Abstract
Limited data exist on patients with limb liposarcoma (LLS) with metastasis at presentation Moreover, the potential prognostic factors of this patient population are poorly documented because of its rarity. Therefore, we conducted this study to evaluate the clinicopathologic characteristics and prognostic factors for patients with metastatic LLS.
All patients with LLS with metastasis at presentation from 1975 to 2016 were identified by using the Surveillance, Epidemiology, and End Results (SEER) database. The following clinical data were derived from this clinical database: age, sex, histologic grade, subtype, size of tumor, surgery, radiotherapy, chemotherapy, vital status, cause of death, and survival duration. The Kaplan-Meier method was performed to calculate median survival time and draw survivorship curves. Cox-proportional hazards regression model was used to reveal the statistical independence between various variables.
The present study collected 184 cases from SEER database for survival analysis. Mean age was 57.8 years with 63.6% (n = 117) men. The 3-year overall survival (OS) and cancer-specific survival (CSS) rates of this population were 27.8% and 30.1%, respectively. Univariate analysis revealed that age, tumor grade, and surgery were significantly correlated with survival. Sex and tumor size did not reach significant predictor status of survival. Multivariate analysis revealed that age at diagnosis <60, low tumor grade, and local surgery were significantly correlated with improved OS and CSS.
Patients with LLS with metastasis at diagnosis experienced quite poor prognosis. Currently, surgery for the primary tumor significantly prolonged the survival of those patients, whereas chemotherapy and radiotherapy need to be further confirmed.
Keywords: limb liposarcoma, metastasis, prognosis, treatment
1. Introduction
Liposarcoma (LS) is a malignant mesenchymal neoplasm, originating from the adipose tissue. It is the most common subtype of soft tissue sarcoma (accounts for 20%).[1] It predominantly occurs in adults older than 50 years, with a slight male predilection.[2] It can occur at almost any site and most cases occur in the limbs and retroperitoneum, especially the upper legs.[3,4] Treatment for limb liposarcoma (LLS) includes surgical resection, radiotherapy, and chemotherapy. However, there is still no standard treatment strategies for those patients especially patients with metastatic LLS.[5] LS obtains local invasiveness and metastatic propensity with high mortality rate.[6] The lung is the most common site of metastasis for LS. Patients usually experience an adverse prognosis if they developed metastatic disease. Although radiotherapy can provide local control and reduce risk of local recurrence,[7] the role of radiotherapy in prolonging survival time of patients with LLS with metastasis at presentation remains unknown. For patients with metastatic LS, chemotherapy is usually required.[2] But whether it can provide a satisfactory prognosis also remains unknown.
We performed this study and analyzed the prognosis of patients with LLS with metastasis at presentation from 1975 to 2016, based on Surveillance, Epidemiology, and End Results (SEER) database. This research is aimed to reveal demographic and prognostic information for patients with LLS with metastasis at presentation, which is helpful for an improved understanding of this cohort.
2. Methods
2.1. Study cohort
Patients with LLS with metastasis at presentation diagnosed from 1975 to 2016 were retrospectively identified by searching SEER program database. They were enrolled consecutively from the SEER 18 registries in the United States. The database collects tumor information from 20 geographic areas, covering 28% of the US population (https://seer.cancer.gov/). This study does not require informed consent of patients as it is a public database and contains no identifiable data. The study was approved by the Institutional Review Board of Ningbo No. 6 Hospital.
We followed the International Classification of Diseases for Oncology, third edition (ICD-O-3) codes[8] to select LLS cases (9040–9043). We also defined the primary site ICD-O-3 codes (C40.0–C41.9). All patients had a positive histological diagnosis, based on specimen from the biopsy or the surgery. Only patients with metastatic LLS met the requirements of this study. Patients with missing survival information or diagnosed based on autopsy were excluded. The following clinical data were derived from this clinical database: age, sex, histologic grade, subtype, size of tumor, surgery, radiotherapy, chemotherapy, vital status, death causes, and survival duration. Radiotherapy or surgical resection analyzed in this study was performed for primary tumors not metastasis.[8]
2.2. Statistical methods
All statistical analyses were conducted using IBM SPSS Statistics 20.0. We defined cancer-specific survival (CSS)[8] as the duration from initial diagnosis to death resulting from LS. Kaplan–Meier method was employed to evaluate the relationship between variables and survival and generate median survival time. Then we used the Cox regression model to confirm the independent predictors of survival by univariate and multivariate analyses. We simultaneously calculated hazard ratios and 95% confidence interval to show the impact of covariates on survival. Bilateral P <.05 was statistically significant.
3. Results
3.1. Patients’ characteristics
The present study included a total of 184 eligible patients with LLS with metastasis at presentation for survival analysis. Clinicopathological characteristics of the patients with metastatic LLS are presented in Table 1. We divided age into 2 categories: <60 years and ≥60 years. Mean age was 57.8 years with 63.6% (n = 117) men. Grade distribution was low grade 17.9%, high grade 50.0%, and unknown 32.1%. About one third of patients were diagnosed with myxoid liposarcoma (34.8%). A total of 41 (22.3%), 118 (64.1%), and 25 (13.6%) patients had ≤10 cm, >10 cm, and unknown size, respectively. A total of 69.6% of patients received local surgical treatment, 51.6% received radiation treatment, and 60.3% received chemotherapy.
Table 1.
Clinical and pathological features of 184 patients with metastatic limb liposarcoma.
| Variable | Value |
| Age at diagnosis (yr) | |
| <60 | 97 (52.7%) |
| ≥60 | 87 (47.3%) |
| Sex | |
| Female | 67 (36.4%) |
| Male | 117 (63.6%) |
| Histological grade | |
| Low (grade 1–2) | 33 (17.9%) |
| High (grade 3–4) | 92 (50.0%) |
| Unknown | 59 (32.1%) |
| Subtype | |
| Liposarcoma, NOS | 20 (10.9%) |
| Liposarcoma, well differentiated | 9 (4.9%) |
| Myxoid liposarcoma | 64 (34.8%) |
| Round cell liposarcoma | 22 (12.0%) |
| Pleomorphic liposarcoma | 40 (21.7%) |
| Mixed liposarcoma | 12 (6.5%) |
| Dedifferentiated liposarcoma | 17 (9.2%) |
| Tumor size | |
| ≤10 cm | 41 (22.3%) |
| >10 cm | 118 (64.1%) |
| Unknown | 25 (13.6%) |
| Surgery | |
| Yes | 128 (69.6%) |
| No | 56 (30.4%) |
| Radiation treatment | |
| Yes | 95 (51.6%) |
| No | 89 (48.4%) |
| Chemotherapy | |
| Yes | 111 (60.3%) |
| No | 73 (39.7%) |
| Dead | |
| Yes | 144 (78.3%) |
| No | 40 (21.7%) |
| OS rate (3-yr) | 27.8% |
| OS rate (5-yr) | 18.8% |
| CSS rate (3-yr) | 30.1% |
| CSS rate (5-yr) | 19.0% |
CSS = cancer-specific survival, NOS = not otherwise specified, OS = overall survival.
3.2. Survival and prognostic factors
The 3- and 5-year overall survival (OS) rates of metastatic LLS patients were 27.8% and 18.8%, respectively (Table 1). Table 2 summarizes median survival time of this population, including median survival data stratified by various factors.
Table 2.
Median survival time of 184 patients with metastatic limb liposarcoma.
| Variable | OS (mo) | 95% CI | CSS (mo) | 95% CI |
| Overall | 15.0 ± 3.1 | 8.9–21.1 | 20.0 ± 3.1 | 14.0–26.0 |
| Age at diagnosis (yr) | ||||
| <60 | 23.0 ± 3.9 | 15.3–30.7 | 24.0 ± 3.7 | 16.8–31.2 |
| ≥60 | 10.0 ± 1.6 | 6.9–13.1 | 11.0 ± 1.7 | 7.6–14.4 |
| Sex | ||||
| Female | 16.0 ± 2.8 | 10.6–21.4 | 19.0 ± 3.9 | 11.4–26.6 |
| Male | 14.0 ± 2.9 | 8.4–19.6 | 20.0 ± 5.1 | 10.0–30.0 |
| Histological grade | ||||
| Low (grade 1–2) | 37.0 ± 15.6 | 6.4–67.6 | 40.0 ± 29.9 | 0.0–98.7 |
| High (grade 3–4) | 11.0 ± 1.4 | 8.3–13.7 | 11.0 ± 1.8 | 7.6–14.4 |
| Tumor size | ||||
| ≤10 cm | 14.0 ± 3.7 | 6.7–21.3 | 21.0 ± 10.7 | 0.0–42.0 |
| >10 cm | 15.0 ± 3.1 | 9.0–21.0 | 19.0 ± 2.9 | 13.4–24.6 |
| Surgery | ||||
| Yes | 19.0 ± 3.3 | 12.6–25.4 | 22.0 ± 2.7 | 16.7–27.3 |
| No | 11.0 ± 1.8 | 7.5–14.5 | 11.0 ± 2.6 | 5.9–16.1 |
| Radiotherapy | ||||
| Yes | 17.0 ± 4.8 | 7.6–26.4 | 22.0 ± 3.1 | 16.0–28.0 |
| No | 13.0 ± 2.6 | 8.0–18.0 | 16.0 ± 4.6 | 6.9–25.1 |
| Chemotherapy | ||||
| Yes | 21.0 ± 3.3 | 14.6–27.4 | 24.0 ± 2.8 | 18.5–29.5 |
| No | 11.0 ± 2.0 | 7.2–14.8 | 11.0 ± 3.9 | 3.4–18.6 |
CI = confidence interval, CSS = cancer-specific survival, OS = overall survival.
Univariate analysis (Table 3) revealed that age, tumor grade, and surgery were significantly correlated with both OS and CSS. Sex and tumor size did not reach significant predictor status of survival. A significant increase in survival was seen in patients who received local surgery. OS and CSS were well stratified according to surgery (Fig. 1A and B). Patients receiving radiotherapy or chemotherapy, however, demonstrated no survival benefit (P < .05) in univariate Cox analysis.
Table 3.
Univariate analysis of variables in 184 patients with metastatic limb liposarcoma.
| OS | CSS | |||
| Variable | HR (95% CI) | P | HR (95% CI) | P |
| Age at diagnosis (yr) | ||||
| <60 | 1 | 1 | ||
| ≥60 | 1.711 (1.232–2.377) | .001 | 1.738 (1.178–2.564) | .005 |
| Sex | ||||
| Female | 1 | 1 | ||
| Male | 0.954 (0.682–1.335) | .786 | 0.941 (0.635–1.394) | .762 |
| Histological grade | ||||
| Low (grade 1–2) | 1 | 1 | ||
| High (grade 3–4) | 2.117 (1.305–3.435) | .002 | 2.379 (1.345–4.208) | .003 |
| Unknown | 1.478 (0.874–2.500) | .145 | 1.588 (0.859–2.934) | .140 |
| Tumor size | ||||
| ≤10 cm | 1 | 1 | ||
| >10 cm | 1.165 (0.775–1.751) | .463 | 1.200 (0.753–1.912) | .444 |
| Unknown | 1.009 (0.579–1.756) | .976 | 1.110 (0.582–2.117) | .752 |
| Surgery | ||||
| Yes | 1 | 1 | ||
| No | 1.545 (1.074–2.224) | .019 | 1.629 (1.076–2.466) | .021 |
| Radiotherapy | ||||
| Yes | 1 | 1 | ||
| No | 1.066 (0.765–1.486) | .704 | 1.057 (0.720–1.551) | .778 |
| Chemotherapy | ||||
| Yes | 1 | 1 | ||
| No | 1.338 (0.955–1.874) | .091 | 1.340 (0.900–1.994) | .150 |
CI = confidence interval, CSS = cancer-specific survival, HR = hazard ratio, OS = overall survival.
Figure 1.
Kaplan-Meier overall (A) and cancer-specific (B) survival curves of patients with metastatic LLS stratified by surgery.
We integrated significant variables from univariate analysis into the multivariate analysis. On multivariate analysis (Table 4), age ≥60, high tumor grade, and surgery were identified as significant adverse prognostic predictors.
Table 4.
Multivariate analysis of variables in 184 patients with metastatic limb liposarcoma.
| OS | CSS | |||
| Variable | HR (95% CI) | P | HR (95% CI) | P |
| Age at diagnosis (yr) | ||||
| <60 | 1 | 1 | ||
| ≥60 | 1.774 (1.270–2.477) | .001 | 1.727 (1.164–2.560) | .007 |
| Histological grade | ||||
| Low (grade 1–2) | 1 | 1 | ||
| High (grade 3–4) | 2.471 (1.504–4.060) | <.001 | 2.623 (1.470–4.678) | .001 |
| Unknown | 1.668 (0.977–2.848) | .061 | 1.694 (0.910–3.155) | .096 |
| Surgery | ||||
| Yes | 1 | 1 | .011 | |
| No | 1.748 (1.200–2.544) | .004 | 1.732 (1.135–2.644) | |
CI = confidence interval, CSS = cancer-specific survival, HR = hazard ratio, OS = overall survival.
4. Discussion
We retrospectively identified a total of 184 eligible patients with LLS with metastasis at presentation diagnosed between 1975 and 2016 from the SEER database. Many previous studies described the clinicopathologic characteristics and explored the prognostic factors of primary LS. Due to the rarity of metastatic LS, little is known about the clinicopathologic features and survival outcomes of them. In addition, the benefits of various treatment strategies for patients with metastatic LLS are rarely explored. Notably, this is the first and largest study to investigate the clinicopathologic characteristics and prognostic factors of patients with LLS with metastasis at presentation, which is beneficial for clinicians to treat patients with LS with metastasis more efficiently.
The mean age at diagnosis of metastatic LLS patients was 57.8 years, which is similar to that of all LS.[9,10] Male predominance (63.6%) was observed in metastatic LLS cohort, and as was consistent with previous studies.[11–13] Patients with metastasis usually had significantly poorer OS than those without metastasis. A recent study showed that the 5-year OS rate of 181 patients with LS of the extremity and truncal wall was 93.3%, whereas this study reported a very poor prognosis (5-year OS rate, 18.8%) among patients with metastatic LLS.[14] The median OS from in this special cohort was 15.0 ± 3.1 months, which is similar to results reported from inoperable or metastatic LS.[13] Treatments for patients with metastatic LLS are, however, rarely reported and remain unknown. Thus, how to treat such patients and find effective prognostic factors is the urgent task at present.
This study found that age at diagnosis was a significant independent predictor of survival. Greto et al,[15] confirmed that age older than 65 years was an adverse independent predictor of recurrence and OS among patients with operable LS. Maybe elderly patients obtain specific genomic alterations and present with larger tumors at diagnosis.[15–17] Langman et al,[13] however, reported that age at diagnosis of advanced disease was not associated with OS based on univariate analysis. We noted that sex was not a prognostic predictor, which was congruent with many previous studies.[2,13,15] Survival benefits were usually pronounced in patients with LS with low tumor grade.[14,15] Our multivariate analysis also showed tumor grade was independently correlated with OS and CSS among metastatic patients with LLS. Tumor size is one of the common predictors of survival among patients with LS.[18,19] However, some studies failed to find that tumor size was associated with survival among patients with LS.[2,14,20] Similar survival outcomes were found in metastatic patients with LLS. Interestingly, previous studies also reported the lack of a size effect on metastases, which was an important event for survival time.[21–23] However, this departure from the expected relationship between tumor size and survival has not been well explained. Thus, further studies are needed to confirm the relationship between tumor size and survival among specific patients with LS.
Although surgical resection is the mainstream treatment for patients with local LLS, little is known of the role of surgery among patients with metastatic LLS. This study first confirmed the positive role of local surgery for primary tumor in prolonging survival among patients with metastatic LLS. Radiotherapy provided local control in patients with LS after surgical resection but not significantly reduced the rate of metastasis or improved survival.[24,25] We did not observe a survival benefit with radiotherapy among patients with metastatic LLS. Simultaneously, we demonstrated that patients with metastatic LLS who received chemotherapy did not benefit from survival. Maybe chemotherapy resistance is common among metastatic LS.[26] This study initially delineated therapeutic management of metastatic LLS, and more studies are needed in the future.
Although this study provided survival information for metastatic LLS, it has several limitations: it was a retrospective study with certain bias; information about local or distant recurrence during follow-up were not documented in the SEER database, which might affect the outcome; other clinical factors, such as surgical margin and detailed systemic chemotherapy regimen, were not available in the SEER database. Despite these defects, the SEER database is a very important clinical research tool for rare tumor populations, such as patients with LLS with metastasis at presentation.
5. Conclusion
The present study revealed that patients with LLS with metastasis at presentation experienced quite poor prognosis. Surgery for the primary tumor may be beneficial for prolonging survival time, whereas combination therapies such as chemotherapy and/or radiotherapy need to be further explored.
Acknowledgments
The authors thank the contribution of the SEER database.
Author contributions
Conceptualization: Jing Ling.
Data curation: Shicheng Wang, Yuanxi Zhou.
Formal analysis: Shicheng Wang, Yuanxi Zhou, Jing Ling.
Investigation: Shicheng Wang, Yuanxi Zhou, Haifeng Wang.
Methodology: Shicheng Wang, Yuanxi Zhou, Haifeng Wang.
Project administration: Shicheng Wang.
Software: Shicheng Wang, Haifeng Wang.
Writing – original draft: Shicheng Wang.
Writing – review & editing: Jing Ling.
Footnotes
Abbreviations: CI = confidence interval, CSS = cancer-specific survival, ICD-O-3 = 3rd edition of International Classification of Diseases for Oncology, LLS = limb liposarcoma, LS = liposarcoma, OS = overall survival, SEER = Surveillance, Epidemiology, and End Results.
How to cite this article: Wang S, Zhou Y, Wang H, Ling J. Survival analysis and treatment strategies for limb liposarcoma patients with metastasis at presentation. Medicine. 2021;100:13(e25296).
The authors report no conflicts of interest
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
References
- [1].Mack TM. Sarcomas and other malignancies of soft tissue, retroperitoneum, peritoneum, pleura, heart, mediastinum, and spleen. Cancer 1995;75: 1 suppl: 211–44. [DOI] [PubMed] [Google Scholar]
- [2].Oh YJ, Yi SY, Kim KH, et al. Prognostic model to predict survival outcome for curatively resected liposarcoma: a multi-institutional experience. J Cancer 2016;7:1174–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Dalal KM, Kattan MW, Antonescu CR, et al. Subtype specific prognostic nomogram for patients with primary liposarcoma of the retroperitoneum, extremity, or trunk. Ann Surg 2006;244:381–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Bagaria SP, Gabriel E, Mann GN. Multiply recurrent retroperitoneal liposarcoma. J Surg Oncol 2018;117:62–8. [DOI] [PubMed] [Google Scholar]
- [5].Ortiz-Ibanez B, Amaya JV, Baixauli F, et al. Surgical resection of massive liposarcomas at the extremities: a 10-year experience in a referral musculoskeletal sarcoma unit. World J Surg Oncol 2015;13:206. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Matthyssens LE, Creytens D, Ceelen WP. Retroperitoneal liposarcoma: current insights in diagnosis and treatment. Front Surg 2015;2:4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Hosaka Y, Kitahara A, Tsuchida M. Dedifferentiated liposarcoma of the anterior mediastinum: report of a case. Kyobu Geka 2019;72:958–61. [PubMed] [Google Scholar]
- [8].Wang Z, Chen G, Chen X, et al. Predictors of the survival of patients with chondrosarcoma of bone and metastatic disease at diagnosis. J Cancer 2019;10:2457–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Shmookler BM, Enzinger FM. Liposarcoma occurring in children. An analysis of 17 cases and review of the literature. Cancer 1983;52:567–74. [DOI] [PubMed] [Google Scholar]
- [10].Wortman JR, Tirumani SH, Jagannathan JP, et al. Primary extremity liposarcoma: MRI features, histopathology, and clinical outcomes. J Comput Assist Tomogr 2016;40:791–8. [DOI] [PubMed] [Google Scholar]
- [11].Corey RM, Swett K, Ward WG. Epidemiology and survivorship of soft tissue sarcomas in adults: a national cancer database report. Cancer Med 2014;3:1404–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Mastrangelo G, Coindre JM, Ducimetiere F, et al. Incidence of soft tissue sarcoma and beyond: a population-based prospective study in 3 European regions. Cancer 2012;118:5339–48. [DOI] [PubMed] [Google Scholar]
- [13].Langmans C, Cornillie J, Van Cann T, et al. Retrospective analysis of patients with advanced liposarcoma in a tertiary referral center. Oncol Res Treat 2019;42:396–404. [DOI] [PubMed] [Google Scholar]
- [14].Goertz O, Pieper A, Lauer H, et al. Long-term outcome of 181 patients with liposarcomas of the extremity and truncal wall. Anticancer Res 2019;39:5747–53. [DOI] [PubMed] [Google Scholar]
- [15].Greto D, Saieva C, Loi M, et al. Influence of age and subtype in outcome of operable liposarcoma. La Radiol Med 2019;124:290–300. [DOI] [PubMed] [Google Scholar]
- [16].Al-Refaie WB, Habermann EB, Dudeja V, et al. Extremity soft tissue sarcoma care in the elderly: insights into the generalizability of NCI Cancer Trials. Ann Surg Oncol 2010;17:1732–8. [DOI] [PubMed] [Google Scholar]
- [17].Taubert H, Bartel F, Greither T, et al. Association of HDM2 transcript levels with age of onset and prognosis in soft tissue sarcomas. Mol Cancer Res 2008;6:1575–81. [DOI] [PubMed] [Google Scholar]
- [18].Wu J, Qian S, Jin L. Prognostic factors of patients with extremity myxoid liposarcomas after surgery. J Orthop Surg Res 2019;14:90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [19].Salduz A, Alpan B, Valiyev N, et al. Neoadjuvant radiotherapy for myxoid liposarcomas: oncologic outcomes and histopathologic correlations. Acta Orthop Traumatol Turc 2017;51:355–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].Karadayi K, Yildiz C, Karakus S, et al. Well-differentiated abdominal liposarcoma: experience of a tertiary care center. World J Surg Oncol 2015;13:166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Yu KD, Jiang YZ, Chen S, et al. Effect of large tumor size on cancer-specific mortality in node-negative breast cancer. Mayo Clin Proc 2012;87:1171–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Zheng YZ, Wang L, Hu X, et al. Effect of tumor size on breast cancer-specific survival stratified by joint hormone receptor status in a SEER population-based study. Oncotarget 2015;6:22985–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [23].Verschraegen C, Vinh-Hung V, Cserni G, et al. Modeling the effect of tumor size in early breast cancer. Ann Surg 2005;241:309–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197–203. [DOI] [PubMed] [Google Scholar]
- [25].Pisters PW, Harrison LB, Leung DH, et al. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859–68. [DOI] [PubMed] [Google Scholar]
- [26].Nassif NA, Tseng W, Borges C, et al. Recent advances in the management of liposarcoma. F1000Res 2016;5:2907. [DOI] [PMC free article] [PubMed] [Google Scholar]