31% of primary hepatic malignancies were histologically confirmed as hepatoblastoma and hepatocellular carcinoma, respectively. Applying these percentages to the multiple-causeof-death database, an estimated 615 children (average, 34 per year) and 284 children (average, 16 per year) would have died of hepatoblastoma and hepatocellular carcinoma, respectively, between 1979 and 1996. As reflected in the SEER data, hepatoblastoma is generally a disease of children less than 5 years of age. Rates of hepatoblastoma are 20-fold higher than rates of hepatocellular carcinoma for children under 5 years of age. Based on SEER data, the rates among boys and girls did not differ significantly (M/F ratio was 1.32 for hepatoblastoma and 1.27 for hepatocellular carcinoma). This contrasts with previous reports, in which a stronger male predominance for both hepatoblastoma and hepatocellular carcinoma has been observed.11,18-21,23,24 Risk factors for hepatoblastoma are not well characterized. Hepatoblastoma has been shown to be associated with Beckwith-Weidmann syndrome25,26 hemihypertrophy, and familial adenomatous polyposis, none of which have unique ICD-9 codes.27 The relatively low incidence of these conditions did not allow us to examine their association with hepatoblastoma in the multiple cause of death database. Recent reports from the United States and Japan have suggested an increased incidence of hepatoblastoma in extremely low birth weight infants.28-31 Because birth weight is not collected in the SEER database, we could not analyze this association.
Table 1. Five-Year Observed Survival Rates for Childhood Hepatoblastoma and Hepatocellular Carcinoma, SEER, 1973-1996 Years of Survival Following Diagnosis (%) Age Group
Hepatoblastoma survival rates 0-4 y 5-9 y 10-14 y 15-19 y Total Hepatocellular carcinoma survival rates 0-4 y 5-9 y 10-14 y 15-19 y Total
No. of Patients
1y
2y
3y
4y
5y
162 9 3 4 178
73.9 76.5 100 75.0 81.3
60.8 62.6 66.7 25.0 53.8
57.8 62.6 66.7 25.0 53.0
56.9 62.6 66.7 25.0 52.8
55.2 62.6 66.7 25.0 52.4
9 15 22 22 68
33.6 44.8 59.1 52.4 47.4
22.4 37.4* 39.4* 31.4* 32.6*
22.4 22.4* 22.5* 15.8* 20.7*
22.4 22.4* 16.9* 10.5* 18.0*
22.4 22.4* 16.9* 10.5* 18.0*
NOTE. For hepatoblastoma, 6 patients were excluded from the analysis because they were autopsy or death certificate case (2), because race values were not provided (2), and because they were alive with no survival time (2). For hepatocellular carcinoma, 2 patients were excluded from the survival analysis because of development of a second malignancy (1), and because they were autopsy or death certificate cases (1). Data are age adjusted to the 1970 U.S. standard population. *Denotes P ⬍ .001 compared with percentage surviving 1 year following diagnosis.
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Risk factors for hepatocellular carcinoma in children are also not well characterized. Between 1970 and 1992, hepatocellular carcinoma was the third most frequently seen pediatric liver tumor at the Armed Forces Institute of Pathology.18 Associated conditions were seen in less than 25% of cases, including biliary atresia, congenital hepatic fibrosis, Byler disease, and Wilson disease. Hepatorenal tyrosinemia is associated with an early age of onset of hepatocellular carcinoma.32 This condition could not be examined specifically in the multiple-cause-of-death database; aromatic amino acid disorders in general were reported in less than 2% of hepatocellular carcinoma deaths. Hepatocellular carcinoma is strongly associated with hepatitis B virus infection in adults.33 In young children with hepatitis B virus infection, hepatocellular carcinoma has been reported from Southeast Asia and Europe.8-10,34 Of all 918 deaths reported in the multiplecause-of-death database, less than 6% had any associated liver disease coded, e.g., chronic liver disease, hepatitis B, and others. The relative absence of contributory conditions reported with hepatocellular carcinoma in the multiple-cause-of-death database suggests that these conditions may have been underdiagnosed or unrecognized. However, the higher proportion of foreign-born children with hepatitis B listed as a contributory cause of death compared with U.S.-born children highlights an important feature of the epidemiology of hepatitis B virus infection in the United States. Although prevalence of hepatitis B virus infection is relatively low in the United States, where, overall, only 5% of the general population has serologic evidence of past infection and less than 1% are chronically infected,35 the extent to which children acquire hepatitis B virus infection in the United States has not been appreciated, primarily because most infections in this age group are asymptomatic. Not including perinatal infections, recent estimates indicate that 16,000 children less than 10 years old were being infected annually in the United States prior to implementation of routine infant hepatitis B immunization in 1992.36 However, by 2000, 90% of 19- to 36-month-old children had been fully immunized with 3 doses of hepatitis B vaccine,37 and the incidence of acute hepatitis B among children less than 15 years old had decreased by 75%.38 Because the risk of developing chronic infection and its sequelae such as hepatocellular carcinoma is inversely related to age, routine childhood hepatitis B immunization will eventually have a major impact on hepatitis B-related chronic liver disease deaths among both children and adults. The success of routine childhood hepatitis B immunization in interrupting hepatitis B virus transmission and preventing chronic infection has been demonstrated in developing countries where most infections are acquired
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in infancy and early childhood. During the 15 years after routine childhood hepatitis B immunization was implemented in Taiwan, chronic hepatitis B virus prevalence among children less than 15 years old declined 93%, and hepatocellular carcinoma rates among 6- to 14-year-old children declined 50%.12,13,39 Given the absence of alcoholic liver disease in children and the association of some inborn errors of metabolism with hepatocellular carcinoma in childhood, we expected that the epidemiology of hepatocellular carcinoma in U.S. children might differ from that for adults. For childhood hepatocellular carcinoma, we observed (1) no increase in the annual incidence over the last 2 decades compared with the rate for adults, which increased from 1.4/100,000 during 1976-1980 to 2.4/100,000 during 1991-199540; (2) an underlying liver disease was less often a contributing cause in children than adults; (3) lack of male predominance compared with adults among whom incidence is 3-fold higher in men versus women40; (4) no difference in incidence in whites versus blacks compared with a 2-fold higher incidence in blacks compared with whites in adults40; and (5) poorer 5-year survival rates compared with those in adults.40 The 5-year survival rate for children with hepatoblastoma was 52%. An improvement in surgical techniques and improved chemotherapy along with selective use of transplantation could account for these survival rates.41-43 However, hepatocellular carcinoma survival rates continue to be poor. The 18% overall 5-year survival rate in the U.S. children with hepatocellular carcinoma in this study is similar to that reported from previous studies.18,20 In contrast, the 5-year survival rate in adults from an International Registry of Hepatic Tumors in Liver Transplantation has been shown to be 44.4%.43 Survival rates are better with surgical resection plus transplantation in selected groups of individuals41-43 compared with resection alone and better for resection compared with no resection both in adults41 and in children.41,44 Newer techniques such as intrahepatic chemoembolization have been shown to be promising in children with unresectable tumors.45 The United Network for Organ Sharing (UNOS) has operated the Organ Procurement and Transplantation Network (OPTN) under contract with the Health Resources and Services Administration of the U.S. Department of Health and Human Services since 1986.46 To review whether liver transplantation had any effect on primary hepatic malignancies, we reviewed the OPTN data from 1988 to 1996, corresponding to the period studied in SEER and NCHS databases. Viewed ecologically, liver transplantation appears to have minimal affect on liver cancer mortality. Between 1988 and 1996, 72
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of hepatocellular carcinoma have been relatively stable. Survival rates for hepatoblastoma are substantially higher than for hepatocellular carcinoma. Finally, the epidemiology of hepatocellular carcinoma in children appears to differ from that in adults. Risk factors and conditions contributing to both hepatoblastoma and hepatocellular carcinoma need to be better characterized to optimize the medical and surgical management and to improve the survival of children with such highly fatal malignancies.
References Fig. 4. Liver transplantation for primary hepatic malignancies by age groups for persons less than 18 years of age, United States, 1988-1996 (Organ Procurement and Transplantation Network Data, United Network for Organ Sharing).
patients younger than 18 years of age (4-9 patients annually, with the exception of 18 transplantations performed during 1993) were listed as having received liver transplantation for hepatoblastoma, hepatoma (hepatocellular carcinoma) and cirrhosis, or hepatoma (hepatocellular carcinoma).46 Furthermore, the majority of liver transplantations performed among children under 5 years of age were for hepatoblastoma, whereas those for children over 10 years of age were for hepatocellular carcinoma (Fig. 4), similar to the findings in our study. A lack of awareness for this highly fatal malignancy among physicians caring for children could result in a delay in the diagnosis in children. This could result in vascular invasion and be considered a factor for worse survival in adults, even with resection.41,43 We hope to improve the awareness of childhood hepatocellular carcinoma among physicians caring for children so that these children are diagnosed earlier and their survival is improved. This study has several limitations. Autopsies are not routinely performed to verify cause of death; therefore, diagnoses may not be accurate. Lack of differentiation between hepatoblastoma and hepatocellular carcinoma based on ICD-9 CM codes in the multiple-cause-of-death database makes finer analyses impossible. The SEER database is representative of 14% of the U.S. population and should not be extrapolated to the entire United States. Our study highlights the need for inclusion of contributing causes of death in these databases. Primary hepatic malignancies in children are predominantly hepatoblastoma in children less than 5 years of age and hepatocellular carcinoma in children older than 5 years. Over the last 2 decades, rates of hepatoblastoma in children less than 20 years of age have increased, but rates
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