Predicting MDM2 Amplification in Well-Differentiated Liposarcomas

Research Article

Ann Hematol Oncol. 2021; 8(13): 1384.

Predicting MDM2 Amplification in Well-Differentiated Liposarcomas

Tran V1*, Slavin J4, Spelman T1,5, May D3 and Choong PFM1,2,3

1Department of Surgery, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia

2Bone and Soft Tissue Sarcoma Service, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

3Department of Orthopaedics, St. Vincent’s Hospital, Melbourne, Victoria, Australia

4Department of Anatomical Pathology, St. Vincent’s Hospital, Melbourne, Victoria, Australia

5Karolinska Institute, Stockholm, Sweden

*Corresponding author: Vanessa Tran, Department of Surgery, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia

Received: November 01, 2021; Accepted: November 25, 2021; Published: December 02, 2021


Background: Well-Differentiated Liposarcoma (WDLPS) is the most common subtype of malignant lipomatous tumours. This low-grade neoplasm carries a risk of local recurrence and dedifferentiation into higher-grade subtypes, and therefore requires aggressive treatment with wide local excision and neoadjuvant radiotherapy. WDLPS, however, shares overlapping features with its benign counterpart, lipoma. Diagnostically challenging cases can be resolved with molecular testing for Mouse Double Minute 2 (MDM2) amplification, which is found in almost all WDLPS. This study aimed to determine the predictors of MDM2 amplification to better inform the decision for tumours to undergo molecular testing.

Methods: A retrospective study was performed on 173 lipomatous tumours. Demographic, clinical, radiology and pathology data were obtained from institutional records. Multivariate analysis was performed to determine the features of lipomatous tumours that correlate with MDM2 amplification. The relative strength of the associations between predictor variables and MDM2 amplification were measured via derivation of coefficients of determination (Pseudo-R2).

Results: The significant predictors of MDM2 amplification were age of diagnosis ≥60 years (odds ratio (OR)=25.71; 95% confidence interval (CI)=4.47- 148.02); size ≥15cm (OR=11.68; 95% CI=2.70-50.59); presence of thick septa (OR=78.13; 95% CI=3.23-1890.71) on MRI; variable cell morphology (OR=22.19; 95% CI=4.03-122.20); and cytological atypia (OR=15.03; 95% CI=3.07-73.68).

Conclusion: Molecular testing for MDM2 amplification should be considered for tumours 15cm or greater, in patients aged 60 years or older, with thick septa on MRI, even in the absence of concerning histological features.

Keywords: Lipoma; Well-differentiated liposarcoma; MDM2 amplification; Molecular genetics


CI: Confidence Interval; FISH: Fluorescence In Situ Hybridization; MDM2: Mouse Double Minute 2; OR: Odds Ratio; WDLPS: Well- Differentiated Liposarcoma


Well-Differentiated Liposarcoma (WDLPS) is the most common liposarcoma subtype, accounting for almost half of all liposarcomas [1,2]. These often arise in the extremities and retroperitoneum, though are also found in the spermatic cord, mediastinum, and head and neck regions [1]. WDLPS are low-grade malignant tumours characterized by the predominance of mature adipocytes of variable size with fibrous septa containing atypical spindle cells. While these tumours lack metastatic potential, WDLPS carry a risk of local recurrence or dedifferentiation into a higher-grade subtype, namely DDLPS [3,4]. Importantly, WDLPS may be mistaken for a simple lipoma and treated in a suboptimal fashion. Identification of WDLPS is therefore important to provide adequate treatment and prevent local recurrence.

Molecular cytogenetic analysis is increasingly recognized as a valuable diagnostic tool for soft tissue sarcomas, given the many overlapping histological features and presence of characteristic genetic aberrations [5]. It is well recognized that WDLPS harbour characteristic amplified sequences of the chromosomal 12q13-15 region. This region almost invariably contains the Mouse Double Minute 2 (MDM2) gene, which is subsequently also amplified. Previously, amplification of this region was detected by the presence of supernumerary ring or marker chromosomes in conventional karyotyping, which were surrogate representations of the amplified sequence. More recently, Fluorescence In Situ Hybridization (FISH) has been interrogated as an accurate tool in the identification of MDM2 amplification. The use of FISH in distinguishing WDLPS from lipoma has yielded a sensitivity and specificity of up to 100% in several studies [6-8]. The characterization of MDM2 amplification in WDLPS has proven particularly useful in histologically challenging cases. A retrospective analysis by de Vreeze et al. found that incorporation of cytogenetic analysis in the diagnosis of lipoma and liposarcoma can change the diagnosis in up to 26% of cases [9]. Further studies have also reported that the addition of MDM2 amplification testing may lead to the reclassification of WDLPS and lipomas, which were previously diagnosed based on histology alone [7,10,11]. In the era of precision diagnostics, molecular testing has proven to be a valuable diagnostic tool.

This study interrogated the impact of MDM2 amplification testing on diagnosis of WDLPS and investigated the clinical, radiological, and histological features of lipomatous tumours that predict MDM2 amplification. Knowledge of these features and their relevance to WDLPS will allow clinicians to risk stratify lipomatous tumours and make more informed decisions about molecular testing.


A retrospective study was conducted on all patients diagnosed with lipoma or WDLPS at St Vincent’s Hospital Melbourne (SVHM) and St Vincent’s Private Hospital Melbourne (SVPHM). This study received ethics approval from the Research Governance at both hospitals (LRR 064/20 and P009/20). This was a retrospective analysis of institutional data without patient contact and informed consent was therefore not required.


There were 544 consecutive tumours diagnosed as lipoma or WDLPS between 1997 and 2019 at SVHM and SVPHM. Of these, 182 tumours from 176 patients underwent FISH testing for MDM2 amplification. Local recurrences were counted as a separate diagnosis. The inclusion criteria for statistical analysis were a diagnosis of lipoma or WDLPS; and testing for MDM2 amplification by FISH. Tumours, which did not undergo MDM2 amplification testing, and local recurrences were excluded from the final analysis.


SVHM is part of the Victorian Sarcoma Service, a collaborative tertiary referral service that provides comprehensive multidisciplinary bone and soft tissue cancer care to patients across Australia. All patients in this study were primarily managed in a multidisciplinary oncology team setting. Pathology specimens were examined by a specialist sarcoma pathologist and FISH testing for MDM2 amplification was performed by a cytogeneticist at the single institution. As part of the diagnostic workup, all patients underwent MRI with contrast studies and a CT-guided biopsy to obtain a pathological diagnosis. Some patients also underwent thallium scan, which was an investigative decision guided by the treating clinician. Resected tumours were also sent to pathology for confirmation of the diagnosis.

From January 2014, testing for MDM2 amplification by FISH was conducted at SVHM for lipomatous tumours suspected of malignancy to differentiate between a diagnosis of lipoma and WDLPS. The decision to test samples was guided by a senior sarcoma pathologist and was performed to (a) confirm a diagnosis of WDLPS or (b) to differentiate WDLPS from lipoma in histologically equivocal cases.


The decision for surgical management was variable and guided by the diagnosis. Patients with a diagnosis of WDLPS in the extremities or trunk received neoadjuvant radiotherapy and excision of the tumour with wide margins. Those with WDLPS located in the head and neck or retroperitoneum received neoadjuvant radiotherapy and marginal excision of the tumour. Patients with a diagnosis of lipoma were offered marginal excision without radiotherapy. Surgical margins were classified according to the Enneking staging system (intralesional, marginal, wide, radical) [12].

Clinical, radiological, and histological predictors

Demographic, clinical, radiological, and histological features were collected from online medical records. In classifying the site of the tumour, lower limb referred to the thigh, leg and foot; upper limb referred to the axilla, arm, forearm and hand; pelvis referred to the groin, scrotum, pelvis and buttock; and trunk referred to the chest wall and abdominal wall. The retroperitoneum and intra-abdominal site remained separate. Radiological features were collected from preoperative, pre-radiotherapy MRI scans and thallium scan reports. Histological features were obtained from pathology reports of the resected specimen, where available, or the biopsy specimen. MDM2 amplification status was obtained from the molecular cytogenetics database. Patient follow up information was also obtained, including any local recurrence, the date of last review, and last known survival status.

Impact of MDM2 amplification on diagnosis and local recurrence

The number of diagnoses and local recurrences of lipoma and well-differentiated liposarcoma were stratified according to year. A cut off at January 2014 was used to divide cases into those before and after the introduction of MDM2 amplification testing at SVHM and SVPHM. The number of MDM2 amplification tests performed each year was also recorded.

Statistical analysis for predictors of MDM2 amplification

Categorical outcomes were summarised using frequency and percentages. Continuous variables were presented as mean and Standard Deviation (SD) or median and Interquartile Range (IQR), as appropriate. Univariable and multivariate logistic regression were used to investigate the correlation between MDM2 amplification and demographic information, clinical features, radiological features, and histological features. As individual patients were permitted to contribute multiple tumours to the analysis, the tumour was used as the statistical unit of the analysis with the logistic regression clustered at the level of the patient. Selection of baseline covariates as independent variables in the model was based on the univariate p value < 0.05 in addition to clinical relevance. Overall goodness-of-fit of the adjusted models were assessed using a Hosmer & Lemeshow model.

The relative strength of the associations between predictor variables and MDM2 amplification were measured via derivation of coefficients of determination (Pseudo-R2) for each regression model, with higher coefficients of determination representing greater correlation between an explanatory variable and the MDM2 amplification outcome. All analyses were conducted in R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria).


Between 1997 and 2019 a total 544 cases comprising of 477 lipomas and 67 WDLPS were identified. Within this group, 182 cases were tested for MDM2 amplification by FISH, resulting in a diagnosis of 134 lipomas and 48 WDLPS. 139 samples were negative, and 43 samples were positive for MDM2 amplification. Notably, 5 cases were diagnosed as WDLPS despite a negative MDM2 amplification result.

Trend of WDLPS diagnosis and local recurrence rates

The cases were divided temporally with a cut-off on 1st January 2014, being the time point at which FISH testing for MDM2 amplification was introduced (Table 1). Prior to 2014, the rate of diagnosis of WDLPS was 19 in 276 lipomatous tumours (6.884%). This increased to 48 WDLPS in 268 lipomatous tumours (17.910%) following the introduction of MDM2 amplification testing (Figure 1). The rate of local recurrences of lipomas prior to 2014 was 12 in 256 lipomas (4.688%). This decreased to 2 in 220 lipomas (0.909%) after 2014.