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Original Articles: Hepatology

Predisposing Conditions to Pediatric Hepatocellular Carcinoma and Association With Outcomes: Single-center Experience

Cowell, Elizabeth; Patel, Kalyani; Heczey, Andras; Finegold, Milton; Venkatramani, Rajkumar; Wu, Hao; López-Terrada, Dolores§; Miloh, Tamir||

Author Information
Journal of Pediatric Gastroenterology and Nutrition: May 2019 - Volume 68 - Issue 5 - p 695-699
doi: 10.1097/MPG.0000000000002285


What Is Known

  • Pediatric hepatocellular carcinoma has been linked to varied chronic viral, metabolic, and systemic conditions.
  • Although hepatocellular carcinoma is known to be associated with a number of conditions, surveillance guidelines are poorly defined given a lack of information about risk factors for hepatocellular carcinoma development.

What Is New

  • We report a large case series of pediatric hepatocellular carcinoma in which the majority of these patients did not have predisposing liver or associated disease.
  • Patients with de novo hepatocellular carcinoma were older at diagnosis and had a higher rate of metastatic disease, larger tumor size, and decreased overall survival.

Hepatocellular carcinoma (HCC), the second most common primary malignant liver tumor in children, is particularly challenging to cure due to difficulty in early detection and resistance to chemotherapy (1,2). The outcomes for children with HCC remain poor, with an overall 5-year survival of 24% reported in a recent large series of pediatric HCC cases (1). Complete resection of the tumor by surgery or liver transplantation is associated with significant improvement in survival to >50% at 5 years. Addressing the gap in our understanding about risk factors may allow for improvement in surveillance of those with underlying conditions and potentially lead to earlier HCC diagnosis and better outcomes.

A range of diseases promote pediatric HCC carcinogenesis through different mechanisms (Table 1) (3). Globally, the most prevalent diseases associated with the development of HCC in children are chronic hepatitis B and C infections (4–6). Up to 37% of patients with tyrosinemia have been reported to develop HCC (7–9). Within the family of progressive familial intrahepatic cholestasis (PFIC) disorders, PFIC type 2 is a high-risk category for development of HCC in young children (10,11). In addition, diseases affecting the biliary tree such as biliary atresia and Alagille syndrome pose a risk for HCC, which has been reported in infants with biliary atresia as young as 6 months old (12,13). Conditions resulting from germline mutations such as familial adenomatous polyposis and neurofibromatosis can predispose patients to HCC (7,14,15). HCC has also been reported as a late effect of the Fontan procedure with a latency of 14 to 28 years (16).

Conditions associated with pediatric hepatocellular carcinoma

The incidence of HCC in children with predisposing conditions and their outcomes are not well defined, because current literature is limited to case reports and disease-specific case series. We retrospectively reviewed the underlying medical conditions of pediatric patients with HCC and analyzed patterns of presentation and outcomes between clinical subgroups. Understanding the conditions that predispose to HCC will strengthen our knowledge of the epidemiology of pediatric HCC and may guide the surveillance of specific clinical groups.


A retrospective chart review of patients 21 years or younger with HCC was conducted after approval from the institutional review board of Baylor College of Medicine. All cases diagnosed as HCC from 1996 to 2016 were identified from the pathology database. They included both patients treated at our institution and patients whose pathology was reviewed by our pathologists but were managed elsewhere. All slides were reviewed by a single pathologist (M.F.).

The following characteristics were tabulated for patients treated at our institution: age, sex, medical history, family history, presenting complaints, metastasis at presentation, laboratory parameters, and imaging studies at diagnosis, tumor histopathology, treatment, and clinical outcome. Laboratory parameters tabulated included the following: alpha-fetoprotein (AFP), complete blood count including white blood cell count, hemoglobin, and platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase and alkaline phosphatase (ALP) levels, bilirubin, and prothrombin time/international normalized ratio. Recorded imaging characteristics included size of tumor, solitary, or multifocal lesion, and presence of vascular invasion. Frequency of laboratory and imaging surveillance before diagnosis was recorded, if present. Treatment and outcome data were limited to presence or absence of medical or surgical intervention (resection, liver transplant) and clinical outcome at last follow-up. For the consulting patients, the data were fully deidentified and data collection was limited to age, sex, and predisposing liver condition as described in pathology reports or from chart review by primary providers at these institutions.

Tumors in children and adolescents showing overlapping morphologic features with hepatoblastoma and HCC have been shown to harbor distinct molecular abnormalities (17). These are referred to as hepatocellular neoplasms, not otherwise specified and were excluded from the study (18). Moreover, patients for whom there was no medical history available were also excluded from this study (n = 9 patients). Predisposing condition was defined as any pre-existing medical condition that has been previously associated with HCC (see Introduction and Table 1). Predisposing conditions were abstracted systematically based on chart review of medical history and diagnostic testing including genetic testing, and review of histopathologic characteristics of noncancerous background liver tissue.

Correlations between categorical and continuous variables including subgrouping based on presence of predisposing conditions were examined using Fisher exact test and Mann-Whitney test, respectively. The Kaplan-Meier method was used for survival analysis. Survival duration was calculated from the time of the initial diagnosis to the date of last contact or date of death if the patient was deceased. Mann-Whitney test was employed to evaluate survival differences between subgroups. For all statistical tests, the significance threshold was set at 0.05.


Presenting Characteristics

Sixteen cases of pediatric HCC diagnosed and treated at our institution (56% boys, median age 9.5 years) and 45 patients whose pathology was reviewed in consultation (66% boys, median age 8.0 years) between 1996 and 2016 were identified. Family history was unremarkable among the cohort treated at our institution, with only 1 patient with a relevant family history—MPV17-related DNA duplication syndrome in both patient and sibling (case 3 in Supplemental Digital Content 1, One case was detected by surveillance (see below) and 1 was found incidentally in a liver explant after transplantation for tyrosinemia. A majority of patients (88%) were diagnosed after symptomatic presentation with the following complaints: abdominal pain (44%), abdominal distension (31%), vomiting or hematemesis (25%), with more uncommon complaints including jaundice, fever, palpable mass, and diarrhea (each seen in 1 of 16 patients, or 6%).

The initial imaging modality was ultrasound in 5 cases, computed tomography scan in 6 cases, ultrasound and computed tomography in 2 cases, and magnetic resonance imaging (MRI) in 2 cases. Full radiology reports were available for 10 of 16 patients: 6 of 10 patients (60%) had tumors >4 cm in diameter, 5 of 10 patients had multifocal tumors, and 4 of 10 patients had tumors with vascular invasion on imaging (Supplemental Digital Content 2, Metastatic disease was identified on presentation in 5 of 16 (31%) of these patients, all of whom had pulmonary metastases, and 1 patient had additional peritoneal metastases.

AFP was elevated for age in 8 of 12 patients (67%) and not available in 4 patients (median 2049 ng/mL, range 0.7–1 million ng/mL; Supplemental Digital Content 2, Complete blood count at presentation was normal in a majority of patients, with significant anemia (hemoglobin <10 g/dL) present in 3 of 16 patients. Regarding liver enzyme levels, 6 of 15 (40%) patients had elevated AST and 5 of 15 (33%) had elevated ALT on presentation (median AST 78 u/L, range 31–321 u/L; median ALT 49 u/L, range 19–311 u/L). Gamma-glutamyltransferase levels were available in 12 of 16 patients and were abnormal in 6 of 12 cases (50%) with a median of 84 u/L and a range of 25 to 257 u/L; ALP levels were available in 14 of 16 patients and were abnormal in 12 of 14 cases (86%) with median 219 u/L and range 60 to 750 u/L. Bilirubin levels were abnormal in 1 of 16 cases, with a median of 0.4 u/L and range 0.2 to 1.2 u/L. International normalized ratio was available in 10 cases and was elevated in 4 of 10 patients (40%) with a median 1.2 and a range of 1 to 1.5.

Pathology samples were available for 14 of 16 of the patients treated at our institution, and these were reviewed by a single pathologist (M.F.). Among these 14 cases, 4 were well-differentiated, 2 were moderately differentiated, 4 were poorly differentiated HCCs, and 4 demonstrated fibrolamellar histology (Supplemental Digital Content 2, Background liver tissue pathology was available for 13 of 16 patients, and in all cases was consistent with medical history obtained by chart review. The gross and histopathologic specimens from case 2 in Supplemental Digital Content 1 ( are illustrated in Figure 1.

A, Gross section of explanted liver from a 2-year-old boy with progressive familial intrahepatic cholestasis (PFIC) type 4 (case 2, Supplemental Digital Content 1, Pigmented nodules indicate bile secretion by the tumor, whereas a large pale nodule is typical of hepatocellular carcinoma (HCC). B, Histopathology of a small nodule displaying mild nuclear variation (hematoxylin-eosin × 100). C, Histopathology of the larger nodule showing poorly differentiated HCC (hematoxylin-eosin × 200).

Predisposing Conditions

Seven patients treated at our institution (44%) had predisposing liver or associated disease including cryptogenic cirrhosis (1), tyrosinemia (1), hepatitis B (1), PFIC type 3 (1), PFIC type 4 (1), mitochondrial disorder with MPV17 gene mutation (1), and idiopathic aplastic anemia (1). Four of 9 patients with de novo HCC had tumors with fibrolamellar histology.

Forty-five additional patients had their pathology reviewed by our pathology department for expert opinion. Background liver tissue pathology was available for 39 of 45 patients. Eighteen of the 45 patients (40%) had a predisposing condition including cryptogenic cirrhosis/fibrosis (5), macrovesicular steatosis (3), Alagille syndrome (3), malignancy (2) (adrenal cortical carcinoma, metastatic leiomyoma), PFIC type unknown (2), PFIC type 2 (1), biliary atresia (1), and Fanconi anemia (1). Of the 27 patients with de novo HCC, 9 had fibrolamellar carcinoma.


Of the 7 patients with predisposing conditions, only 2 received surveillance for HCC development. One case of HCC was diagnosed based on surveillance (elevated AFP, case 2 in Supplemental Digital Content 1, This patient also received serial MRI every 6 months, which was sensitive in the detection of HCC at the time of AFP elevation. Case 5 was a patient with PFIC type 3 who presented symptomatically with a large tumor despite surveillance by AFP levels every 12 months. This patient did not receive imaging as part of the surveillance program.

Patterns of Presentation

Age at diagnosis was available for the full cohort of 61 patients. Mean age at diagnosis was 7.2 years for those with and 10.2 years for those without predisposing disease (P < 0.05). Within our institution, metastatic disease at presentation was seen in 15% (1/7) of patients with predisposing disease, compared to 44% (4/9) of those with de novo HCC (P = n.s.). AFP was elevated at diagnosis in 80% (4/5) of patients with and 57% (4/7) without predisposing disease (P = n.s). Among the 10 patients for which imaging was available, those patients with predisposing conditions were more likely to have smaller tumors at presentation (<4 cm) compared to those with de novo HCC (100% vs 80%; P < 0.05). Histopathological review demonstrated 33% (3/9) of moderate-poorly differentiated HCCs and 44% (4/9) fibrolamellar HCCs in patients without predisposing conditions. Fifty percent of patients with a predisposing condition were diagnosed with well differentiated HCC and 50% with moderate to poorly differentiated HCC. Three of the 4 patients with fibrolamellar HCC included within the group of de novo HCC patients had normal AFP at diagnosis (median 2.3 ng/mL, unavailable in 1).

Clinical Outcomes

For the patients treated at our institution, median follow-up was 45 months from diagnosis (range 2 days–16 years; Supplemental Digital Content 2, Five of the 7 patients with predisposing conditions received a liver transplant and were in complete remission at last follow-up. Three of the 9 patients with de novo HCC achieved remission after curative surgery (1 liver transplant, 2 gross-total resection), and the remainder died due to disease progression (1 unknown).

Overall, 8 of 16 patients (50%) died due to progressive HCC (Fig. 2). All patients with metastatic disease at presentation died due to progressive disease, with a median survival of 26 days (range 2–170 days). All 6 patients who received liver transplant were alive at last follow-up. Patients with predisposing conditions were more likely to have an increased overall survival compared to those with de novo HCC (4.3 vs 0.5 years; P < 0.05). Kaplan-Meier curves also depict a trend in survival difference between patients with and without predisposing conditions (Fig. 2, P = n.s.).

Overall survival in children with hepatocellular carcinoma (HCC). Overall survival by Kaplan-Meier method in 16 children with HCC treated at our institution stratified by presence or absence of predisposing condition, P = 0.07 by Wilcoxon test. Note: Clinical group of 9 patients with “no predisposing condition” includes 4 patients with fibrolamellar HCC.


This retrospective review investigated the frequency of predisposing conditions in 61 children with HCC, delineating patterns of clinical characteristics, pathologic features, and outcomes within subgroups. Basic demographic information highlights a male predominance of pediatric HCC consistent with what has been previously reported in the literature (1,19).

Our primary goal was to investigate the overall frequency of predisposing conditions in children with HCC. Predisposing conditions were identified in 41% of patients, the most common being cryptogenic cirrhosis, macrovesicular steatosis, Alagille syndrome, PFIC, and other malignancies. Notably, while PFIC type 2 is a known risk factor for HCC development, we describe 2 cases of pediatric HCC developing in patients with underlying PFIC type 3 and 4. We also report 1 patient who developed HCC in the setting of MPV17-related DNA duplication syndrome, which has not been previously reported in the literature. In addition, we identified cases of HCC developing in patients with macrovesicular steatosis, which is particularly concerning given the current obesity epidemic and related increasing incidence of nonalcoholic fatty liver disease earlier in life.

We found a lower frequency of tyrosinemia in our series of pediatric patients with HCC than previously described, possibly due to the early widespread use of nitisinone and selection bias (8). There was only 1 patient in our cohort with viral hepatitis B, which is consistent with the overall low prevalence of this disease in our region (3). The majority of children with HCC in our cohort did not have predisposing liver or associated disease, a frequency of de novo HCC similar to what has been reported in smaller studies (19,20). We included patients with fibrolamellar HCC within the clinical group of de novo HCC patients, as fibrolamellar HCC is known to arise in patients without predisposing liver disease. The frequency of fibrolamellar HCC in our series (13 cases, 21%) appears similar to that reported in the pediatric HCC literature (1). A recent retrospective review also identified predisposing conditions among 25 children with HCC who received liver transplantation, reporting an increased incidence of patients with predisposing conditions (21). This discrepancy may be explained by the study's inclusion of many cases of incidental HCC detected during transplantation for another condition, which comprises 40% (10/25) of patients in that cohort.

We found that AFP had a low sensitivity of 67%, similar to previous reports in pediatric and adult literature (7,22,23). This low sensitivity can be partially attributed to the absence of AFP elevation in patients with fibrolamellar HCC within our cohort. AFP may, however, be useful in surveillance of patients with predisposing conditions, as its sensitivity appears higher in this group (80% vs 57%). Many other laboratory parameters included in the basic workup for HCC were neither sensitive nor specific, suggesting that imaging is essential to making this diagnosis. The laboratory test with the highest sensitivity in our cohort was ALP (86%). As a biologic marker of both hepatobiliary disease and malignancy of bone, liver, and lung, the high sensitivity of ALP levels in our cohort may reflect its overlapping role as a marker of both hepatocyte function and malignancy (24).

A small number of patients in our institutional cohort who had a predisposing condition before developing HCC received regular surveillance (Supplemental Digital Content 1, One patient in our cohort was initially diagnosed with HCC by increasing AFP, which was monitored every 4 to 6 months (case 2, Supplemental Digital Content 1, This patient also received advanced imaging with serial MRI every 6 months. The ideal frequency of surveillance is not clear, but in our experience a latency of 12 months is not sufficient for early detection of HCC, based on the presentation of a patient with PFIC Type 3 with advanced stage HCC despite yearly AFP levels (case 5, Supplemental Digital Content 1, In the pediatric radiology literature, surveillance with periodic ultrasound is recommended in children with cirrhosis; however, this recommendation has not been adopted by the pediatric hepatology community (25). Although routine surveillance is standard of care in the adult population, in which HCC is most likely to occur in the context of underlying cirrhosis, the cost-effectiveness and feasibility of surveillance are not established in pediatrics (19).

The clinical course and outcomes of children with HCC seem to differ based on the presence or absence of predisposing conditions. Among all patients in our cohort, those with de novo HCC were more likely to present at an older age (P < 0.05). Among patients at our institution, those with de novo HCC were more likely to present at an advanced stage with a higher incidence of larger tumors (>4 cm; P < 0.05) and a trend toward increased metastatic disease at presentation. We also found that patients with predisposing conditions were more likely to receive liver transplant and to enter complete remission, and that the median overall survival was found to be significantly decreased in those patients with de novo HCC (P < 0.05). These results may support that surveillance and/or routine medical care of patients with predisposing conditions is useful to detect HCC at an earlier stage, or alternatively that HCC tumorigenesis may differ biologically in these 2 contexts.

Overall, more than one half of children with HCC in our study did not have a predisposing condition, and these patients displayed later diagnosis and higher rate of metastatic disease, larger tumor size, and decreased overall survival. Large multicenter studies are needed to determine whether routine surveillance should be recommended in patients with predisposing conditions.


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epidemiology; histopathology; liver transplantation; pediatric oncology

Supplemental Digital Content

Copyright © 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition