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Original Article

Hepatoblastoma incidence in Taiwan: A population-based study

Hung, Giun-Yia,b,c; Lin, Li-Yiha; Yu, Ting-Yenb,c; Lee, Chih-Yinga,c,d; Yen, Hsiu-Jua,b,c; Horng, Jiun-Line,*

Author Information
Journal of the Chinese Medical Association: June 2018 - Volume 81 - Issue 6 - p 541-547
doi: 10.1016/j.jcma.2017.11.012

    Abstract

    1. Introduction

    Hepatoblastoma is most commonly found in infants and young children aged <5 years.1 Historically, the existence of hepatoblastoma in adults has been reported but remains controversial.2–3 A review article demonstrated that only 45 adult cases of hepatoblastoma had been reported through March 2011.4 Some of these cases were hepatitis B virus (HBV)- and hepatitis C virus (HCV)-negative and had no underlying liver disease, in contrast to classical hepatocellular carcinoma (HCC) cases that have cirrhosis or fibrosis of the remaining liver tissue and HBV or HCV seropositivity. Moreover, previous case reports and review articles revealed that prognoses of hepatoblastoma in adults were uniformly poor,2–11 which contrasted with those in children. Population-based surveillance can help to survey the existence of adult hepatoblastoma and further characterize these rare tumors. Hence, using the data from the population-based Taiwan Cancer Registry (TCR), this study surveyed hepatoblastoma incidences among children and adults; moreover, secular trends of HB incidence among age groups during 1995–2012 were also analyzed.

    2. Methods

    2.1. Data collection

    The data of patients with hepatoblastoma diagnosed from 1995 to 2012 were obtained from the TCR. Specifically, for children, the incidence data of HCC was also extracted to explore the trend of distribution in liver cancer subtypes during the study period. The TCR is organized and funded by the Health Promotion Administration, Ministry of Health and Welfare, Taiwan. A Cancer Registry Advisory Board was organized and responsible for standardizing the procedures, definitions of terminology, and coding of the reporting system for the registry. The TCR was launched in 1979, since the enactment of the Cancer Control Act in 2003, hospitals with a capacity of 50 or more beds that provide outpatient and hospitalized cancer care are mandated to submit cancer data to a central cancer registry office, and a trace-back procedure was also implemented, which substantially improved the completeness and case ascertainment of cancer registration.12,13 In addition, Taiwan launched the single-payer National Health Insurance (NHI) program in 1995.14 This compulsory universal social insurance system now covers 99.6% of Taiwan's population, and 93% of the hospitals and clinics are NHI-contracted, making it extremely convenient for all residents to get care. Beginning with 2002 incidence data, the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) was used by TCR for coding instead of the ICD-O, Field Trial Edition. In the ICD-O-3, primary liver cancer is classified in “C22, cancer of the liver and intrahepatic bile ducts,” and the histology code for hepatoblastoma is 89703 (and 81703, 81713, 81723, 81733, 81743, and 81753 for HCC). The Census data by 5-year age group and sex were obtained from the Department of Statistics, Ministry of the Interior, Taiwan. Regarding the main measures of data quality defined by the International Agency for Research on Cancer (IARC), the proportion of microscopically verified cases (MV%) was 91.54% for all cancers combined in 2012. The percentage of cancer cases identified with death certification-only (DCO%) is another indicator of data validity, which decreased from 19.63% in 1995 to 0.72% in 2012. Specifically, for primary liver cancers, the mortality to incidence rate ratio was 1.05 in 1995 and decreased to 0.70 in 2012. MV% ranged from 38.9% in 1995 to 47.61% in 2012, and DCO% was 1.41% in 2012.15 These measures reflect the high quality of the TCR data, with steady improvement over time, and its achievement of a standard comparable to other cancer registries in Western countries.16,17 The data source of this study is the TCR public-access database (http://www.hpa.gov.tw/BHPNet/Web/Stat/Statistics.aspx) that consists of case numbers grouped according to the year of diagnosis, sex, and age (in 5-y age intervals). In addition, the MV% of hepatoblastoma and HCC were obtained via the Health and Welfare Data Science Center (HWDC), Taiwan. The HWDC guards the privacy of all enrollees, and provided the data to researchers who have obtained ethical approval. Before the release, all information that could potentially identify an individual person was encrypted. This observational study was approved by the Institutional Review Board of Taipei Veterans General Hospital, Taiwan (IRB-TPEVGH No.: 2016–10–001C). Because these data contain no identifiable personal information, the review board requirement for written informed consent was waived.

    2.2. Analyses

    Incidence rates were calculated and are expressed per million person-years by the age group and sex. Age-specific incidence rates were stratified into 18 subgroups by 5-year age intervals (from 0 to 4 to ≥85 y). The age-standardized incidence rate (ASIR) is the weighted average of the age-specific rate, where the weight is the proportion of individuals in the corresponding age group of a standard population. Calculating the ASIRs of subgroups by using the same standard population can correct for potential confounding effects derived from differences in the age composition of the population over time. In this study, the World Health Organization World Standard Population was used to calculate the ASIRs and to examine variations among age groups (http://www.who.int/healthinfo/paper31.pdf). Three age groups were compared, as follows: children (aged 0–14 y), adolescents/adults (aged 15–59 y), and elderly people (aged ≥60 y). By using Microsoft Office Excel 2007, this study employed the published methods of IARC to calculate the incidence rates, standard errors, 95% confidence intervals (CIs), and standardized incidence rate ratios (SIRRs).18 The relative risks of cancer, ratio of ASIRs (ie, SIRRs), and 95% CIs were calculated to compare the cancer incidence by sex. The SIRRs were considered to significantly differ if the estimated 95% CI did not contain 1. Time trends in incidence rates were examined by fitting joinpoint models (Joinpoint Regression Program, version 4.0.4; Statistical Methodology and Applications Branch, Surveillance Research Program, National Cancer Institute, Bethesda, MD) to the ASIRs, which were restricted to a maximum of 3 joinpoints (4 line segments).19,20 The annual percent change (APC) and corresponding 95% CI were calculated to express the trends in incidence rates among age groups. APC was considered statistically significant if the 95% CI did not include 0 (p < 0.05).

    3. Results

    In total, 211 patients were diagnosed with hepatoblastoma during the 18-year study period, yielding an annual average of 12 patients. Hepatoblastoma accounted for 0.22% of all cancers of the liver and intrahepatic bile ducts in 1995 and 0.15% in 2012. The MV% for hepatoblastoma and HCC during the study period was 97.0% and 51.3%, respectively. Incidence rates according to the age group and sex are illustrated in Table 1. The crude rate and ASIR of all patients were 0.52 and 0.76 per million person-years, respectively. The ASIR for the age groups of 0–14, 15–59, and ≥60 years were 2.67, 0.04, and 0.32 per million person-years, respectively. Hepatoblastoma was predominantly diagnosed in children, who accounted for 87.2% (10.2 cases annually) of all cases. By contrast, adolescents/adults and elderly people were rarely affected, with proportions of 4.7% (0.6 cases annually) and 8.1% (0.9 cases annually), respectively. A significant male predilection was only found in children and elderly people, with male-to-female SIRRs of 1.23 and 1.89, respectively. No significant sex predilection was found in the age group of 15–59 years. Fig. 1 depicts the age-specific incidence rate curves, which shows a peak in the age group of 0–4 years with corresponding ASIR of 7.3 per million person-years, a dramatic decline to nearly 0 after the age of 5 years, and a slight increase for the age group of 60–84 years.

    T1-8
    Table 1:
    Incidence rates per million person-years of hepatoblastoma by age group and sex (1995–2012).
    F1-8
    Fig. 1.:
    Age-specific incidence rates of hepatoblastoma according to sex during 1995–2012 in Taiwan.

    3.1. Secular trends

    Incidence trends according to age groups are summarized in Table 2 and Fig. 2. During 1995–2012, the overall incidence of hepatoblastoma significantly increased (APC, 7.4%; 95% CI, 4.4%–10.5%, p < 0.05) (Fig. 2A). The trends of incidence rates could only be evaluated in children (APC, 7.4%; 95% CI, 3.9%–11.1%, p < 0.05), with a significant increase in boys (APC, 6.5%; 95% CI, 1.9%–11.2%, p < 0.05) (Fig. 2B). The trend analysis in girls and age groups other the 0–14-y age group could not be performed owing to at least one annual rate of 0 during the 18-year study period (Fig. 2C and D).

    T2-8
    Table 2:
    Incidence rates (per million person-years) of hepatoblastoma by age groups, sex, and year of diagnosis.
    F2-8
    Fig. 2.:
    Time trends of incidence rates of hepatoblastoma according to the age group and sex during 1995–2012 in Taiwan. A: Total study population and the age groups of B: 0–14 y, C: 15–59 y, and D: ≥ 60 y.

    Fig. 3 illustrates the incidence trends of hepatoblastoma and HCC in children during 1995–2012; the rates of both liver cancer subtypes were similar until 2003, when the rate of hepatoblastoma was higher than the rate of HCC and continued to increase through 2012. The incidence trend of hepatoblastoma contrasts with the decreasing trend of HCC through 2011.

    F3-8
    Fig. 3.:
    Age-standardized incidence rates of hepatoblastoma and hepatocellular carcinoma for the group of 0–14 y during 1995–2012 in Taiwan.

    4. Discussion

    This study demonstrated that only 27 patients aged ≥15 y had hepatoblastoma during the 18-year study period. Similar to other regions in Asia, Taiwan also exhibits viral hepatitis endemism and a high rate of HCC.21 Some researchers may argue that these adult hepatoblastoma cases are actually misdiagnosed HCC. The authors of the second edition of the Atlas of Tumor Pathology Tumours of the Liver and Intrahepatic Bile Ducts declared that not a single adult hepatoblastoma case had been recorded at the Armed Forces Institute of Pathology and assumed that the majority or all reported adult hepatoblastoma cases were actually misdiagnosed HCC, combined HCC–cholangiocarcinomas, or carcinosarcomas.22 To date, the occurrence of adult hepatoblastoma is still under debate owing to difficulty in differential diagnosis between hepatoblastoma and HCC, because clinical presentations and molecular and histological findings often overlap. These features are even more confusing in adults than in children.2–4,6 Moreover, both hepatoblastoma and HCC can exist in the same tumor or sequentially develop in the same patient.4 Nevertheless, in countries such as Taiwan with HCC endemism and extremely experienced pathologists for liver tumor diagnosis, histological diagnoses of hepatoblastoma were still made in adults during 1995–2012, as shown by the current study. A search of the most updated English literature through PubMed revealed at least 3 adult hepatoblastoma cases during 2013–2015 (one each from the Netherlands,2 South Korea,11 and China5). It is likely that until novel molecular tools are established to enable differential diagnosis between hepatoblastoma and HCC, adult hepatoblastoma cases will still be sporadically reported worldwide, and this issue will continue to remain highly controversial.

    In this study, no significant incidence trend was identified for adult hepatoblastoma during 1995–2012. However, a changing distribution pattern of liver cancers was observed in Taiwanese children during the study period. The rates of hepatoblastoma and HCC were similar until 2003, when the rate of hepatoblastoma was higher than the rate of HCC, and hepatoblastoma exhibited a significant upward trend through 2012. One of the factors contributing to this changing pattern is the decreased rates of chronic HBV infection and HBV-related HCC in children resulting from the world's first nationwide universal HBV vaccination program launched 30 years ago.23 Moreover, previous studies in developed countries have also reported the upward trend of hepatoblastoma and concluded that this trend is associated with an increase in very-low-birth-weight (VLBW) prematurity, a known risk factor for childhood hepatoblastoma, although the reason for this association is unknown.24,25 Premature infants require specialized care, including drugs (eg, antenatal or prenatal steroid treatment and antibiotics), total parenteral nutrition, and the use of oxygen and ventilators for respiratory distress syndrome. The contribution of the interplay of these potential risk factors and the baby's immature organs to hepatoblastoma development should be further investigated. In Taiwan, the percentage of VLBW infants (birth weight <1500 g) increased by only 0.1% in the past 10 years.26 However, the survival rates for VLBW prematurity significantly increased from 72% in 2007 to 78% in 2012.27,28 Thus, the relationship between the upward trend in childhood hepatoblastoma and increased survival of prematurity in Taiwan deserves further study to elucidate. Pediatricians and obstetricians should be made aware of this fact and should make efforts to reduce deliveries of VLBW premature infants to potentially reduce this trend in Taiwan.

    The results of the current study showed a high rate of childhood hepatoblastoma (2.67 per million person-y, 1995–2012) compared with the rates in Europe (1.5 per million person-y, 1988–1997)29 and the USA (2.2 per million person-y, 2006–2010).30 In Beijing, China, a high rate of childhood hepatoblastoma was also reported (3.57 per million person-y, 2000–2009).31 This finding of a high rate of hepatoblastoma in the same ethnic group (Han Chinese) in different regions (Taiwan and China) is evidence supporting that the genetic background is involved in the pathogenesis of childhood hepatoblastoma. Moreover, hepatoblastoma is associated with several cancer predisposition syndromes, including familial adenomatous polyposis (FAP)32–34 and Beckwith–Weidemann syndrome (BWS).35 The reported relative risks of hepatoblastoma in patients with FAP and BWS are 1220 (95% CI, 230–2168) and 2280 (95% CI, 928–11,656) during the first 4 years of life, respectively.32,35,36 A previous study reported that 2.5% of 163 patients with FAP also developed hepatoblastoma,37 and another study reported that 8.6% of 93 patients with hepatoblastoma had a family history of FAP.38 Collectively, these findings support that genetic factors are involved in the carcinogenesis of childhood hepatoblastoma. In contrast to adult cancers, in which long-term exposure to extrinsic risk factors substantially contribute to carcinogenesis,39 embryonal tumors such as hepatoblastoma in children are more likely to be associated with genetic alterations, with an extremely short period of carcinogenesis.40 Because FAP is classically characterized by a mutation in the adenomatous polyposis coli gene on the long arm of chromosome 5,41 genetic testing for this mutation in newborns and infants with a known family history of FAP and subsequent screening for hepatoblastoma by alpha-fetoprotein and liver sonogram in those with the mutation can achieve the goal of early detection. Hence, smaller tumors can be detected, enhancing the rate of complete tumor excision, and the rate of distant metastasis can also be reduced, which are key to increasing patient survival. Although there are ethical, practical, and psychosocial considerations in the management of these inherited cancers in children,42 genetic testing for the adenomatous polyposis coli gene mutation and subsequent screening for hepatoblastoma could still be considered in newborns and infants who have first-degree relatives with FAP.

    A diagnosis of adult hepatoblastoma is made according to the histological findings of tumor biopsies at diagnosis or tumor excision.4 A limitation of this study is the pathological difficulty in distinguishing hepatoblastoma from HCC. Perhaps the incidence of adult hepatoblastoma is underestimated because approximately half of patients with HCC are clinically diagnosed based on imaging studies, tumor markers, and viral hepatitis seropositivity and treated accordingly without pathological proof. The diagnosis of adult hepatoblastoma remains questionable; however, based on the data from population-based TCR, this study presents the most reliable incidence estimates of adult hepatoblastoma in Asians, and contributed to the state of knowledge on this largely unknown topic.

    In conclusion, hepatoblastoma in adolescents, adults and elderly people is extremely rare and accounted for only 1.5 newly diagnosed cases annually in Taiwan. Because of the difficulty of obtaining a definite differential diagnosis from HCC pathologically, the existence of adult hepatoblastoma is still being debated. Novel molecular tools should be established in the future to elucidate the existence of adult hepatoblastoma. Like findings from other developed countries, the incidence of hepatoblastoma is increasing in children in Taiwan. This trend might be associated with increased survival rates of premature infants especially VLBW babies, a known risk factor for hepatoblastoma. Efforts to prevent prematurity, including reducing high-risk pregnancies, should be effective in reducing this trend. Genetic testing (adenomatous polyposis coli gene mutation) could be considered for certain newborns and infants with a family history of FAP to identify those at risk for hepatoblastoma and requiring screening (eg, alpha-fetoprotein, liver sonogram) for early detection, more favorable tumor control, and improved disease survival. This approach could be preferably adopted in countries with a high rate of childhood hepatoblastoma, such as Taiwan and China.

    Acknowledgments

    The authors would like to express their sincerest gratitude to the Taiwan Cancer Registry, Health Promotion Administration, Ministry of Health and Welfare, Taiwan, for kindly providing incidence data and statistical consulting.

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    Keywords:

    Hepatoblastoma; Incidence; Taiwan

    © 2018 by Lippincott Williams & Wilkins, Inc.