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Lung and right atrial metastases from hepatoblastoma in children: A case series and literature review

 Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China

Date of Submission21-Dec-2018
Date of Decision22-Mar-2019
Date of Acceptance19-Jan-2020
Date of Web Publication02-Aug-2022

Correspondence Address:
Dongsheng Huang,
Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_824_18


Hepatoblastoma (HB) in children with both lung and right atrial metastases is an unusual situation. The therapy for these cases is challenging and the prognosis is not good. We present three children with HB showing both lung and right atrial metastases and who underwent surgery and received preoperative/postoperative adjuvant-combined chemotherapy to achieve complete remission. Therefore, HB with lung and right atrial metastases could have a good prognosis through active and multidisciplinary treatment.

Keywords: Atrium, hepatoblastoma, lung, metastasis, prognosis

How to cite this URL:
Hu H, Zhang W, Yi Y, Gao Y, Zhi T, Huang D. Lung and right atrial metastases from hepatoblastoma in children: A case series and literature review. Indian J Cancer [Epub ahead of print] [cited 2022 Dec 5]. Available from:

  Introduction Top

Although hepatoblastoma (HB) is a relatively rare malignant solid tumor, with an incidence of 1.2–1.5 million people/year,[1] it is still the most common malignant liver tumor in children.[2] The overall prognosis of HB is good with a survival rate of 70%–80%; however, the survival rate before combined chemotherapy is only 30%.[3] The main factors affecting HB prognosis are the pretreatment extent of disease (PRETEXT) stage, serum alpha-fetoprotein (AFP) level, presence of multiple lesions and distant metastasis, age >5 years, and pathological classification of undifferentiated small cell tumor.[4]

The lung is the most common site of distant metastasis; 10%–20% of HB patients have lung metastasis with an overall survival rate of 25%–50%.[5],[6] Related prospective studies have shown that lung metastasis is related to poor prognosis.[7] Although vascular involvement is commonly associated with HB, it is not a major prognostic factor.[4]

There are few reports of HB cases involving both lung and right atrial metastases. Huang et al.[8] reported patients with HB and atrial metastasis who died of fungal meningitis after two chemotherapy cycles. However, Sayed et al.[9] reported one case of HB with atrial tumor thrombus and multisite metastases that was successfully treated through systematic multidisciplinary surgery. Similarly, Kesik et al.[10] reported a case of HB with lung and right atrial metastases that was completely cured after six chemotherapy cycles; a case of complete HB remission after liver surgery was also reported. These findings indicate that adjuvant chemotherapy, including preoperative neoadjuvant and postoperative chemotherapy, and surgery are key strategies for metastatic HB treatment.

The chemotherapy regimens for HB change according to the disease stage and risk grouping. Particularly for high-risk patients, improved survival has been reported using an intensified schedule of cisplatin and doxorubicin.[11] However, these agents show significant toxicity, limiting the cumulative doses that can be administered. Alternatively, a new regimen including the second-line chemotherapy drugs vincristine and irinotecan has shown substantial activity against high-risk HB.[12]

The controversy surrounding the need for preoperative neoadjuvant chemotherapy and its optimal duration may be resolved by a new, international pediatric hepatic malignancy therapeutic trial by the Children's Oncology Group (COG), Japanese Pediatric Liver Tumours (JPLT) group, and the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL), which would combine both case experiences and therapeutic approaches.[2]

Therefore, to summarize the clinical, therapeutic, and prognostic characteristics of HB with concomitant lung and right atrial metastases, three children admitted to our department were analyzed.

  Case Reports Top

Case 1

A 4-year-old boy was admitted to a local hospital about 6 years ago for abdominal pain. Abdominal ultrasonography showed a hepatic mass. Chest and abdominal computed tomography (CT) and cardiac ultrasonography confirmed the presence of a large mass in the liver occupying the left, median, and right hepatic veins, the right portal vein, and the inferior vena cava. Right atrial tumor thrombus, bilateral pleural effusion, and bilateral pulmonary nodules were also detected. At diagnosis, his serum AFP level was 30,883 ng/mL; whole-body examination showed no other distant metastases. He had no significant clinical history or similar family history. A biopsy was not performed because his parents refused the procedure.

Three days later, he received preoperative neoadjuvant chemotherapy in our hospital according to the following protocol: cisplatin 20 mg/m2 on Day 1–5, pirarubicin 25 mg/m2 on Day 1–3, and cyclophosphamide 800–1,000 mg/m2 on Day 1 (regimen 1), which was alternated with a second regimen wherein cyclophosphamide was replaced by etoposide 100 mg/m2 on Day 1–4 (regimen 2).[13] After two cycles of this preoperative neoadjuvant chemotherapy, the liver and lung tumors and the atrial tumor thrombus had significantly reduced in size, and his serum AFP level had decreased to 4,077 ng/mL.

Two months later, he underwent hepatic mass resection and inferior vena cava vein/right atrial tumor thrombectomy. Postoperative pathological examination revealed HB of the embryonal and fetal subtypes. After surgery, he received 10 cycles of postoperative chemotherapy in our hospital: regimen 1 in which the medication on Day 1 alternated between cisplatin 90 mg/m2 and vincristine 1.5 mg/m2 and regimen 2 consisting of 5-fluorouracil 300 mg/m2 on Day 2–3 (regimen 3).[14] Following this treatment, the lung metastatic lesions completely disappeared.

Six months later, postoperative chemotherapy was stopped, at which time the patient's serum AFP level was 2.47 ng/mL; no tumors were detected in the liver and lungs. He was followed-up for 2 months with regular imaging and serum AFP measurement, after which his AFP level increased to 526 ng/mL. Chest and abdominal CT revealed recurrence in both the lung and liver, and he underwent resection of both the liver and lung tumors 1.5 years later. The pathological diagnosis was again HB (embryonal and fetal subtypes), and the postoperative serum AFP level decreased to 82.04 ng/mL.

Six cycles of postoperative chemotherapy were then administered according to the following protocol: irinotecan 50 mg/m2 and cisplatin 20 mg/m2 on Day 1–5, vincristine 1.5 mg/m2 on Day 1, and cyclophosphamide 250 mg/m2 on Day 2–4 (regimen 4, based on a previously reported combination of vincristine and irinotecan[12]); this regimen was alternated with regimen C5VD: cisplatin 20 mg/m2 and 5-fluorouracil 200 mg/m2 on Day 1–5, vincristine 1.5 mg/m2 on Day 1, and pirarubicin 25 mg/m2 on Day 2–3 (regimen 5).[14] Two years later, postoperative chemotherapy was discontinued, at which point his serum AFP level was 1.21 ng/mL. He was followed-up regularly without evidence of recurrence and has remained in complete remission for 5 years and 2 months as of this publication.

The liver tumor and lung and right atrial metastases detected at diagnosis are shown in [Figure 1]a, [Figure 1]b, [Figure 1]c; total resection was performed and there were no residual tumors after the first surgery [Figure 1]d, [Figure 1]e, [Figure 1]f. Signs of postoperative recurrence in the liver and lung are shown in [Figure 2]a and [Figure 2]b, whereas those of complete remission after the second surgery are shown in [Figure 2]c and [Figure 2]d.
Figure 1: Case 1: Chest/abdominal CT at initial diagnosis. (a) Right atrium showing a filling defect (right atrial metastatic tumor thrombus, arrow); (b) multiple liver mass occupation (uneven density; arrow), and tumor invasion into the inferior vena cava (arrow); (c) signs of right lung metastasis (arrow); (d) the right atrium showing no filling defect post-operation; (e) no signs of liver occupation nor inferior vena cava metastasis; (f) disappearance of lung metastasis after chemotherapy

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Figure 2: Case 1: Chest and abdominal CT after liver and lung relapse. (a) Right liver lobe showing a low-density shadow at recurrence; (b) signs of left lower lung metastasis at recurrence; (c) the liver post-surgery and post-chemotherapy showing no tumor signs; (d) the lung post-surgery and post-chemotherapy showing no signs of metastasis

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Case 2

Around 4 years ago, a girl aged 1 year and 7 months was admitted to Beijing Children's Hospital for fever and abdominal mass. Abdominal ultrasonography, chest and abdominal enhanced CT, and cardiac color doppler showed a multifocal liver tumor involving the left and median hepatic veins and inferior vena cava. Right atrial tumor thrombus, right lower lung atelectasis, and pleural effusion were also observed. At diagnosis, her serum AFP level exceeded 484,000 ng/mL (the highest level ever detected in our hospital); whole-body examination did not reveal distant metastatic lesions. She had no significant clinical history or similar family history. A biopsy was not performed because her parents refused the procedure.

One month later, she started receiving preoperative neoadjuvant chemotherapy in our hospital. Five cycles of alternating regimens 1 and 2 were administered. After preoperative neoadjuvant chemotherapy, the tumor was reduced, and her serum AFP level decreased to 119,108 ng/mL.

Four months later, she underwent resection of the liver tumor and inferior vena cava/right atrial tumor thrombectomy. Postoperative pathological examination confirmed the diagnosis of HB (epithelial type); the postoperative serum AFP value decreased further to 4,188 ng/mL. Subsequently, she completed six cycles of postoperative chemotherapy comprising regimens 1 and 3 administered in alternation, after which the lung lesions disappeared. Ten months later, postoperative chemotherapy was discontinued, at which point her serum AFP level was 6.39 ng/mL.

She was followed-up for 6 months with regular measurement of serum AFP level and imaging. Fourteen months later, her AFP level increased to 593.40 ng/mL, and chest and abdominal CT confirmed recurrence in the liver. The hepatic tumor was resected in that month, and her postoperative serum AFP level decreased to 246.44 ng/mL. Six additional cycles of postoperative chemotherapy, regimens 4 and 5 in alternation, were administered. Twenty-six months later, the chemotherapy was discontinued, at which time her serum AFP level was 6.39 ng/mL. No recurrences were detected during the follow-up period, and the patient has remained in complete remission for 16 months as of the date of this publication.

Case 3

A boy aged 2 years and 10 months was admitted due to an abdominal mass and generalized distention. Whole-body examination revealed a tumor occupying the liver and involving both the hepatic and portal veins; atrial and lung metastases were also detected. At the initial diagnosis, his serum AFP level was 480,000 ng/mL, and other physical examinations showed no additional distant metastatic lesions. He had no clinically relevant history, but his grandmother had lung cancer with bone metastases. The patient's parents refused to provide consent for biopsy.

One and a half years ago, the patient had received a combination of cisplatin and pirarubicin[11],[14] in a local hospital, followed by two cycles of chemotherapy (regimen 5) in our hospital. After the three cycles, the liver, atrial tumor thrombus, and lung lesions had shrunken substantially; in addition, his serum AFP level had decreased to 797 ng/mL. Three months later, he underwent atrial tumor thrombectomy and hepatic tumor resection; the tumor was pathologically classified as HB (mixed epithelial and mesenchymal type). His serum AFP level decreased to 93.64 ng/mL after surgery.

Chemotherapy (regimen 5) was continued in our hospital for one cycle after surgery. Later, in accordance with the results of a tumor cell drug sensitivity test, the regimen was changed to one cycle of vincristine + pirarubicin(Pirarubicin is one kind of anthracycline, but its cardiac toxicity is lower than daunorubicin)+ cyclophosphamide (VDC) consisting of vincristine 1.5 mg/m2 on Day 1, cyclophosphamide 400 mg/m2 on Day 1–3, and pirarubicin 25 mg/m2 on Day 2–3 (regimen 6). After this cycle, the serum AFP level decreased to 3.97 ng/mL and regimens 5 and 6 were alternately administered for an additional four cycles. By this time, no lesions were noted in the liver, lung, or atrium. Although the serum AFP level was within the normal range, six chemotherapy cycles were administered thereafter, as planned. The patient was followed-up regularly and has remained in complete remission for 4 months thereafter.

  Discussion Top

We reported three cases of HB involving pulmonary metastasis and right atrial tumor thrombosis. According to the latest HB risk stratification system,[15] these three patients were high-risk cases with poor prognoses.

The 3-year disease-free survival rate of children with both liver and lung lesions is 55.6%, and it is only 36.9% in cases of complete liver resection with residual lung lesions.[16] This is consistent with the fact that pulmonary metastasis is the main factor affecting HB prognosis.

The three patients reported herein were treated by liver tumor resection after preoperative neoadjuvant chemotherapy; for high-risk HB, such preoperative chemotherapy is necessary.[2] The recent SIOPEL-4 study provided evidence of the efficacy of an intensified cisplatin-based approach prior to surgery for the treatment of metastatic HB.[11] Considering this and our previous experience with HB chemotherapy, we administered treatments that alternated cisplatin-based regimens 1 and 2.[13] After the publication of consensus guidelines on the multidisciplinary management of HB, we mainly administered the C5VD adjuvant chemotherapy regimen (regimen 5, also containing cisplatin) for metastatic cases.[14]

Preoperative neoadjuvant chemotherapy for metastatic HB can reduce the size of liver tumors and facilitate their complete resection and the reduction or disappearance of metastatic lung lesions. Therefore, in this study, preoperative neoadjuvant chemotherapy was administered to all three patients before liver resection, following which the lung lesions completely disappeared or greatly improved. Thus, preoperative neoadjuvant chemotherapy is important in HB cases. Postoperative chemotherapy was also administered in all cases to prevent relapse.

During the follow-up period of 7–63 months (median, 37 months), two patients showed relapse post-treatment (66.7%) within 6 months of stopping chemotherapy. Patient 1 showed hepatic and pulmonary recurrences, and Patient 2 showed a hepatic recurrence. No recurrences in the lung or liver were observed in Patient 3, probably because of the short follow-up period; the serum AFP levels remained within the normal range for 4 months. However, none of the patients showed recurrences in the right atrium after right atrial tumor thrombectomy. Therefore, the right atrial metastases did not appear to have a significant effect on the prognosis of HB after atrial surgery. Furthermore, although lung lesions may disappear after preoperative neoadjuvant and postoperative chemotherapy, HB with pulmonary metastases in children requires close monitoring within the first 6 months of treatment discontinuation for the early detection of recurrence, especially in the liver and lung. In cases of lung recurrence, surgical removal of the metastases and postoperative chemotherapy are required for complete remission.

Cases of HB with tumor extension through the inferior vena cava into the right atrium are considered as high-risk cases. However, considering their rarity, no related complications have been reported. The three patients in our study showed no heart and lung complications. Thus, the right atrial metastases may have little effect on cardiopulmonary function. Further studies with larger sample sizes are needed to confirm whether relapse can influence the prognosis of HB in such cases.

Serum AFP levels are significantly increased in most HB cases, which is helpful in diagnosis, monitoring treatment response, and determining patient prognosis. Based on the changes observed in all three patients preoperatively, postoperatively, and during chemotherapy, we concluded that serum AFP level may be a valuable indicator for the early detection of tumor recurrence and is an important tumor marker of HB.

The use of second-line chemotherapy drugs in HB treatment is expected to improve the prognosis. The combination of vincristine and irinotecan for high-risk or relapsed HB is effective, with tolerable adverse reactions.[12],[17] In our study, the three patients received effective preoperative neoadjuvant chemotherapy (including cyclophosphamide, pirarubicin, cisplatin, fluorouracil, and vincristine), and marked tumor reduction enabled resection and right atrial tumor thrombectomy. Continued postoperative chemotherapy resulted in complete elimination of the lung lesions and normalization of serum AFP levels. Although recurrence occurred in two cases, no recurrence of the atrial tumor thrombus was noted, and lung and/or liver re-surgery could be performed. After relapse, chemotherapy was adjusted to an alternative protocol combining C5VD (regimen 5) with a new regimen comprising vincristine, irinotecan, cisplatin, and cyclophosphamide. Complete remission was achieved in all cases of relapse, supporting the efficacy of the second-line drug irinotecan as a part of the chemotherapy regimen for HB recurrence or lung metastasis.

In conclusion, HB with pulmonary metastasis and vascularized right atrial tumor thrombosis is rare and most often associated with advanced disease. However, multidisciplinary treatments, including surgery and both preoperative neoadjuvant and postoperative chemotherapies, are the main treatments in these cases. Preoperative neoadjuvant chemotherapy can shrink the atrial thrombus, allowing complete removal, while postoperative chemotherapy can prevent atrial tumor thrombus recurrence. Lung and liver tumors are prone to recurrence and require close follow-up for the early detection of relapse. In such cases, irinotecan combined with conventional chemotherapy drugs can be effectively used with a good overall prognosis.

Ethical approval

This study was approved by the ethics committee of Beijing Tongren Hospital, Capital Medical University and followed the Declaration of Helsinki. Informed consent was received from all patients and guardians.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the guardians have given their consent for patients' images and other clinical information to be reported in the journal. The guardians understand that patients' names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.


This work is supported by Beijing Yizhuang Economic and Technological Development Zone Leading Talent Program [(2017)-8].

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Czauderna P, Lopez-Terrada D, Hiyama E, Häberle B, Malogolowkin MH, Meyers RL. Hepatoblastoma state of the art: Pathology, genetics, risk stratification, and chemotherapy. Curr Opin Pediatr 2014;26:19-28.  Back to cited text no. 1
Czauderna P, Garnier H. Hepatoblastoma: Current understanding, recent advances, and controversies. F1000Res 2018;7:53.  Back to cited text no. 2
Chopra A, Iyer VK, Agarwala S, Mathur SR, Aron M, Gupta SD, et al. Apoptotic protein expression, glycogen content, DNA ploidy and cell proliferation in hepatoblastoma subtyping and their role in prognostication. Pediatr Surg Int 2010;26:1173-8.  Back to cited text no. 3
Maibach R, Roebuck D, Brugieres L, Capra M, Brock P, Dall'Igna P, et al. Prognostic stratification for children with hepatoblastoma: The SIOPEL experience. Eur J Cancer 2012;48:1543-9.  Back to cited text no. 4
Brown J, Perilongo G, Shafford E, Keeling J, Pritchard J, Brock P, et al. Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL1. Eur J Cancer 2000;36:1418-25.  Back to cited text no. 5
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O'Neill AF, Towbin AJ, Krailo MD, Xia C, Gao Y, McCarville MB, et al. Characterization of Pulmonary Metastases in Children With Hepatoblastoma Treated on Children's Oncology Group Protocol AHEP0731 (The Treatment of Children With All Stages of Hepatoblastoma): A Report From the Children's Oncology Group. J Clin Oncol 2017;35:3465-73.  Back to cited text no. 7
Huang YL, Shih SL, Liu HC, Yeh TC. Hepatoblastoma with tumor extension through the inferior vena cava into the right atrium. J Pediatr Gastroenterol Nutr 2010;50:577.  Back to cited text no. 8
Sayed S, Prabhu S, Fawcett J, Choo K, Alphonso N. A systematic surgical approach to hepatoblastoma with intracardiac extension. Asian Cardiovasc Thorac Ann 2017;25:300-3.  Back to cited text no. 9
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Zsiros J, Brugieres L, Brock P, Roebuck D, Maibach R, Zimmermann A, et al. Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm, feasibility study. Lancet Oncol 2013;14:834-42.  Back to cited text no. 11
Katzenstein HM, Furman WL, Malogolowkin MH, Krailo MD, McCarville MB, Towbin AJ, et al. Upfront window vincristine/irinotecan treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 study committee. Cancer 2017;123:2360-7.  Back to cited text no. 12
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Meyers RL, Maibach R, Hiyama E, Häberle B, Krailo M, Rangaswami A, et al. Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration. Lancet Oncol 2017;18:122-31.  Back to cited text no. 15
Hishiki T, Watanabe K, Ida K, Hoshino K, Iehara T, Aoki Y, et al. The role of pulmonary metastasectomy for hepatoblastoma in children with metastasis at diagnosis: Results from the JPLT-2 study. J Pediatr Surg 2017;52:2051-5.  Back to cited text no. 16
Zsíros J, Brugières L, Brock P, Roebuck D, Maibach R, Child M, et al. Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma--A phase II trial of the childhood liver tumour strategy group (SIOPEL). Eur J Cancer 2012;48:3456-64.  Back to cited text no. 17


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