Retroperitoneal lipoma (RPL) is a controversial diagnosis amongst soft tissue pathologists, traditionally thought to be better classified as well-differentiated liposarcoma (WD-LPS). However, confidence in making this diagnosis has increased in recent decades with the support of fluorescence in situ hybridisation (FISH) to assess for MDM2/CDK4 amplification. In this study, we examined the clinicopathological features of a series of RPL and compared them to retroperitoneal WD-LPS, with particular focus on biological behaviour. RPL was defined as a discrete mass-forming lipomatous lesion arising in the retroperitoneum, composed of bland fat with absence of atypical histological features and without MDM2/CDK4 amplification confirmed on FISH analysis. Seventeen cases of RPL were identified from our database and compared to an equal number of WD-LPS. RPL occurred more frequently in females (65% vs 29%, p=0.04), with a median age of 59 years (range 18-73). Tumour size was significantly smaller (median 140 vs 200 mm, p=0.04). There were no recurrences of RPL over a median follow-up period of 29 months (range 2-94), significantly different from the 29% recurrence observed for WD-LPS (p=0.01). This difference was observed despite the majority (82%) of patients with RPL being treated with more conservative organ-preserving surgery (R1 or R2 resection) compared to radical surgery (R0 resection) for those with WD-LPS (82%, p<
0.01). Our results also show the utility and reliability of core biopsy to separate RPL and WD-LPS preoperatively to guide the extent of surgery (assuming that the sample is both adequate and representative), with an overall accuracy of 95%. This study supports RPL as a discrete entity with unique clinicopathological features compared to WD-LPS, including the expected benign clinical behaviour. Recognition and increased acceptance of RPL as a distinct diagnosis amongst pathologists and surgeons is important to avoid over-treatment and unnecessary surveillance. However, the benign behaviour demonstrated would benefit from additional confirmation over longer follow-up periods.