Clinical analysis of 5-year survival and recurrence in giant retroperitoneal liposarcoma after surgery.

To the Editor: Retroperitoneal liposarcoma (RLS) pertains to one of the rare malignant tumors originated from the retroperitoneum. It is evaluated as the most common type of retroperitoneal sarcoma. RLS can be divided into four subtypes according to the pathological classification, which includes well-differentiated liposarcoma (WDL), dedifferentiated liposarcoma (DDL), myxoid cell liposarcoma (MLS), and pleomorphic liposarcoma (PLS).[1] Giant RLS refers to the RLS with long diameter two times larger than the specified length of pathologic tumor stage-4 (pT4) category (≥30 cm) according to the eighth version of the American Joint Committee on Cancer (AJCC) Staging Manual.[2] Despite relatively low incidence, it brings great health burdens for patients and the standard therapeutic strategies remain to be explored. There are specific features of giant RLS according to clinical experience. For instance, giant RLS can occupy almost the entire abdominal cavity, close to or even wrapping around the inferior vena cava. Due to its location in the deep abdomen, patients usually have untypical symptoms at the early stage. The obvious signs and symptoms can be perceived only when the tumor becomes giant. These features increase difficulties in achieving complete resection during surgery and satisfactory patient outcomes. In addition, there is a lack of comprehensive research on the characteristics of giant RLS, which hinders the further progress of its diagnosis and targeted therapies. Identification of giant RLS characteristics may have great significance in clinical practice. Herein, we conducted a single-center retrospective study to reveal the clinicopathological features and outcomes of patients with giant RLS. This study was approved by the Protection of Human Subjects Committee of the Chinese People's Liberation Army (PLA) General Hospital (No. S2015-106-01). Informed written consent was provided by all participants included in this study. A total of 61 patients with giant RLS who received treatment at the First Medical Center, PLA General Hospital from January 2000 to December 2015 were enrolled in this study. Those with remote metastasis or perioperative death, or who received chemoradiotherapy were excluded from this study. The complete surgical margin referred to the resected margin without observable tumors. The complete resection was defined as the operation that macroscopically resected RLS without residual tumors. The time point of recurrence was when the recurrent region of RLS was detected. Overall survival (OS) referred to the time from surgical complete resection to the end of 5-year follow-up or death. Recurrence-free survival (RFS) was defined as the time from surgical complete resection to the onset of recurrence or death within 5 years.[3] Univariate analysis was performed for the selection of factors that were correlated with OS or RFS. The candidate factors were next included in the multivariate analysis to determine independent prognostic factors using Cox regression model. The categorical data were expressed as number (percentage); continuous variables were expressed as median (Q1–Q3) since they are not normally distributed. All data were analyzed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp, Armonk, New York, USA). A two-sided P-value < 0.05 was considered statistically significant. In this retrospective study, there were 34 male (56%) and 27 female (44%) patients. The median age of them was 55 (46–63) years. The median size of tumors was 35 (31–40) cm [Supplementary Table 1, https://links.lww.com/CM9/B211], and the giant tumors could occupy the entire abdominal cavity [Supplementary Figure 1, https://links.lww.com/CM9/B211]. Considering the proportions and differentiation status of the four pathological subtypes of giant RLS, the patients were divided into two subgroups: WDL and non-WDL groups. WDL group accounted for the largest proportions among the four subtypes (34/61, 56%); the remaining 27 cases with DDL, MLS, and PLS subtypes were classified as the non-WDL group (44%). A total of 41 patients underwent organ resection (67%) and 17 cases were subjected to the resection of three and more organs (28%) [Supplementary Table 1, https://links.lww.com/CM9/B211]. The colon was the most frequently removed organ [Supplementary Figure 2, https://links.lww.com/CM9/B211]. Postoperative complications were evaluated according to the Clavien–Dindo classification.[4] There were 19 cases scored as Grade I (31%); while 42 cases underwent more serious complications were scored as Grades II–IV (69%) [Supplementary Table 1, https://links.lww.com/CM9/B211]. Subgroup analysis showed that 52% of cases in WDL group who received complete resection suffered from the Grade II–IV complications (13/25), while 81% of cases in non-WDL group who received complete resection had the Grade II–IV complications (13/16) [Supplementary Figure 3, https://links.lww.com/CM9/B211]. The median OS of all patients was 40 months during the 5-year follow up. The 1-, 3-, and 5-year OS rates were 83.8%, 51.7%, and 31.3%, respectively [Figure 1A]. To explore prognostic factors of 5-year OS for patients with giant RLS, univariate analysis was performed and indicated that resection times, resection method, intraoperative bleeding volume, total transfusion volume, postoperative complication, tumor morphology, tumor number, completeness of tumor capsule, pathological subtype, and status of surgical margin had significant correlations with 5-year OS (all P < 0.05) [Supplementary Table 1, https://links.lww.com/CM9/B211]. Variables with statistical significance were further examined using multivariate analysis. The results showed that postoperative complication and status of surgical margin were the prognostic factors of 5-year OS (both P < 0.05) [Supplementary Table 1, https://links.lww.com/CM9/B211].Figure 1: The 5-year OS and RFS analysis of patients with giant RLS. (A) The 5-year OS analysis of all 61 giant RLS patients included in this study. (B and C) The 5-year OS analysis of patients with WDL subtype (B) and non-WDL subtype (C) undergoing complete and incomplete resection. (D and E) The 5-year OS analysis of patients based on postoperative complication grades (D) and surgical margin status (E). (F) The 5-year RFS analysis of all 41 patients who received complete resection. (G and H) The 5-year RFS analysis of patients based on tumor capsule completeness (G) and resection times (H). OS: Overall survival; RFS: Recurrence-free survival; RLS: Retroperitoneal liposarcoma; WDL: Well-differentiated liposarcoma.The patients were next stratified to investigate the 5-year OS of subpopulations. Patients with WDL subtype of giant RLS who received complete resection had significantly better 5-year OS than those who received incomplete resection (P < 0.05) [Figure 1B]; whereas, for those with non-WDL subtypes, the difference between the two groups with complete or incomplete resections was not significant (P > 0.05) [Figure 1C]. In addition, we found that the patients who had milder postoperative complications or negative surgical margins obtained better 5-year OS (P < 0.05) [Figures 1D and 1E]. For the investigations into prognostic factors of RFS, data of 41 of the 61 patients, who received complete resection, were analyzed [Supplementary Table 2, https://links.lww.com/CM9/B211]. A total of 33 patients experienced local recurrence within 5 years. The median RFS was 15 (8–25) months. The 1-, 3-, and 5-year RFS rates of patients were 61.6%, 18.7%, and 13.4%, respectively [Figure 1F]. According to the univariate analysis, resection times, pathological subtype, and completeness of tumor capsule were correlated with 5-year RFS (all P < 0.05). After multivariate analysis, only the pathological subtype (P < 0.05) showed as an independent prognostic factor of 5-year RFS [Supplementary Table 2, https://links.lww.com/CM9/B211]. In addition, we found that the 5-year RFS of patients who had incomplete tumor capsules or multiple surgeries (resection times >3) was worse (both P < 0.05) [Figures 1G and 1H]. Few studies focused on the clinicopathological characteristics and survival outcomes of patients with giant RLS. Our study aimed to investigate the clinical features and risk factors of giant RLS, providing basic evidence for the development of giant RLS therapy. Compared with the survival outcomes of patients with non-giant RLS reported by other studies, those who suffered from giant RLS may have a worse prognosis.[5] Moreover, the processes of giant RLS resection are complicated, which may increase the risks of postoperative complications. In this study, we found that serious postoperative complication was significantly associated with the poor prognosis of patients with giant RLS. The importance of postoperative management of complications should be emphasized for patients with giant RLS. The role of pathological subtype in predicting the survival time of patients with ordinary RLS has been revealed in recent years. In this study, however, the pathological subtype was not proved to be an independent prognostic factor of 5-year OS. This contradiction may be attributable to the progression of giant RLS. The pathological subtype presented in this study was identified during the last surgery before follow-up. Well-differentiated giant RLS may progress to poorly-differentiated subtype, promoting tumor invasion, and attenuating survival benefits of patients. Additionally, the follow-up endpoint for RFS is tumor recurrence or a patient's death. RFS can reflect the effects of detected pathological subtype on survival time, free from potential influences of subsequent progression. Our findings proved that pathological subtype served as an independent factor of 5-year RFS, which further verifies our assumption that giant RLS may have a natural tendency to malignant progression. The completeness of surgical resection has been reported as an independent prognostic factor of patients with RLS. Supported by this evidence, wide application of complete RLS resection has been recommended. However, this opinion may be inappropriate for the treatment of giant RLS. In this study, giant tumors in many cases were found wrapping around abdominal organs and large vessels, which increased difficulties in achieving complete resection. Rigid conduction of complete resection may conversely elevate surgical risks and impair benefits from operations. Hence, a complete resection strategy for a giant RLS requires cautious consideration. Patients with WDL subtype of giant RLS could obtain significant survival benefits from complete resection when compared with those receiving incomplete resection. However, there were no significant differences in survival time between non-WDL patients who received complete and incomplete resections, and they were more likely to have severe postoperative complications. This suggests that pathological subtype may serve as an indicator for surgical decision-making. Radical resection may fit for patients with WDL subtype of giant RLS, while the cases with non-WDL subtype may need staging or palliative operations. Further clinical investigations should be conducted to prove the effectiveness of this strategy. It has to be admitted that there are several limitations. First, the study only included the cases from one center and the sample size is small due to the extremely low incidence of giant RLS. It impairs the representativeness of this research. Second, as a retrospective study, the range of collected information is limited and some potential biases cannot be eliminated. Third, several indicators of pathological examination, such as tumor necrosis and mitotic count, were not reported in some cases. It increases difficulties in more deeply identifying mechanisms underlying giant RLS progression. In conclusion, the status of surgical margins and postoperative complications were independent factors of OS, and the pathological subtype was proved as an independent marker for the recurrence of giant RLS. Complete resection for the WDL subtype of giant RLS contributed to prognosis improvement. However, survival benefits from complete resection were not obtained for the patients with non-WDL subtype of giant RLS. The pathological subtype may serve as an important reference indicator for the surgical decision-making process of giant RLS. Funding This study was supported by the National Natural Science Foundation of China (No. 82073192) and the National Key Research and Development Project of China (No. 2019YFB1311505). Conflicts of interest None.