Histomorphological and molecular characteristics of liposarcoma (Review)

Abstract

Liposarcomas represent the most prevalent subtype of soft-tissue sarcomas, comprising 15-20% of all documented cases. However, sarcomas demonstrate notable clinical and pathological variability, which complicates the processes of diagnosis and treatment. Histomorphological analysis can produce inconsistent results due to inter-examiner variability, which highlights the need for more reliable biomarkers. Genetic and epigenetic alterations may delineate the biological behavior of liposarcomas and assist in the prediction of liposarcoma prognosis. The present review highlights the related genomic alterations in sarcoma and their associations with relevant histomorphology, predilection, targeted therapy and prognosis. Well-differentiated and dedifferentiated liposarcomas exhibit amplified genes, MDM2 proto-oncogene and cyclin-dependent kinase 4, which are potential targets for therapy. Myxoid liposarcoma, characterized by the chromosomal translocations t(12;16) with fused in liposarcoma-DNA damage-inducible transcript 3 protein (DDIT3) fusion and t(12;22) with Ewing sarcoma RNA-binding protein 1-DDIT3 fusion, demonstrate a favorable response to treatment; however, myxoid liposarcoma displays elevated recurrence rates. Moreover, the complex karyotype and lack of specificity in pleomorphic liposarcoma are associated with poor treatment outcomes and increased recurrence rates. Integration of morphological features with molecular biomarkers may potentially enhance diagnosis, facilitate targeted therapies and improve sarcoma prognosis in the future.

Keywords: biomarker; diagnostic precision; molecular marker; sarcoma; targeted therapy.

Figure 1.

Histopathological images of WDL. (A) WDL tumor exhibiting mature adipocytes along with atypical stromal cells and (B) a small number of lipoblasts. Hematoxylin and eosin staining; magnification, ×100 and ×400, respectively. WDL, well-differentiated liposarcoma.

Figure 2.

Histopathological images of DDL. (A) DDL including a well-differentiated adipose tissue component mixed with non-lipogenic elements, such as (B) a fibrosarcomatous component. Hematoxylin and eosin staining; magnification, ×100 and ×400, respectively. DDL, dedifferentiated liposarcoma.

Figure 3.

MDM2 and CDK4 involvement in the pathogenesis of liposarcoma. CDK4 gene amplification results in increased expression of the CDK4 protein, which promotes RB phosphorylation, thereby driving cell-cycle progression. MDM2 negatively regulates p53 through various mechanisms, inhibiting p53 transcription and facilitating p53 degradation by ubiquitination. MDM2, murine double minute 2; RB, retinoblastoma; CDK4, cyclin-dependent kinase 4; P, phosphorus.

Figure 4.

Histopathological images of ML. (A) ML comprising non-lipogenic mesenchymal cells with distinct myxoid background and a chicken wire vasculature, and (B) a high-grade ML, exhibiting a >5% round cell component alongside necrotic areas. Hematoxylin and eosin staining; magnification, ×100 and ×400, respectively. ML, myxoid liposarcoma.

Figure 5.

The pathogenesis of ML. ML pathogenesis involves the upregulation and activation of RTKs, including MET, RET and VEGFRs, leading to enhanced PI3K pathway activity. Growth factors that bind to RTKs, such as IGF-IR, activate PI3K, transforming PIP2 into PIP3 and triggering AKT signaling and phosphorylating downstream targets. PTEN inhibits PI3K signaling by conversion of PIP3 back to PIP2. Moreover, RTKs activate genes linked to angiogenesis, proliferation and survival by Ras and the PI3K/AKT pathway. ML is associated with AKT activation and PIK3CA and PTEN alterations. The oncogenic circuit includes FUS-DDIT3, the IGF-IR/PI3K/AKT pathway and the Hippo/YAP1 axis. FUS-DDIT3 induces IGF-2 expression, forming an autocrine IGF-II/IGF-IR signaling loop that activates the IGF-IR/PI3K/AKT pathway. Signals from IGF-IR and PI3K inhibit Hippo kinase LATS1, enabling nuclear accumulation of YAP1. FUS-DDIT3 interacts with YAP1/TEAD in the nucleus, regulating oncogenic gene programs involved in apoptosis, adipogenesis, the cell cycle and proliferation. ML, myxoid liposarcoma; RTK, receptor tyrosine kinase; MET, MET proto-oncogene receptor tyrosine kinase; RET, ret proto-oncogene; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (–5)-trisphosphate; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α; IGF, insulin-like growth factor; IGF-IR, IGF-1 receptor; FUS-DDIT3, fused in liposarcoma-DNA damage-inducible transcript 3; YAP1, Yes-associated protein 1; LATS1, large tumor suppressor kinase 1; TEAD, transcriptional enhanced associate domain; HGF, hepatocyte growth factor; GDNF, glial cell line-derived neurotrophic factor.

Figure 6.

Histopathological images of PL. PL demonstrating (A) spindle to epitheloid pleomorphic cells, (B) pleomorphic lipoblasts with vacuolated cytoplasm and (C) other features of pleomorphic lipoblasts. Hematoxylin and eosin staining; magnification, ×100, ×400 and ×400, respectively.