PROGNOSTIC BIOMARKERS IN RETROPERITONEAL DEDIFFERENTIATED LIPOSARCOMA AND THEIR CLINICAL IMPACT ON PATIENTS’ MANAGEMENT

BACKGROUND The prognosis of patients with retroperitoneal dedifferentiated liposarcoma (DDLPS) is primarily driven by clinical-pathological factors such as tumor size, grade, patient age, and the quality of surgical resection. These variables have been incorporated into prognostic nomograms, such as Sarculator. Prognostic stratification has also been refined through transcriptomic signatures, most notably the Complexity INdex in SARComas (CINSARC). Furthermore, the expression of myogenic markers has been associated with poorer survival outcomes. However, given the rarity of these tumors and the consequent lack of robust evidence to guide treatment, improving patient outcomes remains a major challenge. This study aimed to evaluate the impact of clinical, morphological, and molecular features on survival, and to assess the performance of Sarculator and CINSARC in patients with retroperitoneal DDLPS, with the ultimate goal of identifying prognostic biomarkers. EXPERIMENTAL METHODOLOGY We conducted a retrospective observational study on patients with retroperitoneal DDLPS treated at the Veneto Institute of Oncology (IOV)-IRCCS between 2004 and 2024. Tumor samples with adequate material underwent morphological, immunohistochemical, and molecular analyses, including CINSARC assessment. We evaluated the impact of clinical and pathological variables on DFS and OS in surgically treated patients (Cohort 1), and on PFS and OS in those receiving first-line chemotherapy (Cohort 2). The Sarculator nomogram was applied to Cohort 1, and its discriminative performance was assessed using ROC curve analysis. Concordance between CINSARC and Sarculator was also examined. Univariate and multivariable analyses were performed using the Cox regression model, and survival curves were estimated with the Kaplan-Meier method. RESULTS Data from 119 patients were analyzed. In the overall population, histologic grade (p=0.034), along with age (p=0.015), were the strongest determinant of OS. In Cohort 1, age and histologic grade remained the main predictors of survival, whereas in Cohort 2, differentiation, sex, and tumor size had a significant impact on survival, with rhabdomyoblastic differentiation (p=0.045) conferring a particularly dismal prognosis. Applying Sarculator to Cohort 1, 46 (44.2%) scored as Sarc-LR and 58 (55.7%) as Sarc-HR. Moderate agreement was found between predicted and observed OS (Cohen's Kappa = 0.4057) and modest concordance for DFS (Cohen's Kappa = 0.3471). Sarculator showed moderate discriminative ability for OS (AUC=0.747) and lower performance for DFS (AUC = 0.638). Molecular analyses were performed on 32 samples (26.9%). MYOG transcripts, indicative of rhabdomyoblastic differentiation, were detected in 8 samples. Based on CINSARC, 11 patients (34.4%) were low-risk (C1) and 21 (65.6%) high-risk (C2). Moderate agreement was observed between Sarculator and CINSARC for 5-year predicted OS (Cohen’s Kappa = 0.4026) and DFS (Cohen’s Kappa = 0.5526). CONCLUSIONS This is the first study evaluating the impact of clinicopathological features and the performance of Sarculator and CINSARC specifically in retroperitoneal dedifferentiated liposarcoma. Our findings support the negative prognostic impact of rhabdomyoblastic transdifferentiation in retroperitoneal DDLPS. Further investigation of differentiation patterns, alongside the use of prognostic nomograms and transcriptomic signatures, may aid in identifying patients at higher risk who could benefit from tailored therapeutic strategies.