Undifferentiated embryonal sarcoma of the liver in pediatric patients: a single-institution retrospective case series
Case Series

Undifferentiated embryonal sarcoma of the liver in pediatric patients: a single-institution retrospective case series

Jian Li1#, Lulu He2#, Qizi Wu3#, Jianfeng Zhou1, Li Zhou1, Tao Li1

1Department of Oncology, Children’s Hospital of Nanjing Medical University, Nanjing, China; 2Department of Hematology, Children’s Hospital of Nanjing Medical University, Nanjing, China; 3Department of Hematology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

Contributions: (I) Conception and design: L Zhou, T Li; (II) Administrative support: T Li; (III) Provision of study materials or patients: L He, J Zhou; (IV) Collection and assembly of data: J Li, L He; (V) Data analysis and interpretation: J Li, Q Wu; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Tao Li, MD; Li Zhou, MD. Department of Oncology, Children’s Hospital of Nanjing Medical University, Code 8, Jiangdongnan Road, Nanjing 210008, China. Email: ltcrlcq@yeah.net; zhoulinjey@163.com.

Background: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and highly aggressive malignancy predominantly affecting children and adolescents. Managing UESL is particularly intricate due to its aggressive nature and the limited array of treatment options available. This study is dedicated to elucidating the efficacy of a multimodal therapeutic strategy in the successful management of UESL.

Case Description: Four pediatric patients (two males, two females; aged 6–11 years) diagnosed with UESL were treated at the Children’s Hospital of Nanjing Medical University between November 2019 and June 2023. Surgical resection with lymph node dissection achieved complete primary tumor eradication. Adjuvant chemotherapy tailored to each patient’s needs was followed by localized radiation therapy. After 9–42 months of follow-up, one patient who did not undergo immediate radiotherapy experienced a relapse. Following a second operation coupled with radiotherapy, the patient achieved complete remission, and mirroring the status of the other three patients who are now presently in remission. The overall cohort exhibited commendable tolerance to the treatment regimen, with manageable chemotherapy-related toxicities.

Conclusions: This case series suggests that implementing a standardized protocol of resection, followed by adjuvant chemotherapy and radiation, can lead to favorable outcomes in pediatric patients diagnosed with UESL. Nevertheless, the need for comprehensive large-scale studies is imperative to substantiate the effectiveness of this approach.

Keywords: Undifferentiated embryonal sarcoma of the liver (UESL); multimodal treatment; radiation therapy; case series

Submitted Jan 14, 2024. Accepted for publication May 07, 2024. Published online May 27, 2024.

doi: 10.21037/tp-24-10

Highlight box

Key findings

• Local radiotherapy is a crucial component in the prevention of distant recurrence of undifferentiated embryonal sarcoma of the liver (UESL), particularly in cases where tumour rupture is present during the early stages of disease progression.

What is known and what is new?

• The prognosis of children diagnosed with UESL can be significantly improved through a combination of surgical intervention and intensive chemotherapy.

• It is noteworthy that radiotherapy plays a significant role in preventing distant recurrence of UESL in pediatric patients.

What is the implication, and what should change now?

• It is recommended that local radiotherapy be administered following surgical intervention and chemotherapy as part of the comprehensive management strategy for children diagnosed with UESL, particularly those presenting with tumour rupture.

Introduction

Undifferentiated embryonal sarcoma of the liver (UESL) emerges as a rare and highly aggressive malignancy, predominantly affecting pediatric patients, with a peak incidence between 6 and 10 years of age. Typical clinical manifestations encompass nausea, anorexia, right upper abdominal mass, abdominal pain, bloating, diarrhoea and fever (1-3). Imaging studies frequently unveil a large hepatic mass in the right lobe, consisting of cystic and solid components, occasionally involving the portal venous system, thus complicating surgical resection (2,4). Due to its rarity and diagnostic challenges, establishing an optimal treatment approach for this disease remains elusive. The limited available literature on UESL suggests that conventional interventions, such as surgery, chemotherapy, and radiotherapy, have shown varying efficacy but with limited success.

The majority of relevant research revolves around pediatric patients, revealing a poor prognosis even in cases of complete surgical removal of the tumor (1,5,6). However, a growing body of evidence advocates for a multidisciplinary approach that integrates surgical resection and neoadjuvant chemotherapy in the management of UESL (7-9). This combined therapeutic strategy demonstrates promising results, improving overall survival rates, reducing the risk of recurrence, and enhancing long-term outcomes. Notably, several cases of liver transplantation in refractory or inoperable cases have been successfully reported (10,11). Despite the emerging evidence, there remains a paucity of studies reporting comprehensive outcomes in pediatric patients with UESL, and the efficacy of radiotherapy in UESL has been rarely investigated.

Within our Department of Oncology, Children’s Hospital of Nanjing Medical University, we have encountered four pediatric patients diagnosed with UESL who successfully underwent combined surgical resection, chemotherapy, and radiation therapy. The purpose of this retrospective study is to evaluate the feasibility, safety, and efficacy of this integrated treatment approach in this rare subset of patients. By presenting these clinical cases, we aim to contribute to the existing knowledge and provide valuable insight into the potential of combined therapy for UESL in children. We present this article in accordance with the AME Case Series reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-10/rc).

Case presentation

We conducted a retrospective review of the four pediatric patients who were diagnosed with UESL and treated with a combination of surgical resection, chemotherapy, and radiation therapy at Children’s Hospital of Nanjing Medical University between November 2019 and June 2023. The inclusion criteria of the patients are as follows: (I) a histologically confirmed diagnosis of UESL; (II) age less than 18 years; and (III) received a combination of surgical resection, chemotherapy, and radiation therapy as the primary treatment regimen. Patients with incomplete medical records or those who received alternative treatment approaches will be excluded from the study. Children’s Hospital of Nanjing Medical University’s ethics and plan review committee approved the study. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the parents of all children for publication of this case series and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. The data were abstracted for demographic characteristics (age, gender), clinical presentation, diagnostic procedures, treatment modalities, surgical details, chemotherapy agents and regimens, radiation therapy details, duration of treatment, response to therapy, and follow-up data. The results were documented as a descriptive analysis of a case series. All data will be anonymized and recorded in a secure database.

Results

Patient and tumor characteristics

The clinical summaries of the four patients are shown in Table 1. The age range of these patients was between 6 and 11 years. The male-to-female ratio was 1:1. Symptoms at presentation included acute abdominal pain, abdominal mass, fever, nausea, vomiting, dyspnoea, and acute abdomen. Right upper quadrant or generalized abdominal discomfort was the most frequent presenting symptom. All four patients exhibited tumors localized within the right lobe of the liver. The maximum diameter of the tumors varied between 7.4 and 25 cm. The initial ultrasound imaging of Case 1 and Case 4 revealed a substantial cystic, solid mass accompanied by peritoneal fluid. Subsequent magnetic resonance imaging (MRI) scan showed a lobulated cystic solid mass in the liver, featuring multiple septations, local short T1T2 signals, and mild delayed enhancement within the lesion after enhancement (Figure 1). Cases 2 and 3 displayed hypoechoic masses in the right lobe of the liver. Cases 1, 2, and 4 all exhibited tumors that were ruptured and bleeding upon initial diagnosis, thus requiring immediate surgical intervention. Histopathological examination demonstrated that the tumor tissues consisted of hyperplastic spindle cells, astrocytes, and multinucleated giant cells (Figure 2). Immunohistochemistry analysis revealed positive expression of desmin, vimentin, and CD68 in all four cases (Figure 3).

Table 1

Clinical characteristics, treatment, and outcome of four patients with UESL

Patient Age
(year)/sex		 Tumor location Tumor stage (size)
(mm × mm × mm)		 Surgery Chemotherapy Salvage chemotherapy Radiation Site of recurrence Follow-up
1 11/male Right lobe Stage III (140 × 200 × 250) GTR [2] VDC/IE IE/VCD Yes Liver, pelvis NED 42 mo, local recurrence (18 mo)
2 9/male Right lobe Stage III (102 × 68 × 140) GTR VDC/IE No Yes No NED 25 mo
3 6/female Right lobe Stage II (98 × 74 × 87) GTR VDC/IE No Yes No NED 26 mo
4 6/female Right lobe Stage II (128 × 89 × 101) GTR VDC/IE No Yes No NED 9 mo

[2] stands for the patient was treated with two complete surgical resections. UESL, undifferentiated embryonal sarcoma of the liver; GTR, gross total resection; VDC, vincristine, doxorubicin, and cyclophosphamide; IE, ifosfamide and etoposide; NED, no evidence of disease; mo, months.

Figure 1 Abdominal MRI images of UESL (Case 1). (A) T1-weighted image of liver tumor lesions shows low signal. (B) T2-weighted image of the lesion with high signal, within which wall nodules and numerous segregations are seen. (C) Scattered streaks within the lesion seen in the arterial phase, with mild enhancement. MRI, magnetic resonance imaging; UESL, undifferentiated embryonal sarcoma of the liver.
Figure 2 The pathological features of UESL (Case 1). (A) Macroscopic examination revealed a large cystic mass containing a significant amount of dark red blood clots in the lumen. (B,C) Microscopic analysis demonstrated a tumor comprised of actively dividing spindle cells, astrocytes, and multinucleated giant cells. The tumor cells exhibited marked heterogeneity, accompanied by laxity of pericytes and focal areas of hemorrhage and necrosis. Additionally, remnants of bile ducts were observed within the tumor (B, HE ×100; C, HE ×400). UESL, undifferentiated embryonal sarcoma of the liver; HE, hematoxylin-eosin staining.
Figure 3 Immunohistochemical analysis of UESL is presented (Case 1). The immunohistochemical staining of tumor cells reveals a widespread positive staining for vimentin (A), CD68 (B), and a focal positive staining for desmin (C), while it demonstrates a negative staining for SMA (D), MyoD1 (E), and CK (F). UESL, undifferentiated embryonal sarcoma of the liver; SMA, spinal muscular atrophy; MyoD1, myogenic differentiation 1; CK, creatine kinase.

Treatment and outcome

Complete resection of the liver tumors was performed in all four patients. Following the treatment protocols at Memorial Sloan Kettering Cancer Center, the P6 regimen was administered post-surgery. The P6 regimen consists of seven cycles of chemotherapy given in 21-day cycles. For cycles 1, 2, 3, and 7, patients received cyclophosphamide at a dosage of 2,100 mg/m2/day for two consecutive days, doxorubicin at a dosage of 37.5 mg/m2/day for two consecutive days, and vincristine at a dosage of 2 mg/m2/dose for one day (with a maximum dose of 2 mg). Cycles 4, 5, and 6 consisted of ifosfamide at a dosage of 1,800 mg/m2/day for five consecutive days and etoposide at a dosage of 100 mg/m2/day for five consecutive days. All patients in the study exhibited grade II–IV hematological toxicity following chemotherapy; however, this adverse effect was generally well tolerated. Patient 1 did not undergo radiotherapy after completing the initial round of chemotherapy. However, recurrence occurred two years later, leading to the administration of P6 regimen chemotherapy after a second surgery. Subsequently, radiotherapy was resumed, and the patient is currently in remission. The other three patients continued to receive local radiotherapy after completing chemotherapy, and they are currently in remission as well.

Discussion

In this study, we examine the cases of four pediatric patients who had UESL. These patients were treated with a consistent approach, which involved removing the tumor followed by adjuvant chemotherapy and radiation if necessary. As a result of this treatment, all four patients are currently free of disease and have been in their first remission for an average of 23 months.

UESL is a rare tumor, with an estimated incidence of one case per million people per year. Predominantly diagnosed in the first decade of life, particularly between the ages of 6 and 10 years, consistent with the findings of this study (1-3). However, there is a growing body of evidence suggesting occasional occurrences in adults (12-14). Clinical manifestations of UESL usually include abdominal pain, fever, and liver enlargement, with only a minority of patients being asymptomatic at the time of diagnosis.

Stocker and Ishak first described and named UESL in 1978 and concluded that the prognosis of UESL is poor, with death occurring in 80% of patients at one year of follow-up (1). Leuschner et al. reported a disease-free survival rate of 37.5% after three years in their review from 1981 to 1988 (15). Recent studies, however, have shown that multimodal therapies commonly used for sarcomas, including primary resection, neoadjuvant or adjuvant chemotherapy, and, in selected cases, radiotherapy and liver transplantation, may improve survival rates. Techavichit et al. recently retrospectively analyzed 198 patients with UESL reported from 1955 to 2014, most of whom underwent surgery and neoadjuvant chemotherapy, with an overall survival rate of 81% (10). Wu et al. summarized 308 patients with USEL reported in the literature before 2019, with a 5-year overall survival rate of 65.8%, emphasizing the role of radical hepatic resection combined with chemotherapy as the preferred treatment approach for UESL (16).

Various chemotherapy regimens have been used in these case reports, including vincristine, actinomycin D and cyclophosphamide (VAC), doxorubicin, cisplatin, carboplatin, ifosfamide, and etoposide (4,8,17,18). Although these studies suggest that the crucial role of adjuvant chemotherapy, optimal drug combinations and regimens remain undiscovered, and the benefits of radiotherapy are yet to be fully elucidated. Mathias et al. demonstrated favorable outcomes with intense chemotherapy regimens, showcasing five patients with UESL who underwent surgery in combination with an intense chemotherapy regimen of the P6/Ewing Family of Tumors (P6/EFT) regimen were disease-free survivors at a median follow-up of 8 years (19). Moreover, the toxicities seen in this series were not outside the range of other combination regimens, although the EFT and P6 chemotherapy regimens are more dose-intensive than other reported regimens. Techavichit et al. reported that isocyclophosphamide combined with adriamycin was effective in the treatment of UESL, and this series of regimens showed that those with 100% tumor cell necrosis after chemotherapy had a good prognosis and long-term survival (10). This study examined the chemotherapy regimen reported by Mathias et al. The conclusive findings indicated that all four patients successfully attained a prolonged remission status.

The role of radiotherapy in treating UESL is currently uncertain. May et al. conducted a study involving five pediatric patients who were treated for this type of sarcoma using a standardized approach of resection followed by adjuvant chemotherapy and radiation (20). The results indicated that all five patients were disease-free during their first remission, with a median follow-up of 53 months. This study suggests that radiotherapy may be beneficial in treating UESL. However, more recently, Guérin et al. reported on the treatment outcomes of 65 patients enrolled in a European clinical trial for UESL (21). Out of these patients, 15 received radiotherapy. The analysis revealed that the use of radiotherapy was not associated with the event-free survival of the patients. Notably, our study distinguishes itself by incorporating local radiotherapy for all four cases, all of whom are currently in remission. Cases involving tumor rupture, especially in Case 1 not immediately treated with radiotherapy after adjuvant chemotherapy, raise important considerations for postoperative management. We propose that a combined approach of chemotherapy and local radiotherapy may reduce recurrence rates in a modified group of patients, particularly those with tumor rupture.

However, the limitations of our study include a small case number and a relatively short follow-up period. Multicenter studies with extended follow-ups are warranted to validate and reinforce our findings, providing a more comprehensive understanding of the optimal management strategies for UESL in pediatric patients.

Conclusions

While UESL in children remains a formidable clinical entity, a tailored approach combining complete surgical resection, adjuvant chemotherapy, and postoperative local radiotherapy offers a practical and effective strategy. Further collaborative efforts and multicenter studies are warranted to refine treatment protocols, establish standardized guidelines, and validate the long-term efficacy of this comprehensive approach in improving the prognosis of pediatric patients with UESL.

Acknowledgments

We gratefully acknowledge the pathologists in Children’s Hospital of Nanjing Medical University for their expertise and generous provision of data.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the AME Case Series reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-10/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-10/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-10/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the parents of all children for publication of this case series and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Li J, He L, Wu Q, Zhou J, Zhou L, Li T. Undifferentiated embryonal sarcoma of the liver in pediatric patients: a single-institution retrospective case series. Transl Pediatr 2024;13(5):784-790. doi: 10.21037/tp-24-10

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