Hepatoblastoma in children of extremely low birth weight: A report from a single perinatal center

Hepatoblastoma in Children of Extremely Low Birth Weight: A Report From a Single Perinatal Center By Takaharu Oue, Akio Kubota, Hiroomi Okuyama, Hisayoshi Kawahara, Keigo Nara, Keisei Kawa, and Hiroyuki Kitajima Osaka, Japan

Background/Purpose: The incidence of hepatoblastoma (HB) in children of low birth weight is increasing. In the authors’ institute, 5 infants of extremely low birth weight (ELBW) were found to have HB. The purpose of this study was to identify the characteristics of these infants to elucidate the pathogenesis of HB arising in ELBW infants. Methods: Birth weight (BW) ranged from 554 to 750 g (mean, 654 g) and gestational age from 23 to 29 weeks (mean, 25.8 weeks). Medical records of the 5 patients were reviewed, and perinatal treatments were compared with those of ELBW infants without HB. Results: One patient with intraabdominal hemorrhage had emergency operation, which was followed by early postoperative death. The parents of one child refused treatment because of associated severe anomalies. He died of the growing tumor 4 months after diagnosis. The remaining 3 patients had radical operation performed after intraarterial chemoembolization and systemic chemotherapy. One died

H

EPATOBLASTOMA (HB) is the most common malignant hepatic tumor in children. Using the database of Japan Children’s Cancer Registry, Ikeda et al1 reported that HBs among children with very low birth weight (VLBW, birth weight under 1,500 g) have increased significantly in Japan and that a significant linear trend toward an increase in the percentage of patients with a birth weight (BW) of less than 1,500 g was observed specifically in HB. The relative risks of HB among children with extremely low birth weight (ELBW, birth weight under 1,000 g) was 15.64 times higher than that among children with a birth weight of 2,500 g or more.2 The same observations were confirmed in other

From the Department of Pediatric Surgery, Pediatrics and Neonatology, Osaka Medical Center & Research Institute for Maternal & Child Health, Izumi, Osaka, Japan. Presented at the 49th Annual Congress of the British Association of Paediatric Surgeons, Cambridge, England, July 23-26, 2002. Address reprint requests to Takaharu Oue, MD, Department of Pediatric Surgery, Osaka Medical Center & Research Institute for Maternal & Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan. Copyright 2003, Elsevier Science (USA). All rights reserved. 0022-3468/03/3801-0028$35.00/0 doi:10.1053/jpsu.2003.50027 134

of hepatic failure 7 months after operation. Two are alive 5 and 9 months after operation. The incidence of HB among ELBW infants was estimated to be about 0.5% in our institute. The mean durations of mechanical ventilation, oxygen inhalation, and hospitalization during the neonatal periods in cases of HB were significantly longer than those in BW matched control infants (P ⬍ .01). Conclusions: ELBW children have a high risk for HB. In follow-up of ELBW infants, serum alpha-fetoprotein or abdominal ultrasonography may be useful to detect early HB. The children with HB received perinatal treatments for a significantly longer time, which suggests that perinatal intensive and long-term medical treatments may be involved in the tumorigenesis in the highly sensitive immature liver. J Pediatr Surg 38:134-137. Copyright 2003, Elsevier Science (USA). All rights reserved. INDEX WORDS: Hepatoblastoma, low birth weight, immature, perinatal treatments.

institutes. Ribons and Slovis3 reviewed their experience of liver tumors at Children’s Hospital in Michigan and found that 6 of the 15 cases of HBs (40%) occurred in premature infants of gestational age ranging from 26 to 36 weeks. Feusner et al4 reviewed the retrospective survey conducted by a Children’s Cancer Group study of HB, and estimated that the incidence of HB in ELBW infants represents 16 to 23 times higher than the expected incidence. The etiologic factors, which contribute to the increase of HB in children of low birth weight, are unclear. We experienced five ELBW infants with HB, and 4 of them were treated in the neonatal care unit (NICU) of our institute. We have tried to elucidate the pathogenic factors of HB arising in ELBW infants by analyzing the characteristics of these patients and comparing them with birth weight–matched controls. MATERIALS AND METHODS Since 1989, 5 ELBW infants with HB were treated at Osaka Medical Center for Maternal and Child Health. They included 3 boys and 2 girls. Their BW ranged from 554 to 750 g (mean, 654 g), and the gestational age ranged from 23 to 29 weeks (mean, 25.8 weeks). Age at diagnosis ranged from 14 to 16 months. Four of them had been treated in our NICU during neonatal period, and the other had been treated in another hospital. No patient had a genetic disorder or family history of hereditary disease. One patient (case 5) had congenital disorders, including tetralogy of Fallot and chondrodysplasia. Journal of Pediatric Surgery, Vol 38, No 1 (January), 2003: pp 134-137

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Table 1. Demographic Data Max GOT (IU/L)

Case No.

Sex

Birth Weight (g)

Gestational Age (wk)

Age at Dx (mo)

Body Weight at Dx (g)

Associated Disease

0-3 mo

4-12 mo

1 2 3 4 5

M F F M M

670 554 574 724 750

23 23 28 26 29

16 14 14 16 16

4,493 6,400 5,500 6,600 5,400

None None PDA, Pierre Robin PDA Chondrodysplasia, TOF

215 28 117 52 71

141 54 176 106 135

Abbreviations: Dx, diagnosis; PDA, patent ductus arteriosus; TOF, tetralogy of Fallot; Max, maximum.

HB was detected in one patient who presented with intraabdominal hemorrhage; in a second, the HB was diagnosed after finding hepatomegaly on examination (case 3), and elevation of serum GOT/GPT (case 4) led to the detection of HB. In the remaining 2 cases the HB was detected on routine follow-up examinations of NICU patients. The characteristics of the 5 patients are summarized in Table 1. Serum alpha-fetoprotein (AFP) level at diagnosis was increased in all patients. It ranged from 4,076 to 585,231 ng/mL. The tumor involved 2 segments of the liver in one patient, 3 segments in 3, and the entire the liver in one. Distant metastasis to the bone and mediastinal lymph nodes was observed in one patient (Table 2). The management of these patients was compared with BW-matched control infants (birth weight under 800 g, without HB) also treated in our NICU during the same period. The medical records of the perinatal period of all patients were reviewed with respect to the duration of oxygen inhalation, mechanical ventilation, total parental nutrition (TPN), and overall treatments. The difference between the 2 groups was evaluated by Student’s t test.

rhage (Table 3). Elevation of serum GOT was observed during perinatal period (0 to 3 months old) in 3 cases, and during follow-up period (4 to 12 months old) in 4 cases (Table 1). Hepatitis B virus infection was not detected in any case. Table 4 shows the duration of perinatal treatments in the patients (n ⫽ 5) and BWmatched controls (n ⫽ 285). There was no significant difference in BW and gestational weeks between the 2 groups. The mean durations of mechanical ventilation, oxygen inhalation, and hospitalization during the perinatal periods were significantly longer in HB patients compared with those in BW-matched controls (P ⬍ .01). There was no significant difference in the duration of TPN. Treatments and Outcome

RESULTS

Incidence of Hepatoblastoma Between 1981 when our NICU was founded and 2001, 744 ELBW infants were treated and discharged alive from the NICU of our institute. During the same period, HB arose in 4 of ELBW patients. Therefore, the incidence of HB among ELBW infants was one in 186 (0.52%). Perinatal Treatments and Complications All of the patients required mechanical ventilation and 4 patients required oxygen inhalation because of pneumonia, bronchopulmonary dysplasia, respiratory distress syndrome, and/or chronic lung disease. They received transfusion for neonatal anemia and phototherapy for hyperbilirubinemia. Four of them had retinopathy of prematurity and 2 of them had intraventricular hemor-

Case 1 presented with intraabdominal hemorrhage, and emergency laparotomy was performed. The tumor involved the entire liver; therefore, biopsy was performed, and chemotherapy was started. However, the patient died of multiple organ failure 7 days after operation. The parents of one patient (case 5) refused any treatment when the diagnosis of HB was established because of other severe maldevelopments, ie, tetralogy of Fallot and chondrodysplasia. He died of the growing tumor 4 months after diagnosis. In the remaining 3 patients, multiagent chemotherapy including cisplatin (CDDP) and pirarubicin (THP-Adriamycin) was given before surgery because of the advanced disease. Transcatheter arterial chemoembolization (TACE) via the hepatic artery was performed at the time of abdominal angiography.5 In response to systemic chemotherapy and TACE, serum AFP was decreased

Table 2. Summary of the Tumor, Treatments, and Outcome Case No.

AFP at Dx (ng/mL)

Involved Segments

Metastasis

Multifocal?

Histologic Subclass

Treatments

Outcome (After Operation)

1 2 3 4 5

ND 40,000 4,076 585,231 113,068

4 3 3 3 3

Bone mediastinum None None None None

Multifocal Multifocal Multifocal Solitary Solitary

Well diff Poorly diff Poorly diff Well diff Poorly diff

Probe laparotomy, Ch Ch, TACE, Op TACE, Ch, Op, Ch TACE, Op None

DOD (7 d) DOC (7 mo) Alive (9 mo) Alive (5 mo) DOD (4 mo)

Abbreviations: Dx, diagnosis; diff, differentiated; Ch, multiagent chemotherapy; TACE, transcatheter arterial chemoembolization; Op, operation; DOD, dead of disease, DOC, dead of complications.

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Table 3. Neonatal Treatments and Complications Case No.

O2 Inhalation (d)

Mechanical Ventilation (d)

TPN (d)

Transfusion

Photo Tx (h)

Complications

Hospital Days

1 2 3 4 5

508 220 39 0 480

485 69 19 112 339

0 15 5 0 14

⫹ ⫹ ⫹ ⫹ ⫹

76 38 96 72 216

Pneumonia, BPD, ROP CLD, IVH, ROP RDS, CLD RDS, CLD, ROP RDS, IVH, ROP

411 228 203 206 480

Abbreviations: Tx, therapy; BPD, bronchopulmonary dysplasia; ROP, retinopathy of prematurity; CLD, chronic lung disease; IVH, intraventricular hemorrhage; RDS, respiratory distress syndrome.

significantly, and tumor size was decreased in all 3 cases. In one case (case 4), systemic chemotherapy was discontinued because of the renal dysfunction. Complete tumor resection was achieved by a right hepatic trisegmentectomy in 2 patients and by a left hepatectomy with partial resection of the right lobe in the other. Macroscopically, the tumor was a solitary growth in 3 patients, and extended multifocally in 2 patients. Histologic examination of surgical or autopsy specimens found that the tumor tissue was predominantly comprised of well-differentiated tumor in 2 patients and poorly differentiated tumor in 3. Postoperative consolidation chemotherapy was only performed in one patient (case 3) of the 3 patients who were eligible for the chemotherapy. One died of hepatic failure 7 months after the operation. The remaining 2 are alive with no evidence of disease for a period of 5 and 9 months after the operation. DISCUSSION

HB is a rare embryonal malignancy, with a reported annual incidence rate in the United States of approximately 1 per million children under age of 15 years.6 Ross and Gurney7 showed an incidence of HB to be 3.8 per million children aged 4 years or younger. Ikeda et al1 reported that the incidence of HB in children with a BW of 500 to 999 g was calculated to be approximately 1 of 10,000 in 1992 and 1 of 15,000 in 1993, which was markedly high compared with the above reports. The incidence of HB in our NICU in ELBW infants during the past 2 decades was estimated to be 0.5% (1 in 186), which was surprisingly high compared with the report by Ikeda et al.1 Up to now, we cannot explain the reason why the incidence of HB arising in children of ELBW treated at our NICU has been increasing. The fact that 4

of 5 cases presented with HB during the last 4 years may suggest that the recent developments of neonatal intensive care may involve in the pathogenesis of HB in ELBW children. Considering the cause of the association of HB with LBW, there are 2 possible explanations. The first explanation is the presence of some genetic disorders responsible for both the patient’s immaturity and the development of HB. The second is that intensive perinatal treatments given to the infants result in the development of HB. In this study, we showed that mean durations of mechanical ventilation, oxygen inhalation, and hospitalization during the perinatal period were significantly longer in HB patients compared with those in BWmatched control infants. These findings strongly support the second explanation. In the current study, there was an episode of serum GOT elevation in 3 of 5 cases (60%) during perinatal period and in 4 cases (80%) during the follow-up period, which indicates the existence of liver damage. Infants of such extreme prematurity share many of the same medical problems and hence will have similar treatments. Their premature liver cells may be damaged easily and transformed under the influence of some exogenous factors, including oxygen inhalation, antibiotics, diuretics, TPN, and frequent radiographs of the chest and abdomen. A study in fetal monkeys showed that fetal liver was most sensitive to genetic damage during midgestation.8 It also is possible that the liver cells, which are exposed to a longer quantity of carcinogens, transform into more unfavorable tumor cells. Maruyama et al9 reported that oxygen therapy, associated ventilation and furosemide treatment were continued for a longer period in stages IIIB and IV patients than stages II and IIIA

Table 4. Prenatal Treatments in Patients With HB and Birth Weight–Matched Controls

Number Birth weight (g) Mechanical ventilation (d) O2 inhalation (d) TPN (d) Hospital stay (d)

Patients With HB

BW-Matched Controls

P Value

5 654.4 ⫾ 87.7 249.4 ⫾ 238.4 204.8 ⫾ 198.8 6.8 ⫾ 7.3 305.6 ⫾ 130.4

285 654.2 ⫾ 101.2 104.7 ⫾ 78.1 53.3 ⫾ 3.8 10.4 ⫾ 18.1 148.9 ⫾ 61.5

NS ⬍.01 ⬍.01 NS ⬍.01

Abbreviations: HB, hepatoblastoma; NS, not significant.

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patients. There is some evidence of an association between tumor development and reactive oxygen and diuretics administration.10,11 The recent rapid increase in the incidence of HB may be the result of an increase in the number of more immature infants with a more sensitive liver and, also, more frequent exposure to risk factors related to perinatal treatments. Ikeda et al1 showed that HBs in patients of VLBW were more advanced in stage, and complete resection of the tumor was difficult. Therefore, the outcome was worse in patients of VLBW than in other patients. In the patients of LBW, organs often are damaged by the perinatal intensive care. These damages, such as respiratory distress, renal dysfunction, and hepatic dysfunction may cause difficulties in the treatments of HB. In our experience, all of the resected patients had hepatic disorder after operation, and one patient (case 3) died of hepatic insufficiency. Dysfunction of organs may decrease the tolerance of antitumoral agents. In the current study, preoperative systemic chemotherapy was stopped

because of renal dysfunction in one patient. We applied TACE as an induction therapy in these patients, because the systemic toxicity of TACE is much lower than conventional systemic chemotherapy.5 Earlier diagnosis might be possible through routine screening with measurements of serum AFP or abdominal ultrasonography (US). The HB patient who did not receive any treatment (case 5) died of tumor progression 4 months after diagnosis. This may suggest that the follow-up should be done closely. In this study, duration of mechanical ventilation, oxygen inhalation, and hospital stay were significantly longer in HB patients of ELBW compared with BW-matched control infants, and most of the HB patients had an episode of serum GOT elevation. These findings suggest that children of ELBW who received longer and aggressive perinatal treatments or had episodes of hepatic disorder are at high risk for HB. These children should be monitored more closely using periodic measurement of serum AFP or ultrasound scan even after their discharge from NICU.

REFERENCES 1. Ikeda H, Matsuyama S, Tanimura M: Association between hepatoblastoma and very low birth weight: A trend or a chance? J Pediatr 130:557-560, 1997 2. Tanimura M, Matsui I, Abe J, et al: Increased risk of hepatoblastoma among immature children with a lower birth weight. Cancer Res 58:3032-3035, 1998 3. Ribons LA, Slovis TL: Hepatoblastoma and birth weight. J Pediatr 131:750, 1998 4. Feusner J, Buckley J, Robison L, et al: Prematurity and hepatoblastoma: More than just an association? J Pediatr 133:585-586, 1998 5. Oue T, Fukuzawa M, Kusafuka T: Transcatheter arterial chemoembolization in the treatment of hepatoblastoma. J Pediatr Surg 33: 1771-1775, 1998 6. Young JL: Incidence of malignant tumors in US children. J Pediatr 86:254-258, 1975

7. Ross JA, Gurney JG: Hepatoblastoma incidence in the United States from 1973 to 1992. Med Pediatr Oncol 30:141-142, 1998 8. Lu LW, Anderson LM, Janes AB, et al: Persistence, gestation stage-development formation and interrelationship of benzo(a)pyreneinduced DNA adducts in mothers, plecentae and fetus of Erythrocebus patas monkeys. Cartinogenesis 14:1805-1813, 1993 9. Maruyama K, Ikeda H, Koizumi T, et al: Prenatal and postnatal histories of low birth weight infants who developed hepatoblastoma. Pediatr Int 41:82-89, 1999 10. Kensler TW, Bush DM, Kozumbo WJ, et al: Inhibition of tumor promotion by a biomimetic superoxide dismutase. Science 221:75-77, 1983 11. Bucher JR, Huff J, Haseman JK, et al: Toxicity and cartinogenicity studies of diuretics in F344 rats and B6C3F1 mice. J Appl Toxicol 10:369-378, 1990

Discussion Y. Tsuchida (Gunma, Japan): In my institution, Dr Ikeda has reported on the first 2 cases of hepatoblastoma associated with low birth weight, we have now 4 cases. Your 5 occurrences of hepatoblastoma have between one year and 2 years, but in my cases we have found an occurrence at the age of 4 years. We have a very small number of cases, so far, and Dr Ikeda considered longterm medication, and use of furosemide could be a factor for survival after hepatoblastoma.

T. Oue (response): I have read Dr Ikeda’s paper, and he said that diuretics and ventilation involved at an advanced stage of hepatoblastomas. I think that these factors are involved in tumorigenesis. I think that other treatments, such as diuretics, antibiotics, oxygen inhalation, TPN, x-ray examination, etc, may contribute to the tumorigenesis. Further study should be done to elucidate which factors are responsible for the tumorigenesis.