The hepatoblastoma (HB) is an embryonal tumor that originates from the precursor of hepatocytes (hepatoblast cells).1 2,3
The HB is the most common primary malignant liver tumor in children and is usually diagnosed during the first 3 years of life.4 4 5,6
Regarding the diagnosis of HB, the only biomarker that is widely used for the diagnosis, stratification and monitoring of the response to therapy is the α-fetoprotein (AFP). Previous studies have investigated the prognostic value of AFP, finding that levels <100 ng/ml, as well as levels greater than 1.2× 106 ng/mL, are related with a poor outcome.7 8
Several imaging studies have been used in the diagnosis and staging of HB, such as Doppler ultrasound, due to its low cost and safety. Other imaging tests are generally requested to provide greater detail, such as computed tomography (CT), magnetic resonance imaging (MRI) and magnetic resonance with dissemination by weight, which is used to differentiate between benign and malignant lesions to avoid a biopsy.9
Currently, the risk stratification protocols take into account the PRETEXT classification, which evaluates the extent of the tumor before treatment, based on the system of Couinaud segmentation, vascular involvement, and metastasis, as evidenced in CT or MRI.10 7,11-13
Thanks to the evolution in the treatment of HB during the past 4 decades, the overall survival has increased from 30% to 80%, mainly as a result of advances in chemotherapy, the introduction of the agent cisplatin, and the ability to perform a complete surgical resection.4 9 14 4
Regarding the surgical resection of HB, the following techniques are included: segmentectomy, sectionectomy, and/or hemihepatectomy for the PRETEXT I and II; trisectomy for PRETEXT III and IV or transplant for tumors with invasion of the bilobar portal vein or the hepatic vein and the inferior vena cava or extensive loss of normal parenchyma.3,4 9
The objective of this article is to present the experience in the management of a series of pediatric patients with HB diagnosis, which had been made by the multidisciplinary group of the Transplant Unit of the Clinic Fundación Valle del Lili (Cali, Colombia).
MATERIALS AND METHODS
A retrospective collection of data was performed from the medical records of pediatric patients with diagnosis of HB in the Transplant Unit of the Fundación Valle del Lili (FVL) in Cali, Colombia. The variables that were included, were divided in 4 modules of study: demographic; diagnostic tools, and histological classification; chemotherapy and surgical treatment; outcomes and patient survival.
Within the first module, the following variables were registered: sex, age in months at the time of diagnosis, and the date of the procedure.
For the second module on diagnostic tools and histological classification, signs and symptoms that had been reported before diagnosis were recorded. Furthermore, the initial studies were noted, which included: type of imaging study performed (ultrasound, MRI, and/or CT), size of the lesion registered (the largest diameter of the tumor mass), which liver lobe was affected, and the PRETEXT classification. The histological variety and report of the levels of AFP in blood (μg/mL) at the time of diagnosis were also included.
The PRETEXT classification was applied for each case, which included the risk evaluation for HB. This classification is based on the extension of the tumor tissue in 4 major regions of the liver: right-hand zone (Couinaud 6, 7); front right area (Couinaud 5, 8); central left zone (Couinaud 4a, 4b); left side area.2,3
The third module included the number of cycles, the chemotherapeutic scheme used before and after the intervention, and the surgical procedure performed, whether it was resection or transplantation. As concerns, the surgical procedure, the duration of the surgery, the amount of intraoperative bleeding, and the transfusion requirement were recorded.
Finally, for the fourth module, the following variables were included: time of stay in the intensive care unit (ICU) and hospitalization (in days); complications; immunosuppressive scheme indicated, which was individualized according to each patient, using tacrolimus, steroids, and mycophenolate mofetil in different combinations; follow-up time in months; and patient survival.
The morbidity of patients who underwent surgery was evaluated by the Clavien-Dindo classification,15 16
Statistical Analysis
The variables were analyzed descriptively with continuous variables summarized as median and interquartile ranges (IQR) and mean ± standard deviation (SD) according to the distribution of the data evaluated using the Shapiro-Wilk test, the categorical variables were summarized in percentages. Survival analysis was carried out using the Kaplan-Meier method. Data were censored at the date of the last follow-up or date of death. Values of P less than 0.05 were considered significant. All analyses were performed with STATA 12.
RESULTS
Module 1, Demographic Data
A series of 16 patients was obtained (Table 1 shows the demographic variables). The median age of the patients at the time of diagnosis was 13.5 months (IQR, 8-35 months). The patients were divided according to the surgical procedure performed, resection and transplant groups. In general, the demographics of the groups were similar. Regarding the surgical intervention, the median of age at the time of the procedure was 15.5 months (IQR, 12-42 months).
TABLE 1: Clinical and demographic characteristics
Module 2, Diagnostic Tools and Histologic Classification
The main reason for the initial consultation, before the diagnosis of HB, was the discovery of a mass (n = 6), followed by abdominal distension (n = 2) and an incidental finding (n = 2). The median of the levels of AFP was of 3211 μg/mL (IQR, 643–30 305 μg/mL), and the difference between the levels of AFP between the 2 groups was not statistically significant (P = 0.29).
The mean of the size of the tumor was 9.2 ± 3.7 cm. According to the results of the images, 53% of patients had the right liver lobe compromised and in 24% of patients, the left lobe had been affected. Further on, it was classified with the PRETEXT classification (Table 1 ), showing a greater number in the transplant group than the patients that underwent resection (P = 0.024). The histological type with the highest prevalence was the epithelial (n = 12).
Module 3, Surgical Treatment and/or Chemotherapy
From 16 patients, 10 (62.5%) required chemotherapy before the surgical procedure. From these, 8 were transplanted and 2 underwent resection (P = 0.007) (Table 1 ).
Eight (50%) of the patients underwent surgical resection and the other half hepatic transplant. In patients that underwent surgical resection, 6 (75%) required a right hemihepatectomy, 1 (12.5%) a left hemihepatectomy with metastasectomy of the segments V-VIII, and 1 (12.5%) required segmentectomy of the segments VII-VIII. As to the transplants, 5 (62.5%) were from cadaveric donors (segments II and III) and 3 (37.5%) from related living donors (segments II and III).
The mean duration of surgical procedure in liver transplantation was 275 ± 27 minutes versus the mean time of the surgical resection 168 ± 52 minutes. The average intraoperative hemorrhage was 265 ± 205 mL, with requirement of transfusion in 14 (87.5%) of the cases.
For the cases of liver transplantation, the most common immunosuppressive scheme was tacrolimus plus prednisone (n = 3).
Module 4, Outcome and Survival
The mean duration of the hospitalization (including ICU and in-patient) from the day of the procedure was of 32.5 days (IQR, 18-45 days) until discharge. Complications were presented in 11 (68.7%) of the patients and classified according to the modified Clavien classification (Table 2 ). The complications were due to portal vein thrombosis stenosis of biliary duct, biliary fistula, sepsis, and pneumonia.
TABLE 2: Outcome and patient survival
In the resection group, 5 (62.5%) where classified I by the Clavien scale (any deviation from the normal postoperative course without need of intervention beyond pharmacological therapy). On the other hand, in the transplant group, 4 (50%) had a score greater than II in the Clavien, including a patient with Clavien V who died in postoperative hospitalization due to pneumonia with high suspicion of infection by Aspergillus. The difference of the complications that the patients presented with in the 2 groups according to the Clavien was statistically significant (P = 0.036).
The mean time of follow-up after the surgical intervention was 27.3 months (4.7-38 months) (Table 2 ). One of the transplant patients had a relapse, confirmed by pathology, and unfortunately, there was a lack of follow-up. Patient survival at 30 months was 100% in the resection group and 64% in the liver transplantation group (P = 0.3232) (Figure 1 ).
FIGURE 1: Survival analysis.
DISCUSSION
This report includes 16 pediatric patients referred to the Transplant and Surgery Unit of the FVL (Cali), due to a diagnosis of HB, during the period 2011 to 2014. It is noted that the epidemiological behaviour regarding the biological characteristics and risk factors of the cases in this series is consistent with what is reported in the literature for HB.17-19
The diagnosis of HB usually occurs when the patient is taken to a medical consult due to the presence of an asymptomatic abdominal mass, which was observed in 6 (37%) of our patients. In 2 (12.5%), the diagnosis was done by a incidental finding, which is consistent with what is reported in the literature, 10% of cases are a incidental finding of hemihyperplasia during a physical examination.20
According to current guidelines, all patients undergo ultrasound and then a CT scan and/or MRI. Further on, a biopsy of the tumor mass is taken,21 21 1
In the majority of cases, the chemotherapy begun extrainstitutionally and was interrupted until the referral to FVL. In these series of patients, this probably has contributed to the progression of the disease, generating the administration of a greater number of neoadjuvant chemotherapy cycles. In all of the cases, a chemotherapy regimen with C5V and doxorubicin was used for patients with intermediate and high risk, and in some patients, another chemotherapeutic agent was added. A great variability of the schemes and the number of chemotherapy cycles indicated was observed, whereas the therapeutic recommendation is to receive a total of 6 cycles of chemotherapy, performing 4 cycles presurgery and 2 cycles after the surgical intervention.4
In one of the cases of the transplant group, the patient had a PRETEXT II; this is because the patient had previous right hepatectomy and chemotherapy after the intervention. Nevertheless, a relapse was confirmed with CT scan where a well-defined mass was evident in the IV and VII segments of the right hepatic lobe, so it was decided to undergo transplant. Concerning the surgical treatment, the liver transplant had a longer operative time and more bleeding compared with the resection procedure (Table 2 ). This is related to the nature of the surgery and the severely ill patients undergoing this procedure.
Regarding the patients who underwent liver transplant, the percentage of surgical complications registered in our cases is comparable with what is reported in literature: vascular thrombosis was 13%, ranging between 8% and 12%, and bile duct stricture was 38%, occurring between 25% and 35% of the cases.22 23
In relation to the stay in the ICU and in-patient, the duration was according to the complexity of the surgical procedure and its complications.
Patients who underwent hepatic resection presented a lower morbidity (lower levels in the Clavien et al, classification) compared with those who received a transplant. The foregoing possibly related to a smaller level of PRETEXT at the time of diagnosis.9
Within the series of cases reported by the specialized international centers in a period of 10 years, Pittsburgh received 21 patients, London reported 40 cases (in a period of 12 years), and Chile reported 9 cases (over a period of 4 years). It is worth pointing out that, over a 4-year period, 17 cases with diagnosis of HB were referred to our institution. This could probably mean that the prevalence of disease at a national level, within Colombia, may be high.
The number of patients that were determined to have a resectable mass was 8 (50%), which is similar to the reported in international series 44% to 91%.18 Figure 1 ). In one of the transplant cases, the patient had a progression of the disease that affected the lung and central nervous system and was therefore referred to palliative care.
We consider that the results previously mentioned are because the patients who required hepatic transplantation had a more advanced state of the disease, at their initial presentation, compared with the group who received a resection.
CONCLUSIONS
FVL is a major referral center aiming to promote a proper diagnosis, record, study, and standardize treatment of the disease, because of the prognosis of the disease changes according to treatment indicated and the experience of the medical groups in specialized centers.24
To our knowledge, this is the first case report of HB with liver resection or liver transplant in Colombia and Latin America. Additionally, it is important to advocate for an increase of reporting in the scientific literature regarding rare pathologies, because there are no data on prevalence, or geographical distribution, as is the case of HB at the national level and Latin America.
Being aware of these diseases would allow a better process of diagnosis and intervention and probably lead to more favorable outcomes in pediatric patients who suffer from this pathology. Likewise, it would aid in the assignment of resources to meet the huge economic burden that such diagnosis and treatment mean for families facing this pathology.
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