Clinical diagnosis and treatment for Well-Differentiated Liposarcoma : A Clinical Practice Guideline

Well-differentiated liposarcoma (WDLPS) is a locally aggressive adipocytic tumor characterized by mature adipose tissue with cellular atypia, representing the most common subtype of liposarcoma (40%–45% of cases). These tumors are most common in individuals over 50 years old, frequently occurring in the extremities (15%) and retroperitoneum (45%) (Figure 1A). It is also referred to as an atypical lipomatous tumor (ALT) when occurring in surgically resectable locations, such as the extremities or superficial trunk. It typically presents as a painless, slow-growing, deep-seated mass that may cause localized discomfort or functional impairment due to compression of adjacent structures, particularly in areas such as the retroperitoneum or mediastinum. WDLPS is typically resectable, with a 5-year local recurrence rate (20%) and no metastatic potential, leading to a favorable prognosis after complete removal. Up to 10% of WDLPS cases may progress to dedifferentiated liposarcoma (DDLPS), a more aggressive form, potentially driven by amplifications of JUN and ASK1 genes. Anatomical location significantly impacts prognosis: peripheral and superficial ALT lesions are often cured with marginal excision, whereas retroperitoneal WDLPS tumors are prone to recurrence and have a dedifferentiation risk of 28%, compared to less than 2% in extremities.

WDLPS is characterized by abnormalities in the long arm of chromosome 12, resulting in extra ring or giant rod chromosomes due to specific amplification of the 12q13-15 region. This region contains key genes such as MDM2 and CDK4, along with co-amplified genes such as HMGA2, TSPAN31, CPM, and YEATS4. MDM2 is a proto-oncogene and an E3 ubiquitin ligase that acts as a negative regulator of p53. The MDM2 gene is located on chromosome 12q15. While MDM2 amplification is relatively uncommon across human cancers, it is highly frequent in soft-tissue tumors, particularly in WDLPS and DDLPS. CDK4, a member of the serine/threonine protein kinase family, is part of the G1/S cell cycle checkpoint complex. CDK4 amplification occurs in up to 90% of WDLPS/DDLPS cases. Several studies suggest that CDK4 amplification levels have prognostic significance in WDLPS/DDLPS, with higher amplification levels associated with poor outcomes and shorter recurrence-free survival (Figure 1B). Histologically, WDLPS exhibits proliferation of pleomorphic mature adipocytes with variable numbers of lipoblasts. Adipocytes vary in size, and lipoblasts show enlarged, hyperchromatic, atypical nuclei and abnormal multinucleated stromal cells, often intersected by fibrous septa. Pathologically, WDLPS is classified into three subtypes: lipoma-like, inflammatory, and sclerosing (Figure 1C). Therefore, the diagnosis of WDLPS relies on molecular genetic testing and immunohistochemistry, in addition to pathological examination.