• myxoid liposarcoma;
  • round cell liposarcoma;
  • outcome;
  • tissue microarray;
  • molecular biomarkers;
  • therapeutic targets


  1. Top of page
  2. Abstract


Myxoid liposarcoma (MLPS), a disease especially of young adults with potential for local recurrence and metastasis, currently lacks solid prognostic factors and therapeutic targets. The authors of this report evaluated the natural history and outcome of patients with MLPS and commonly deregulated protein biomarkers.


Medical records were retrospectively reviewed for patients who presented to the authors' institution with localized (n = 207) or metastatic (n = 61) MLPS (1990 to 2010). A tissue microarray of MLPS patient specimens (n = 169) was constructed for immunohistochemical analysis of molecular markers.


The 5-year and 10-year disease-specific survival rates among patients with localized disease were 93% and 87%, respectively; male gender, age >45 years, and recurrent tumor predicted poor outcome. The local recurrence rate was 7.4%, and the risk of local recurrence was associated with recurrent tumors and nonextremity disease location. Male gender was the main risk factor for metastatic disease, which occurred in 13% of patients. Forty percent of patients who had localized disease received chemotherapy, mostly in the neoadjuvant setting. Immunohistochemical analysis revealed significantly higher expression of C-X-C chemokine receptor type 4 (CXCR4) and platelet-derived growth factor beta (PDGFR-β) in metastatic lesions versus localized lesions. Tumors with a round cell phenotype expressed increased levels of CXCR4, p53, adipophilin, PDGFR-α, PDGFR-β, and vascular endothelial growth factor relative to myxoid phenotype. Only the receptor tyrosine kinase encoded by the AXL gene (AXL) was identified as a prognosticator of disease-specific survival in univariate analysis.


In this study, the authors identified clinical and molecular outcome prognosticators for patients with MLPS as well as several potential therapeutic targets. Cancer 2013. © 2013 American Cancer Society.


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  2. Abstract

Liposarcoma (LPS), a mesenchymal malignancy cohort that demonstrates lipogenic differentiation, is the most common adult soft tissue sarcoma subtype.1 LPS consists of 3 categories: 1) well differentiated LPS and dedifferentiated LPS (WDLPS/DDLPS), 2) myxoid and round cell liposarcoma (MLS and RCL [MLPS]), and 3) pleomorphic liposarcoma (PLS). The RCL variant of MLPS represents histologic progression of pure MLS to hypercellular round cell morphology, defined as >5% RCL phenotype in a given tumor, and is associated with a poor prognosis.2 Both variants bear characteristic reciprocal chromosomal translocations, most frequently the t(12;16) (translocation involving bands 12 and 16) in “fused in sarcoma/DNA-damage–inducible transcript 3” (FUS/DDIT3)3 or, rarely (<5%), Ewing sarcoma breakpoint region 1 (EWSR1)/DDIT3 t(12;22)(q13;q12) (translocation involving 12q13r and 22q12).4 The resultant fusion proteins may play multiple roles in tumorigenesis, including cancer initiation,5 specifically blocking complete MLPS adipocytic differentiation6 however, the exact mechanisms of action remain unknown. MLPS incidence peaks in the fourth and fifth decades of life, predominantly arising in the lower extremities and buttock. Metastasis, which occurs in up to 33% of patients, is characterized by an unusual predilection for fat-bearing areas, including the abdomen, axilla, and bone.7 Surgical resection with or without radiotherapy is the standard of care for patients with localized MLPS. Chemotherapy is usually reserved for patients who have high-risk/advanced disease. Accurately determining prognosis remains problematic. Neither clinical factors (ie, age, resection margin status, tumor location) nor histologic factors (eg, necrosis) consistently correlate with outcome.2,8–13 Several studies have suggested that an RCL subtype either predicted prognosis2,8–11 or was not associated with prognosis,12,13 differences perhaps caused by inconsistent assessment of round cell changes per se.

Prognostic MLPS biomarkers have been suggested and have included the overexpression of p53, insulin-like growth factor 2, insulin-like growth factor receptor 1, the ret proto-oncogene, etc,14,15 without definitive confirmation. Such knowledge deficits, coupled with our limited understanding of MLPS pathogenesis cellular pathways, compromise prognostic assessments while limiting our abilities to develop specific treatment. Consequently, we used human MLPS specimens assembled in a tissue microarray (TMA) to investigate MLPS natural history and clinical outcomes, seeking to identify disease-specific survival (DSS) prognosticators and commonly deregulated molecular processes/biomarkers.


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  2. Abstract

Clinical Database

After we received Institutional Review Board approval from The University of Texas MD Anderson Cancer Center (UTMDACC), records from 268 patients who had histologically proven MLPS (from April 1990 to March 2010) were used to construct a clinical database containing patient, tumor, treatment, and follow-up information.

Tissue Microarray

The TMA included 169 MLPS biopsy and surgical resection samples from 110 patients and 14 control samples of normal fat, WDLPS, PLS, and myxoma; and it was constructed as described previously.16

Immunohistochemical Analysis

Immunohistochemical staining was performed on 4-mm-thick TMA sections. Commercially available antibodies against Ki67, cyclin D1, B-cell lymphoma 2 (BCl2), matrix metalloproteinase 9, p53, chemokine (C-C motif) receptor 7, C-X-C chemokine receptor type 4 (CXCR4), human epidermal growth factor receptor 2 (HER2), receptor tyrosine kinase encoded by the AXL gene (AXL), platelet-derived growth factor alpha (PDGF-α), PDGF-β, PDGF receptor alpha (PDGFR-α), PDGFR-β, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), peroxisome proliferator-activated receptor gamma (PPAR-γ), adipophilin, cMET (a proto-oncogene that encodes the hepatocyte growth factor receptor), cKIT (a proto-oncogene also known as mast/stem cell growth factor receptor or tyrosine-protein kinase Kit), estrogen receptor, and progesterone receptor were used. Specific antigen retrieval, blocking agents, antibody specifications, and concentrations are available upon request. Horseradish peroxidase-labeled secondary antibodies or biotinylated systems (4-plus system; Biocare Medical, Concord, Calif) were used. Labeling intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong); and the percentage of positive tumor cells was estimated. Samples that exhibited an intensity of 0 or 1 were considered “low expression, ” whereas intensities of 2 or 3 were considered “high expression.” Because of poor reproducibility of the distinction between staining intensity of 1 and 2 for PDGFR-α, PDGFR-β, and CXCR4, only cases with a score of 3 were considered to represent high scoring.

Statistical Analysis

Correlations between TMA biomarker expression and tumor or disease status were calculated using the Fisher exact test. Spearman correlation coefficient analysis was used to determine associations between biomarkers. Correlations of clinicopathologic data and immunohistochemical biomarker expression with patient outcomes were evaluated using univariate and multivariable Cox proportional hazards models for DSS, recurrence-free survival, and metastasis-free survival. All variables that were significant in univariate analysis were used in the multivariate model, and only those variables are illustrated.


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  2. Abstract

Characteristics of Localized Myxoid/Round Cell Liposarcoma

Localized MLPS clinicopathologic variables are summarized in Table 1. The mean presenting age was 41 years (range, 13.7–79 years), with male predominance (57.5%). Most patients presented with a primary lesion (89.3%), especially of the extremities (74%). Tumors usually were located in deep soft tissue (76%); the median tumor size was 10 cm (range, 1.7–48 cm), and tumors typically presented as a painless mass (81%). Nearly all patients (96%) underwent surgery. Only 8 patients were deemed unresectable because of anatomic constraints or medical comorbidities. Microscopically clear resection margins (R0) were achieved in 83% of patients, microscopically positive (R1) margins were achieved in 13% of patients, and gross tumor (R2 margins) remained in 4% of patients. Forty percent of patients who were identified as high-risk (tumors >10 cm; RCL histology) received chemotherapy (usually neoadjuvant, 77%), especially doxorubicin and ifosfamide. Seventy-four percent of patients received radiotherapy (usually neoadjuvant).

Table 1. Localized Myxoid/Round Cell Liposarcoma: Patient, Tumor, Treatment, and Outcome Variables
 No. of Patients (%)
VariableTotal, N = 207Myxoid, N = 146Round Cell, N = 61
  • Abbreviations: DSS, disease-specific survival; SD, standard deviation

  • a

    Percentages represent the incidence within a disease variant.

  • b

    Eight patients had unknown tumor location.

Patient variables   
Age: Mean [range], y41 [13–79]3946
Disease status   
Tumor variables   
Tumor size: Median±SD, cm10 ± 6.710 (7.2)10 (5.4)
Tumor site   
Tumor locationb   
Margin status   
R0156 (83)109 (81)a47 (85)a
R125 (13)18 (14)a7 (13)a
R28 (4)7 (5)a1 (2)a
Treatment variables   
Neoadjuvant65 (77)49 (58)a16 (73)a
Adjuvant14 (17)10 (12)a4 (18)a
Chemotherapy alone5 (6)3 (4)a2 (9)a
Neoadjuvant87 (57)61 (58)a26 (54)a
Adjuvant64 (42)43 (41)a21 (44)a
Without surgery2 (1)1 (1)a1 (2)a
Outcome variables   
Follow-up: Median [range], mo68 [1–249]  
Local recurrence rate14 (8)11 (8)3 (6)
Metastasis rate26 (13)14 (10)12 (21)
Sites of metastases   
Bone6 (23)5 (36)a1 (8)a
Abdomen6 (23)2 (14)a4 (33)a
Lung3 (12)1 (7)a2 (17)a
Other11 (42)6 (43)a5 (42)a
DSS, %   

Outcomes of Patients With Localized Myxoid/Round Cell Liposarcoma

The median follow-up for patients with localized disease was 68 months (range, 1–249 months). The local recurrence rate was 7.4%, and the median time to recurrence was 31 months (range, 6–83 months). The risk of local recurrence was associated with disease status (local recurrence vs primary tumor) at the time of diagnosis and nonextremity disease location (Table 2). Metastasis occurred in 13% of patients at a median of 34 months (range, 5–141 months) after diagnosis. Higher rates of metastasis were observed in patients who had RCL patients compared with patients who had MLS (21% vs 10%; P = .042). Although multiple univariate analysis factors were associated with increased risk of metastasis, only male gender remained statistically significant in multivariate analysis (Table 3). The DSS rate was 99% at 1 year, 93% at 5 years, and 87% at 10 years (Fig. 1A). Age >45 years, male gender, and locally recurrent disease were statistically significant prognosticators in multivariate analysis (P = .0252, P = .0159, and P = .049, respectively) (Table 4). Overall survival analysis of patients with localized versus metastatic disease and those with primary tumors versus recurrent disease revealed statistically significant differences (P > .0001 and P = .0127, respectively), mirroring the DSS analysis results, whereas a comparison of overall survival between the MLS and RCL subtypes revealed only a trend toward a better outcome for patients with MLS (P = .0723; data not shown).

thumbnail image

Figure 1. These Kaplan-Meier curves illustrate myxoid/round cell liposarcoma (MLPS)-specific survival stratified according to patients with (A) localized disease (n = 207) versus metastatic disease (n = 61; P < .0001; log-rank statistic), (B) primary disease (n = 185) versus locally recurrent disease (n = 22; P = .0052; log-rank statistic), and (C) histologic myxoid variant (n = 146) versus round cell variant (n = 61; P = .031; log-rank statistic).

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thumbnail image

Figure 2. Biomarker expression levels are illustrated in patients with myxoid/round cell liposarcoma (MLPS). Immunohistochemical images demonstrate high expression levels versus low expression levels of selected markers in specimens from patients with MLPS. CXCR4 indicates C-X-C chemokine receptor type 4; PDGFR-α, platelet-derived growth factor receptor alpha; PDGF-β, platelet-derived growth factor beta; PPAR-γ, peroxisome proliferator-activator receptor gamma; AXL, receptor tyrosine kinase encoded by the AXL gene; Bcl2, B-cell lymphoma 2.

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Table 2. Localized Myxoid/Round Cell Liposarcoma: Prognostic Factors for Recurrence-Free Survival
  Univariate AnalysisMultivariate Analysis
VariableaNo. of PatientsHR95%CIPHR95%CIP
  • Abbreviations: CI, confidence interval; HR, hazard ratio.

  • a

    Age, sex, tumor size and location, histologic variant, disease stage, resection margin status, chemotherapy, and radiotherapy were tested as variables and were not statistically significant.

  • b

    This P value was statistically significant.

Local recurrent/primary disease22/18551.54-16.04.007b4.31.27-14.47.018b
Extremity/nonextremity site153/540.10.04-0.43≤ .001b0.20.05-0.47.001b
Table 3. Localized Myxoid/Round Cell Liposarcoma: Prognostic Factors for Metastatic-Free Survival
  Univariate AnalysisMultivariate Analysis
VariableaNo. of PatientsHR95% CIPHR95% CIP
  • Abbreviations: CI, confidence interval; HR, hazard ratio; MLS, myxoid liposarcoma; RCL, round cell liposarcoma.

  • a

    Tumor size and location, tumor status (primary or locally recurrent), resection margin status, and chemotherapy were tested as variables and were not statistically significant.

  • b

    This P value was statistically significant.

Age >40 y2073.791.51-9.49.004b   
Sex: Women/men88/1190.290.10-0.77.013b0.240.08-0.67.007b
Stage IA/IB/II/III22/100/4/452.041.36-3.05≤ .001b   
Radiation: Yes/no153/544.180.98-17.70.052b   
Table 4. Localized Myxoid/Round Cell Liposarcoma: Prognostic Factors for Disease-Specific Survival
  Univariate AnalysisMultivariate Analysis
VariableaNo. of PatientsHR95% CIPHR95% CIP
  • Abbreviations: CI, confidence interval; HR, hazard ratio; MLS, myxoid liposarcoma; RCL, round cell liposarcoma.

  • a

    Tumor size, chemotherapy, and radiotherapy were tested and were not statistically significant.

  • b

    This P value was statistically significant.

Age >45 y74/2073.151.28-7.44.0122b6.891.27-37.45.0252b
Sex: Women/men88/1190.230.06-0.80.0216b0.050.004-0.57.0159b
Recurrent/primary disease22/1853.811.37-10.58.0099b8.071.004-64.8.0494b
Extremity/nonextremity site153/540.370.15-0.93.0347b   
Tumor location: Deep/superficial158/415.930.79-44.52.0832b   
Surgical margin status: R0/R1/R2156/25/82.071.04-4.10.037b   

Characteristics and Outcomes of Patients With Metastatic Myxoid/Round Cell Liposarcoma

The median follow-up for the 61 patients who presented to UTMDACC with metastatic disease was 24 months (range, 1.7–95 months); their clinicopathologic variables are summarized in Table 5. The median patient age at presentation was 50 years (range, 32–78 years) with a predilection among men (70%). The median time to metastasis from diagnosis of primary disease was 35 months (range, 1–195 months). Fifty-seven percent of patients presented with a single metastatic site, most commonly the abdomen (49%; including the pelvis, groin, and retroperitoneum) followed by bone (23%). Nineteen of 26 patients who presented with multiple-site metastases had abdominal involvement; 14 patients had lung and pleura metastasis; 14 patients had bone lesions; 11 patients had axillary, chest wall, and/or mediastinal involvement. Synchronous primary and metastatic lesions appeared in 23% of patients with disseminated disease. Twenty-five patients underwent metastasectomy, and 6 of those patients achieved R0 resection. The majority of patients (90%) received chemotherapy, most commonly doxorubicin and ifosfamide. In 34% of treated patients, doxorubicin and ifosfamide were combined with additional drugs, such as dacarbazine, gemcitabine, and docetaxel. Twenty-five percent of patients with metastatic disease received trabectedin. Twenty-four patients (40%) received radiotherapy before or after surgical interventions (n = 13), and 2 patients received radiotherapy for palliation only. The DSS rate was 78% at 1 year and 8.2% at 5 years, and no patients who presented with metastasis survived beyond 9 years (P < .0001) (Fig. 1A). In univariate analysis, the presence of lung metastasis or multiple metastases predicted poor outcome, whereas surgical metastasectomy was associated with improved DSS. However, only surgical metastasectomy remained significant as a predictor of improved outcomes in multivariate analysis (Table 6). All but 6 patients with metastatic disease received chemotherapy, including 2 patients who were terminal and chose no treatment, 1 patient who refused treatment, 2 patients with stable disease, and 1 patient for unspecified reasons.

Table 5. Metastatic Myxoid/Round Cell Liposarcoma: Patient, Tumor, Treatment, and Outcome Variables, N = 61
VariableNo. of Patients (%)
  • Abbreviations: DSS, disease-specific survival; MLS, myxoid liposarcoma; RCL, round cell liposarcoma.

  • a

    Abdomen includes sites in the abdomen, retroperitoneum, pelvis, and groin.

  • b, c

    Other includes sites in the head and neck (2 patients) and cites in the axilla, chest wall, and mediastinum (3 patients).

  • c

    Nine patients had unknown status.

  • d

    Two patients had unknown status.

Patient variables 
Age: Median [range], y49.6 [32-78]
Tumor variables 
Tumor type 
Time to metastasis from primary diagnosis: Median [range], mo35 [1-194]
Synchronous primary tumor 
Metastatic sites 
Location of single metastatic site 
Abdomena17 (49)
Skeleton and spine8 (23)
Lung and pleura5 (14)
Otherb5 (14)
No. of recurrences before metastasisc 
Treatment variables 
Curative surgery 
Microscopically clear marginsd11 (48)
Outcome variables 
Median follow-up [range], mo24 [1.7-94.5]
DSS, % 
Table 6. Metastatic Myxoid/Round Cell Liposarcoma: Prognostic Factors for Disease-Specific Survival
  Univariate AnalysisMultivariate Analysis
VariableaNo. of Patients/Total No.HR95% CIPHR95% CIP
  • Abbreviations: CI, confidence interval; HR, hazard ratio.

  • a

    Bone metastasis, abdominal metastasis, myxoid/round cell liposarcoma versus round cell liposarcoma, chemotherapy, and radiotherapy were tested and were not statistically significant.

  • b

    These P values were statistically significant.

Multiple sites of metastasis26/611.951.10-3.44.0216b   
Lung metastasis19/611.790.95-3.34.0675b   

Myxoid/Round Cell Liposarcoma-Related Molecular Biomarkers

Candidate markers, which were selected based on their expression in other malignancies, included cell proliferation, survival, angiogenesis, migration, invasion, and metastasis factors. Biomarker expression levels are illustrated in Figure 2 and are summarized in Table 7; all samples expressed cytoplasmic and nuclear CXCR4 and adipophilin. AXL or PDGFR-β was expressed in most samples. cKIT and cMET staining was negative in all evaluable samples (n = 117 and n = 131, respectively). To evaluate the role of biomarkers in disease progression, expression levels in primary, recurrent, and metastatic tumors were compared. Significantly lower levels of BCL2 and VEGF were observed in primary versus recurrent and metastatic tumors (P = .004 and P = .0042, respectively). CXCR4 and PDGFR-β expression levels were significantly higher in metastatic versus localized lesions (P = .0036 and P ≤ .0001, respectively). Tumors with an RCL phenotype expressed significantly increased levels of nuclear CXCR4, p53, adipophilin, PDGFR-α, PDGFR-β, and VEGF relative to tumors with an MLS phenotype (Table 8). Prognostically, only AXL emerged as a significant predictor of DSS on univariate analysis (hazard ratio, 19; P = .032); on multivariate analysis, AXL failed to predict outcome.

Table 7. Myxoid/Round Cell Liposarcoma Biomarker Expression Pattern
BiomarkerTotal No. of SamplesLow ExpressionHigh ExpressionPercentage of Positive Samples
  • Abbreviations: AXL, receptor tyrosine kinase encoded by the AXL gene; BCL2, B-cell lymphoma 2; CCR7, chemokine (C-C motif) receptor 7; CXCR4, C-X-C chemokine receptor type 4; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; MMP9, matrix metalloproteinase 9; PDGF-α;, platelet-derived growth factor alpha; PDGF-β;, platelet-derived growth factor beta; PDGFR-α, platelet-derived growth factor receptor alpha; PDGFR-β, platelet-derived growth factor receptor beta; PPAR-γ, peroxisome proliferator-activator receptor gamma; VEGF, vascular endothelial growth factor.

  • a

    AXL was a statistically significant prognostic factor for disease-specific survival in univariate analysis (P = .032; hazard ratio, 19.04; 95% confidence interval, 1.28-284.58).

Cyclin D11191081133
CXCR4, cytoplasmic1128626100
CXCR4, nuclear1123181100
PPAR-γ, nuclear100376385
PPAR-γ, cytoplasmic100425889
Table 8. Markers That Differ Between Myxoid and Round Cell Liposarcoma Subtypes
MarkerValid CasesCorrelation CoefficientaPb
  • Abbreviations: CXCR4, C-X-C chemokine receptor type 4; PDGFR-α, platelet-derived growth factor receptor alpha; PDGF-β, platelet-derived growth factor beta; VEGF, vascular endothelial growth factor.

  • a

    A positive correlation means statistically significant higher expression in RCL vs. MLS.

  • b

    P values are 1-sided, and values < .025 are considered statistically significant.

CXCR4, nuclear740.3225.0025
Adipophilin900.3913≤ .0001


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  2. Abstract

This report comprises a comprehensive clinical, pathologic, and molecular study of patients with MLPS based on a large, single-institution cohort in which therapeutic decisions and strategies were managed by an expert multidisciplinary team. The results demonstrated excellent 1-year, 5-year, and 10-year DSS compared with previous studies.2,8–10 Univariate analysis suggested several variables as DSS prognostic factors (Table 4), supporting findings from previous studies.8–10,12 However, multivariate analysis revealed only age >45 years, male gender, and locally recurrent disease as significant prognosticators of a poor outcome. The survival outcome results from of our series are supported further by the similar trend in both DSS and overall survival.

Our 7.4% local recurrence rate is similar to that reported by a recently published large MLPS cohort11 and is better than the rates reported in other published series,8–10,12,13 perhaps because of more frequent positive margins reported by Haniball et al (34%), Kilpatrick et al (49%), and ten Heuvel et al (24%) compared with our current series (17%); less frequent use of radiotherapy; and/or the inclusion of patients with primary retroperitoneal myxoid lesions. Our preferred therapeutic approach since the 1980 s has been radiotherapy (50 grays) followed by surgery, which facilitates excellent local control with smaller radiation fields17 than postoperative radiotherapy, which we reserve for patients who are referred to us after undergoing primary tumor resection elsewhere. Our results indicate that tumor location (nonextremity vs extremity) and tumor status (recurrent vs primary) are predictors of poor recurrence-free survival, whereas resection margins and histology type (MLS vs RCL) do not predict recurrence-free survival, in contrast to other studies.8,9,11 Our 13.1% metastasis rate is at the lower end of published metastasis ranges2,8–11 (up to 38%), perhaps reflecting the aggressive therapeutic algorithms used at UTMDACC. Our univariate analysis indicated that radiotherapy is associated with poorer metastasis-free survival, perhaps because of selection bias, in which patients who have tumors that are deemed more aggressive are more likely to receive radiotherapy.

Male gender was the only significant multivariate analytic prognostic factor for metastasis-free survival. A male predilection in MLPS has been described previously2,8–13,17. however, to the best of our knowledge, this is the first time it has been identified as prognostic of a poor outcome. It is noteworthy that most other MLPS series did not evaluate the association between sex and outcome; therefore, we believe that ours is the largest series to date addressing this question. Seeking an explanation for this finding, we investigated whether hormone receptors (estrogen, progesterone, and androgen receptors) played a role in MLPS. However, negligible expression of these receptors was observed. Other factors may portend an inferior prognosis for men with sarcoma; eg, mutation in RASSF1A (Ras association domain family member 1).18 Although we have not yet identified sex-specific drivers in MLPS, future studies may more clearly accomplish this objective. Surgical resection remains the standard of care for patients with localized MLPS. Recently, the role of radiotherapy in local disease control has been demonstrated,17 and the rates of radiotherapy receipt have increased, as we and others have demonstrated.9,11 The role of chemotherapy for patients with localized MLPS is uncertain, and its rate of administration at some treatment centers is as low as 6%11 compared with 40% at UTMDACC, where any patient with localized disease who is considered high-risk (tumor size >10 cm, RCL histology, and positive resection margins) receives chemotherapy. Chemotherapy did not prolong survival in our patients. However, the absence of a robust “no-treatment” comparison group may be associated with selection bias in favor of treating all patients who are deemed “high-risk.” Chemotherapy in selected patients with MLPS can achieve positive response rates19 and may account in part for the improved local and distant control rates we observed. Nonetheless, the need persists for enhanced identification of patients who may benefit from chemotherapy. The MLPS metastatic pattern is unique. In contrast to other soft tissue sarcomas, MLPS primarily metastasizes to extrapulmonary sites, most commonly the abdomen.20 The analysis of our subgroup of patients who presented with metastatic disease is consistent with this reality. Not surprisingly, lung metastases predicted worse outcomes on univariate analysis, because these generally appear at later disease stages. We speculate that the ability to colonize the lungs may represent an adaptation of the tumor to a nonfatty environment, perhaps reflecting increased tumor aggressiveness. Chemotherapy is the mainstay treatment of metastasis; reminiscent of local disease, our patients who received chemotherapy did not have outcomes superior to those of nontreated patients; whereas surgery conferred a positive outcome effect. These findings may reflect biases in nonrandomized selection for treatment with either modality. Metastasectomy, especially of isolated lesions, may favorably affect outcome. Patient selection for metastasectomy is individualized and is based on general condition, prognosis etc; indications include low tumor grade, age <50 years, a greatest tumor dimension <15 mm, and slow disease progression (>12 months between pulmonary recurrences or >24 months between extrapulmonary recurrences).

Myxoid/Round Cell Liposarcoma-Related Biomarkers

We investigated adipocytic differentiation biomarkers to determine what role (if any) these may play in MLPS tumorigenesis. All samples expressed high levels of adipophilin, a known marker of adipogenesis that appears early in the differentiation process,21 perhaps suggesting that both MLS tumors and RCL tumors differentiate beyond the initial stage(s) before the disruption of complete adipocytic maturation. Moreover, we observed significantly higher levels of adipophilin in RCL tumors versus MLS tumors, perhaps suggesting that adipophilin participates in disease progression. The adipogenesis regulator PPAR-γ is overexpressed in MLPS,15 and our data support this observation. However, it is also known that PPAR-γ has protumorigenic properties22; in this setting, PPAR-γ may function more as a tumorigenic factor than an adipogenic factor.

CXCR4 is a chemokine receptor in many cancers and may facilitate metastases through effects on cell migration, invasion, and angiogenesis.23 All of our MLPS samples demonstrated CXCR4 protein expression, which was higher in the clinically more aggressive RCL variant than in MLS. Cytoplasmic CXCR4 expression also was higher in metastatic MLS compared with localized MLS, a pattern that has been observed in breast cancer, lung cancer, colon cancer, melanoma and other malignancies.24,25 CXCR4 may be involved in aggressive MLPS tumor behavior (RCL and metastases) and may serve as a future viable therapeutic target.

The overexpression of p53 may reflect dysfunctional antiapoptotic signaling and has been linked to a poor response to chemotherapy.26 Expression of p53 in MLPS varies from 7% to 100% positivity in published series.2,14,27 In our study, p53 overexpression in RCL versus MLS tumor variants was comparable to that reported in other studies; however, it did not correlate with outcome, in contrast to others.

Receptor tyrosine kinases (RTKs) and their ligands are expressed in many mesenchymal malignancies and have been targeted by an ever-increasing array of directed therapies. Tumors often express multiple RTKs because of cross-talk with other pathways, such as the RAS/MAPK (rat sarcoma/mitogen-activated protein kinase) and angiogenic signaling pathways. Therefore, we assessed the expression of several RTKs to determine their theragnostic significance. AXL is an RTK associated with tumor invasion, angiogenesis, and metastasis28; its expression correlates with a poor outcome in several malignancies, including MLPS, as reported here, and may be an attractive candidate for targeting given the availability of AXL inhibitors. AXL was expressed in almost all of our MLPS samples (97%); and, for the first time, we demonstrated that high AXL expression predicts a poor outcome in patients with MLPS (univariate analysis). However, the importance of this finding is unclear, because it was not confirmed on multivariate analysis.

Previous reports indicated that PDGFR-β was expressed in MLPS.29 Our finding that PDGFR-β expression was higher in metastatic lesions compared with localized lesions is intriguing given its role in bone metastasis.30 Considering the relatively high prevalence of MLPS bone metastasis and the availability of PDGFR-β inhibitors, this may be an attractive locus for further investigation.

Our study has several limitations. Because it is a retrospective study, it requires prospective validation and cannot be used to justify therapeutic decisions. The major caveat of our histologic analysis is that, of 268 patients who were included in our study, only 169 tissue samples were analyzed, because patients whose tumors were resected elsewhere were not included in our TMA. Also, those patients who received preoperative therapies before surgery, resulting in no residual tumor identified in the resection specimen, were not represented on the TMA. This resulted in a TMA inclusion selection bias that favored more clinically resistant tumors and/or larger tumors that were inadequately resected elsewhere. Finally, although we identified several biomarkers that had prognostic utility, this does not mean that these proteins are integral to MLPS tumor biology; consequently, they may be irrelevant in therapeutic targeting.

In conclusion, we present a large MLPS patient study incorporating comprehensive follow-up and biomarker analysis. Our cohort was notable for the aggressive treatment strategy for localized tumors, which may correlate with lower metastatic rates than previously described. In addition, we identified age, male gender, and abnormal expression of several proteins as potential prognostic factors. Therefore, future prospective studies confirming our results appear to be warranted.


  1. Top of page
  2. Abstract

This work was supported in part by a Deutsche Forschungsgemeinschaft training grant (supporting Dr. Ghadimi) and an Advanced Imaging Research Center fellowship grant (supporting Dr. Creighton). Dr. Hoffman is the recipient of a fellowship grant from the American Physicians Fellowship for Medicine in Israel.


The authors made no disclosures.


  1. Top of page
  2. Abstract
  • 1
    Weiss SW, Goldblum JR. Liposarcoma. In: Weiss SW, Goldblum JR, Enzinger FM, eds. Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, MO: Mosby; 2001: 641693.
  • 2
    Antonescu CR, Tschernyavsky SJ, Decuseara R, et al. Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases. Clin Cancer Res. 2001; 7: 39773987.
  • 3
    Knight JC, Renwick PJ, Dal Cin P, Van den Berghe H, Fletcher CD. Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis. Cancer Res. 1995; 55: 2427.
  • 4
    Panagopoulos I, Mandahl N, Mitelman F, Aman P. Two distinct FUS breakpoint clusters in myxoid liposarcoma and acute myeloid leukemia with the translocations t(12;16) and t(16;21). Oncogene. 1995; 11: 11331137.
  • 5
    Perez-Losada J, Sanchez-Martin M, Rodriguez-Garcia MA, et al. Liposarcoma initiated by FUS/TLS-CHOP: the FUS/TLS domain plays a critical role in the pathogenesis of liposarcoma. Oncogene. 2000; 19: 60156022.
  • 6
    Adelmant G, Gilbert JD, Freytag SO. Human translocation liposarcoma-CCAAT/enhancer binding protein (C/EBP) homologous protein (TLS-CHOP) oncoprotein prevents adipocyte differentiation by directly interfering with C/EBPbeta function. J Biol Chem. 1998; 273: 1557415581.
  • 7
    Fletcher CDM, ed. Pathology and Genetics of Soft Tissue and Bone: World Health Organization Classification of Tumors. Lyon, France: IARC Press; 2002.
  • 8
    Kilpatrick SE, Doyon J, Choong PF, Sim FH, Nascimento AG. The clinicopathologic spectrum of myxoid and round cell liposarcoma. A study of 95 cases. Cancer. 1996; 77: 14501458.
  • 9
    Haniball J, Sumathi VP, Kindblom LG, et al. Prognostic factors and metastatic patterns in primary myxoid/round-cell liposarcoma [serial online]. Sarcoma. 2011; 2011: 538085.
  • 10
    ten Heuvel SE, Hoekstra HJ, van Ginkel RJ, Bastiaannet E, Suurmeijer AJ. Clinicopathologic prognostic factors in myxoid liposarcoma: a retrospective study of 49 patients with long-term follow-up. Ann Surg Oncol. 2007; 14: 222229.
  • 11
    Moreau LC, Turcotte R, Ferguson P, et al. Myxoid/round cell liposarcoma (MRCLS) revisited: an analysis of 418 primarily managed cases. Canadian Orthopaedic Oncology Society (CANOOS). Ann Surg Oncol. 2012; 19: 10811088.
  • 12
    Fiore M, Grosso F, Lo Vullo S, et al. Myxoid/round cell and pleomorphic liposarcomas: prognostic factors and survival in a series of patients treated at a single institution. Cancer. 2007; 109: 25222531.
  • 13
    Nishida Y, Tsukushi S, Nakashima H, Ishiguro N. Clinicopathologic prognostic factors of pure myxoid liposarcoma of the extremities and trunk wall. Clin Orthop Relat Res. 2010; 468: 30413046.
  • 14
    Dei Tos AP, Piccinin S, Doglioni C, et al. Molecular aberrations of the G1-S checkpoint in myxoid and round cell liposarcoma. Am J Pathol. 1997; 151: 15311539.
  • 15
    Cheng H, Dodge J, Mehl E, et al. Validation of immature adipogenic status and identification of prognostic biomarkers in myxoid liposarcoma using tissue microarrays. Hum Pathol. 2009; 40: 12441251.
  • 16
    Demicco EG, Torres KE, Ghadimi MP, et al. Involvement of the PI3K/Akt pathway in myxoid/round cell liposarcoma. Mod Pathol. 2012; 25: 212221.
  • 17
    Guadagnolo BA, Zagars GK, Ballo MT, et al. Excellent local control rates and distinctive patterns of failure in myxoid liposarcoma treated with conservation surgery and radiotherapy. Int J Radiat Oncol Biol Phys. 2008; 70: 760765.
  • 18
    Yee KS, Grochola L, Hamilton G, et al. A RASSF1A polymorphism restricts p53/p73 activation and associates with poor survival and accelerated age of onset of soft tissue sarcoma. Cancer Res. 2012; 72: 22062217.
  • 19
    Katz D, Boonsirikamchai P, Choi H, et al. Efficacy of first-line doxorubicin and ifosfamide in myxoid liposarcoma [serial online]. Clin Sarcoma Res. 2012; 2: 2.
  • 20
    Spillane AJ, Fisher C, Thomas JM. Myxoid liposarcoma-the frequency and the natural history of nonpulmonary soft tissue metastases. Ann Surg Oncol. 1999; 6: 389394.
  • 21
    Heid HW, Moll R, Schwetlick I, Rackwitz HR, Keenan TW. Adipophilin is a specific marker of lipid accumulation in diverse cell types and diseases. Cell Tissue Res. 1998; 294: 309321.
  • 22
    Zhang GY, Ahmed N, Riley C, et al. Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma. Br J Cancer. 2005; 92: 113119.
  • 23
    Kim RH, Li BD, Chu QD. The role of chemokine receptor CXCR4 in the biologic behavior of human soft tissue sarcoma[serial online]. Sarcoma. 2011; 2011: 593708.
  • 24
    Muller A, Homey B, Soto B, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001; 410: 5056.
  • 25
    Murakami T, Cardones AR, Hwang ST. Chemokine receptors and melanoma metastasis. J Dermatol Sci. 2004; 36: 7178.
  • 26
    Kandioler-Eckersberger D, Ludwig C, Rudas M, et al. TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res. 2000; 6: 5056.
  • 27
    Smith TA, Goldblum JR. Immunohistochemical analysis of p53 protein in myxoid/round cell liposarcomas of the extremities. Appl Immunohistochem. 1996; 4: 228234.
  • 28
    Verma A, Warner SL, Vankayalapati H, Bearss DJ, Sharma S. Targeting Axl and Mer kinases in cancer. Mol Cancer Ther. 2011; 10: 17631773.
  • 29
    Olofsson A, Willen H, Goransson M, et al. Abnormal expression of cell cycle regulators in FUS-CHOP carrying liposarcomas. Int J Oncol. 2004; 25: 13491355.
  • 30
    Catena R, Luis-Ravelo D, Anton I, et al. PDGFR signaling blockade in marrow stroma impairs lung cancer bone metastasis. Cancer Res. 2011; 71: 164174.