Report of Seven Children with Undifferentiated Embryonal Sarcoma of the Liver
Undifferentiated embryonal sarcoma of the liver (UESL) is an exceedingly rare and aggressive malignant liver tumor that primarily affects children. It accounts for approximately 9% to 15% of all pediatric liver malignancies, which themselves constitute only 1% to 4% of solid tumors in children. The disease typically manifests in children aged 6 to 10 years, with no significant gender predilection. The clinical presentation of UESL is often nonspecific, with common initial symptoms including abdominal pain and distension. Jaundice is notably absent in these cases, and physical examination typically reveals a palpable liver mass without other significant vital sign abnormalities. The serum alpha-fetoprotein (AFP) test, commonly used as a tumor marker for other liver malignancies, is not sensitive for UESL, further complicating its diagnosis.
The preoperative diagnosis of UESL is challenging due to its rarity and nonspecific clinical presentation. Definitive diagnosis relies on histopathological examination, including immunohistochemical analysis. Characteristically, UESL tumors are positive for vimentin, alpha-1-antitrypsin (AAT), desmin, and smooth muscle actin, with focal positivity for cytokeratin (CK8/18). They are negative for AFP and S-100 protein, which helps differentiate UESL from other liver tumors. The Ki-67 index, a marker of cellular proliferation, is typically high (>50%) in UESL cases, indicating aggressive tumor behavior.
Complete surgical resection of the tumor remains the cornerstone of UESL treatment and is a critical factor influencing prognosis. Historically, UESL has been associated with a poor prognosis, with long-term disease-free survival rates reported to be less than 37%. However, recent advancements in treatment strategies, particularly the combination of surgery with chemotherapy, have significantly improved outcomes. Recent studies have reported 5-year survival rates as high as 92% to 100%. Despite these improvements, UESL has a high recurrence rate, and the overall prognosis remains guarded. The rarity of the disease means that features of recurrence and high-risk factors affecting prognosis are not well-documented in the literature.
This report presents a retrospective analysis of seven cases of UESL treated at a single institution between October 2005 and December 2016. The study aimed to summarize the characteristics of recurrence and identify risk factors affecting the prognosis of UESL. All patients received chemotherapy, and the study was conducted in accordance with the Declaration of Helsinki, with informed consent obtained from all patients and their parents.
The seven patients included five girls and two boys, with an age range of 5.0 to 15.3 years (median age: 9.3 years). The most common initial symptom was abdominal pain, reported in five patients, while one patient presented with abdominal distension and another with poor appetite and irritability. All patients had normal serum AFP levels, consistent with the known insensitivity of this marker for UESL. Pathological examination confirmed the diagnosis of UESL in all cases, with tumors originating in the right hepatic lobe in five patients and the left hepatic lobe in two patients. No distant metastases were observed at the time of diagnosis.
Immunohistochemical analysis revealed that all tumors were positive for vimentin, with most also positive for AAT and ACT. The Ki-67 index was high (>50%) in all cases, reflecting the aggressive nature of the tumors. All tumors were negative for AFP, S-100 protein, and carcinoembryonic antigen (CEA), consistent with the typical immunohistochemical profile of UESL.
All seven patients were treated with a combination of surgery and chemotherapy. One patient (case 3) required emergency surgery for embolization of the right branch of the hepatic artery due to tumor rupture, followed by an extended right hepatectomy once the patient’s condition stabilized. Five patients received postoperative chemotherapy, while two patients received chemotherapy only after the first recurrence of the tumor. One patient received combined treatment with radiotherapy due to multiple recurrences. The chemotherapy regimens included cyclophosphamide, vincristine, pirarubicin, cisplatin or ifosfamide, and etoposide. The number of chemotherapy cycles ranged from 6 to 42. The primary adverse effects of chemotherapy were bone marrow suppression and gastrointestinal symptoms, which were managed with symptomatic treatment.
The follow-up period ended in December 2017, with a median follow-up time of 4.25 years (range: 1–15 years). Three patients died, while four achieved complete remission (CR). The median survival time for the surviving patients was 4.29 years (range: 1–15 years), compared to 2.16 years (range: 1.83–4.56 years) for those who died. The 5-year disease-free survival rate was 33.3%, which is lower than the rates reported in recent literature. This discrepancy may be attributed to the three cases of tumor rupture and two cases where the parents chose to discontinue treatment after recurrence.
Recurrence was observed in five of the seven patients (71.43%). In three of these cases, the patients had received postoperative chemotherapy directly, with only one case showing disease progression after recurrence. The remaining two recurrence cases (case 2 and case 7) had not received chemotherapy immediately after surgery. These patients experienced multiple recurrences, with tumors relapsing in various sites, including the liver, pelvis, hepatonephric gap, and lung. The first recurrence occurred between 0.33 and 6.67 years (median: 0.50 years) after the initial surgery. The most common site of recurrence was the liver, although other sites such as the pelvic cavity, hepatonephric gap, and lung were also involved. Re-resection of recurrent tumors combined with chemotherapy was effective in achieving CR in some cases, as demonstrated by case 7, who achieved CR after three relapses and four resections.
Tumor size and the presence of tumor rupture were identified as significant risk factors for poor prognosis. Among the four patients with tumors larger than 15 cm, three died, and one achieved CR. In contrast, all three patients with tumors smaller than 15 cm achieved CR. Tumor rupture was observed in three cases, with one patient (case 3) progressing to death, one achieving remission after recurrence, and one relapsing and progressing to death. The four patients without tumor rupture all survived, highlighting the significant impact of tumor rupture on prognosis (P = 0.029). The status of the tumor margin (positive or negative) did not significantly affect prognosis in this cohort (P = 1.000).
In summary, UESL is a rare and aggressive liver tumor with a high recurrence rate. The combination of surgery and chemotherapy has improved prognosis, but close follow-up is essential due to the high risk of recurrence. Tumor size and the presence of tumor rupture are critical prognostic factors. For patients with recurrent or metastatic disease, a combined approach involving surgery, chemotherapy, and radiotherapy can achieve CR. The findings of this study underscore the importance of early and aggressive treatment, as well as the need for further research to better understand the factors influencing recurrence and prognosis in UESL.
doi.org/10.1097/CM9.0000000000000429
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