Search Results (60)

Background/Introduction: Soft tissue sarcomas (STS) represent a diverse group of rare cancers that have variable responses to chemotherapy. Although tumor size is an established prognostic factor, its influence on the benefit of chemotherapy within specific histologies is not well understood. Methods: We conducted a retrospective analysis of 3890 patients with five STS subtypes using SEER data from 2000 to 2021. Patients were stratified by tumor size (<5 cm, 5–10 cm, >10 cm) and propensity score matched within each subtype-size cohort to control for confounders. Cox regression assessed the impact of chemotherapy on overall survival, with results presented as hazard ratios (HR) and 95% confidence intervals (95%-CI). Inverse probability of treatment weighting (IPTW) was used to improve selection bias. Results: Chemotherapy use in UPS demonstrated worse survival in smaller tumors <5 cm (HR = 2.65, 95%-CI = 1.19–5.92, p = 0.018) and 5–10 cm tumors (HR = 1.45, 95%-CI = 1.03–2.04, p = 0.031). In larger UPS tumors (>10 cm), a directionally protective association observed in matched analysis attenuated after inverse probability of treatment weighting (IPTW) (HR = 0.82, 95%-CI = 0.60–1.12, p = 0.211). Fibromyxosarcoma 5–10 cm tumors demonstrated worse survival with chemotherapy (matched HR = 3.74, 95%-CI = 2.30–6.10, p < 0.001), which remained consistent after IPTW (HR = 4.47, 95%-CI = 2.63–7.60, p < 0.001), along with >10 cm tumors (IPTW HR = 2.16, 95%-CI = 1.07–4.34, p = 0.031). DDLPS >10 cm tumors demonstrated a directionally harmful association (HR = 1.49, 95%-CI = 0.96–2.29, p = 0.073). Synovial sarcoma 5–10 cm tumors demonstrated a directionally protective trend that remained statistically non-significant across analyses. Conclusions: The effect of chemotherapy on survival in localized STS depends on both histologic subtype and tumor size. However, subgroup estimates with confidence intervals approaching 1.0 should be interpreted cautiously. Full article

The Murine Double Minute 2 (MDM2) gene encodes an E3 ubiquitin ligase that negatively regulates the tumor suppressor p53, maintaining low p53 levels through ubiquitination and proteasomal degradation. MDM2 overexpression in various malignancies leads to reduced p53 activity, contributing to tumor initiation and resistance to therapies. As such, MDM2 is a promising target for drug development. Innovative small-molecule inhibitors are being designed to disrupt the MDM2-p53 interaction, thereby restoring p53’s tumor-suppressive functions. This review focuses on clinical trials evaluating MDM2 inhibition for cancer therapy. MDM2 exerts its oncogenic effects primarily through its interaction with p53 but also has p53-independent functions involved in cell cycle progression and DNA repair. Elevated MDM2 expression is associated with poor prognosis across various cancers, including dedifferentiated liposarcoma, breast cancer, and glioblastoma. Targeting MDM2 with inhibitors has shown promising potential in clinical development, aiming to reactivate p53’s functions in tumors with wild-type TP53, improving therapeutic outcomes in cancer treatment. Full article

Background and Objectives: Primary mesenteric liposarcoma (LPS) is an exceptionally rare malignancy, with most literature data limited to isolated case reports or small series. This papers aims to evaluate the clinicopathological features, treatment outcomes, and prognostic factors in patients with mesenteric LPS. Materials and Methods: Thirteen patients diagnosed with primary mesenteric LPS between 2010 and 2022 were retrospectively analyzed. Data included demographics, tumor location, histological subtype, surgical treatment, recurrence, and survival. Results: The median age was 56 years (range, 22–74), with a slight male predominance (53.8%). Most tumors arose from the small bowel (53.8%) and colonic (38.5%) mesenteries, with one involving the gastric mesentery. The predominant histological subtypes were myxoid (46.1%) and dedifferentiated (23.1%). R0 resection was achieved in 76.9% of patients. During a median follow-up of 55.2 months, nine patients (69.2%) developed recurrence. Mortality was higher in patients with dedifferentiated LPS (66.7%) than in those with myxoid LPS (40%). Five-year survival rate was 100% in patients without recurrence and 28.6% in those with recurrence (p = 0.112, not significant). Patients who received adjuvant chemoradiotherapy suggested longer survival (110.7 vs. 46.2 months; p = 0.620). Conclusions: This 12-year study highlights the aggressive nature of mesenteric LPS, particularly the dedifferentiated subtype which showed the poorest prognosis. Complete resection remains the primary treatment; however, it has high recurrence rates. To diminish the catastrophic poor results of the postoperative period, multidisciplinary treatment strategies become a keystone. Full article

Background: Evidence of the real-world management of dedifferentiated liposarcoma (DDLPS) is limited by the patient size and coding. The objective of this study is to generate consensus expert opinion on locally advanced or metastatic DDLPS diagnosis, treatment, and unmet needs. Methods: A three-round Delphi consensus panel was conducted with 9 DDLPS clinical experts from November to December 2023. Expert panelists were recruited across academic specialty and traditional settings and US regions. The Delphi panel included two rounds of surveys followed by a consensus building workshop. Surveys contained multiple-choice and free response questions, and statements for level of agreement rating. Panelists rated each statement for level of agreement on a 9-point Likert scale. Statements with ≥75% of scores ≥ 7 achieved consensus, and those that did not achieve consensus agreement were modified or removed from subsequent testing. A virtual workshop was held to discuss areas which did not achieve consensus and refine previously agreed upon statements. Results: In total 25 consensus statements were developed by the Delphi panel. Survey 1 achieved 7 consensus statements across the areas of burden, treatment, and unmet needs of DDLPS. Survey 2 generated an additional 10 consensus statements. During the workshop, eight more statements achieved consensus, and four statements were refined for enhanced clarity and precision. The study findings are limited by the number of Delphi panel participants and consensus statements may not be fully representative of clinician perspectives across the US. Conclusions: Consensus areas identified by the Delphi panel help better understand the decision factors for surgical and non-surgical treatments and anticipated utilization. These results could be used to inform both drug development programs as well as care delivery challenges for liposarcoma patients. Full article

Background and Objectives: Prognostic evaluation for patients with liposarcoma and atypical lipomatous tumor is a complex process, considering the marked heterogeneity of this group of mesenchymal neoplasms. At the moment, guidelines recommend determining the tumor’s histological grade by documenting proliferative activity and the presence of tumor necrosis. Proliferative intratumoral activity is an important tool for risk estimation; therefore, it has been studied using both conventional histopathological mitotic count and analysis of the Ki67 proliferation index. The histopathological subtype is of utmost importance for assessing disease progression and survival for liposarcoma, as pleomorphic and dedifferentiated subtypes often have an unfavorable evolution, while a well-differentiated liposarcoma/atypical lipomatous tumor clinically behaves like locally aggressive neoplasms. In a previous study that we published, we created an algorithm with prognostic–predictive significance for liposarcoma, the LEMON (Liposarcoma Evaluation Mitosis Origin Necrosis) two-tiered system, integrating histological subtype, mitotic activity, and tumor necrosis. The aims of the present study are to depict the overall survival of patients with liposarcoma stratified by Kaplan–Meier analysis categorized by tumor histological grade and to underscore the clinical utility of the LEMON score in risk stratification segregating indolent (low-risk) from aggressive (high-risk) liposarcomas across histological grades. Materials and Methods: We carried out a retrospective multicenter study on 99 patients diagnosed with primary liposarcoma between 2009 and 2023 who were followed up to assess the presence of metastases and their survival period. We performed Kaplan–Meier analysis for overall survival. Proliferative tumor activity was analyzed using conventional histopathological examination and Ki67 immunostaining, and the methods’ sensitivity was compared using Bland–Altman analysis. Results: In this respect, tumors with a higher histological grade were associated with worse survival with statistically significant differences in survival between G1 and G3 liposarcomas. Ki67 immunostaining proved to be more sensitive in detecting cellular proliferation compared to histologically observed mitoses. Furthermore, the risk stratification of cases by tumor grade and LEMON score effectively segregates indolent lesions (low risk) from aggressive subtypes (high risk) and may have clinical utility. Conclusions: The histopathological examination for liposarcoma subtype, mitotic index, and tumor necrosis is crucial for assessing the risk of progressive disease and the overall survival of patients. This study focuses on describing the prognostic significance of tumor grade, emphasizing proliferative activity evaluation. The clinical utility of a two-tiered system classifying liposarcomas into “low-risk” and “high-risk” lesions can be evaluated by providing an overview of overall survival in relation to histological grade and LEMON risk score. Risk stratification is particularly important in identifying the patients with liposarcoma who may benefit from intensified surveillance or adjuvant therapies. Full article

High-grade sarcomas often lack typical morphological features and exhibit no clear differentiation, often leading to a diagnosis of undifferentiated sarcoma (US). Pleomorphic leiomyosarcoma (PLMS) is a high-grade sarcoma consisting of a typical leiomyosarcoma (LMS) component alongside dedifferentiated high-grade areas. A few decades ago, PLMS was regarded as a subtype of high-grade sarcoma previously referred to as malignant fibrous histiocytoma; it is now classified as a variant of LMS. The mechanisms underlying myogenic differentiation and their relevance to the pathological diagnosis of high-grade sarcomas remain poorly understood. To investigate the gene expression networks associated with myogenic differentiation, we employed Cap Analysis of Gene Expression (CAGE) to distinguish PLMS from other high-grade sarcoma subtypes. We analyzed 27 frozen high-grade sarcoma samples, comprising 10 PLMSs, 11 high-grade myxofibrosarcomas, 3 dedifferentiated liposarcomas, 2 USs, and 1 high-grade sarcoma not otherwise specified, using CAGE profiling. Hierarchical clustering based on differentially expressed genes identified by CAGE separated 7 of the 10 PLMSs from other high-grade sarcomas, while the remaining 3 PLMSs clustered with a single US case. CAGE analysis also revealed that the myostatin (MSTN) promoter (false discovery rate [FDR] < 0.05) was more strongly activated in the high-grade sarcoma group lacking morphological and immunohistochemical smooth muscle differentiation than in the PLMS group, whereas the alpha smooth muscle actin (ACTA2) promoter (FDR < 0.05) was more prominently activated in the PLMS group. Immunohistochemical analysis showed reduced or absent myostatin expression in PLMSs, in contrast to diffuse myostatin expression in other high-grade sarcomas. Smooth muscle actin, encoded by ACTA2, was expressed in all 10 PLMS cases but only in 11 of 17 other high-grade sarcomas. Furthermore, both conventional immunohistochemistry and double immunostaining revealed that myostatin and myogenic markers exhibited largely mutually exclusive expression patterns within these tumors. A validation study was performed using 59 soft tissue sarcoma cases, including 27 PLMSs and 16 LMSs. Loss or reduction in myostatin expression was confirmed in both LMS and PLMS, and the ratio of myostatin loss was comparable (62.5% in LMS vs. 63% in PLMS). Collectively, these findings suggest that myostatin contributes to smooth muscle differentiation in high-grade sarcomas and has potential utility as a diagnostic marker. Full article

Background: Dedifferentiated liposarcoma (DDLPS) is a rare, aggressive tumour with poor survival outcomes in advanced settings. This study assessed the incidence/prevalence, treatment patterns, survival, healthcare resource utilization (HCRU), and costs for DDLPS patients in Ontario, Canada. Methods: A retrospective cohort study was conducted among DDLPS patients between 2010 and 2022 using administrative databases. Overall survival, all-cause HCRU, and costs (2023 Canadian dollars, CAD) were compared based on advanced disease and resection status. Results: The overall incidence and cumulative prevalence of DDLPS was 0.465 and 1.995 per 100,000 people, respectively. Of all 611 DDLPS cases (64.3% male, median age [IQR]: 67 [57–76] years), 40.3% and 61.0% had advanced and unresected disease, respectively. The median overall survival (mOS) was 69 months [IQR = 15–151] for the entire cohort, but this was significantly lower for advanced and unresected disease (p < 0.0001). Among patients receiving systemic treatments (N = 117), 81.2% were prescribed doxorubicin as first-line treatment. All-cause healthcare costs (2023 CAD) amounted to CAD 34,448 per person-year (PPY), with inpatient hospitalizations being the highest cost driver at CAD 14,522 PPY and 0.8 inpatient hospitalization PPY for all years. Advanced disease had higher HCRU and costs. Conclusions: This is the first comprehensive real-world evidence study that quantifies the high mortality and cost burden associated with DDLPS in Canada. Full article

Calcifications in soft tissue tumors present critical diagnostic challenges in musculoskeletal imaging. Their presence and morphology can provide key clues for differentiating benign from malignant lesions, influencing both prognosis and management strategies. This pictorial review aims to explore the imaging characteristics, patterns, and implications of soft tissue calcifications, with a focus on distinguishing between benign and malignant soft tissue tumors based on the World Health Organization classification. A systematic evaluation of imaging findings in various soft tissue tumor subtypes, including adipocytic, smooth muscle, vascular, chondro-osseous, and tumors of uncertain differentiation, is presented. Additionally, non-neoplastic causes of soft tissue calcifications, such as metabolic and inflammatory conditions, are reviewed for comprehensive differential diagnosis. Our review shows that the presence, distribution, and morphology of calcifications, such as stippled, punctate, coarse, and amorphous patterns, play a crucial role in tumor characterization. Some important examples are phleboliths, which strongly suggest a benign hemangioma, while dystrophic calcification is more commonly associated with malignant entities such as synovial sarcoma and dedifferentiated liposarcoma. Peripheral calcifications with zonal distribution are characteristic of myositis ossificans, whereas central dense calcifications may indicate extra-skeletal osteosarcoma. The review also discusses the significance of calcifications in non-neoplastic conditions, such as calcific tendinitis, tumoral calcinosis, and metabolic diseases, which can mimic soft tissue tumors. Recognizing the imaging characteristics of soft tissue calcifications is essential for accurate tumor classification and appropriate clinical management. This review highlights the importance of integrating radiologic findings with clinical and histopathological data to avoid misdiagnosis and unnecessary interventions. Full article

There has been noteworthy progress in molecular characterisation and therapeutics in soft tissue sarcomas. Novel agents have gained regulatory approval by the FDA. Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with NTRK fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma. The FDA has also recently granted accelerated approval for autologous T-cell therapy with afami-cel in patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. There are other promising treatments that are still investigational, such as MDM2 and CDK4/6 inhibitors in well-/dedifferentiated liposarcoma, immune checkpoint inhibitors in the head and neck angiosarcoma and a subset of patients with undifferentiated pleomorphic sarcoma, and PARP inhibitors in leiomyosarcoma. The challenges in drug development in soft tissue sarcoma are due to the rarity and the molecular heterogeneity of the disease and the fact that many subtypes are associated with complex karyotypes or non-targetable molecular alterations. We believe that progress maybe possible with a better understanding of the complex biology, the development of novel compounds for difficult targets such as proteolysis targeting chimeras (Protacs), the utilisation of modern clinical trial designs, and enhanced collaboration of academia with industry to develop treatments with a strong biologic rationale. Full article

Retroperitoneal liposarcoma (RPLPS) is one of the most common histologic subtypes of soft tissue sarcoma (STS). Complete surgical resection remains the mainstay treatment, while the high rate of locoregional recurrence constitutes the predominant cause of mortality. Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are the most frequent subtypes of RPLPS and present amplified MDM2 gene as a hallmark. However, there are few reports evaluating the role of alternatively spliced MDM2 transcripts in RPLPS. In this study, we assessed MDM2-ALT2 expression levels in a cohort of RPLPS patients and evaluated the biological functions of the MDM2-ALT2 isoform in vitro in DDLPS cell lines. Using BaseScope™ and qPCR, we demonstrated that MDM2-Full Length (MDM2-FL) and MDM2-ALT2 expression levels were upregulated in RPLPS patient-derived tissue samples compared to normal adjacent to tumor tissue (NAT). DDLPS cells overexpressing MDM2-FL or MDM2-ALT2 had higher proliferation rates and increased migration and invasion capacities, as well as increased protein levels of p-AKT, mTOR, p70S6K, MMP2, and cJun. Simultaneous overexpression of MDM2-ALT2 and AKT silencing showed that AKT inhibition impaired p-p70S6K and MMP2 protein increased levels and led to significantly decreased proliferation and migration rates compared to cells overexpressing MDM2-ALT2 only. Taken together, our data suggest that MDM2-ALT2 may promote RPLPS progression. Full article

Sarcomas are a heterogeneous group of neoplasms that develop from bone and soft tissue. Approximately 80% of sarcomas affect soft tissue, with liposarcoma being one of the most common types, accounting for approximately 13–20% of all soft-tissue sarcomas. Per the World Health Organization, liposarcoma can be broadly classified into four different subtypes based on histologic examination: well-differentiated liposarcoma (WDLS)/atypical lipomatous tumors (ALT), dedifferentiated liposarcoma (DDLS), myxoid liposarcoma (MLS), and pleomorphic liposarcoma (PLS). WDLS/ALT is the most common liposarcoma subtype, accounting for approximately 31–33% of liposarcomas; DDLS accounts for 20%; MLS accounts for 19%; and PLS, the least common subtype, represents 7–8% of liposarcomas. Sarcoma diagnosis is challenging because of its rarity, intrinsic complexity, and diagnostic technological complexity. Sarcomas are misdiagnosed in approximately 30% of cases, leading to delays in diagnosis and access to appropriate therapy and clinical trials. Furthermore, treatment options are limited for those diagnosed with liposarcoma. This review discusses the epidemiology, pathology, and treatment options currently available for liposarcoma. Full article

Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive type of cancer primarily reported in humans, with no documented cases in animals. In this study, we present the first case of DDLPS in a wild amphibian species, Maculopaa medogensis. The tumor was discovered during a routine examination and diagnosed through a combination of advanced diagnostic methods, including micro-CT imaging, gross anatomical inspection, histological analysis, and immunohistochemistry. The tumor exhibited both well-differentiated and dedifferentiated components, characteristic of DDLPS, with evidence of tissue invasion and multiple metastases. Immunohistochemical analysis revealed the strong positive expression of markers such as S100A4, CDK4, MDM2, and CD34, while Leptin expression was negative, further confirming the diagnosis. This is the first reported case of DDLPS in a non-human species, expanding our understanding of cancer in wildlife and underscoring the significance of amphibians as environmental indicators. These findings provide valuable insights for veterinary medicine and wildlife conservation, particularly regarding the role of environmental stressors in cancer development. This study highlights the need for comprehensive diagnostic approaches in wildlife pathology. Full article

Atypical spindle cell/pleomorphic lipomatous tumor (ASCPLT) is a rare and recently described adipocytic neoplasm that primarily occurs in the subcutis of the limbs and limb girdles, particularly of middle-aged adults. It has locally recurrent potential if incompletely excised but no risk for distant metastasis. ASCPLT is histologically similar to spindle cell/pleomorphic lipoma and atypical lipomatous tumor and shows a mixture of atypical spindle cells, adipocytes, lipoblasts, floret-like multinucleated giant cells, and/or pleomorphic cells. It has been recently recognized that ASCPLT can undergo sarcomatous transformation. However, the biological significance of morphological sarcomatous transformation in ASCPLT remains uncertain. Immunohistochemically, the tumor cells show variable expression of CD34, S-100 protein, and desmin. Loss of nuclear Rb expression is observed in the majority of cases. ASCPLT lacks MDM2 gene amplification but can show RB1 gene deletion in a significant subset of cases. Complete surgical excision is the treatment of choice. This review provides an overview of the current knowledge on the clinicoradiological features, pathogenesis, histopathology, and treatment of ASCPLT. In addition, we will discuss the differential diagnosis of this new entity. Full article

The purpose of this study was to evaluate the predictive features of baseline F-18-fluorodeoxy-D-glucose positron emission tomography (¹⁸F-FDG PET)/computed tomography (CT) parameters in patients with dedifferentiated liposarcomas (DDLPSs) and well-differentiated liposarcomas (WDLPSs) receiving systemic treatment. A total of 24 patients with liposarcoma who underwent longitudinal ¹⁸F-FDG PET/CT in systemic therapy were included. All volumetric segmentation of each tumor section and semiquantitative imaging parameters were extracted from the axial field of view from both PET and CT images. Maximum, mean, and minimum standardized uptake values (SUVmax, SUVmean, and SUVmin), Hounsfield units (HUs), and their respective changes from baseline and posttreatment were calculated. The voxel values from unenhanced CT images were correlated with PET-derived parameters. The ¹⁸F-FDG uptake decreased by more than 56% on average in responders for both SUVmax and SUVmean in DDLPS. There was a decrease in HUmax in DDLPS among responders. Using AUC > 0.8 as a reasonable predictor, we found that the ratios of SUVmaxD/HUmean, SUVmaxD/HUmedian, and SUVmeanD/HUmedian at baseline were significant indicators of the response to treatment in patients with liposarcoma. The changes in SUVmean and not just SUVmax parameters could be considered as accurate tumor response indicators. For the first time, we introduced baseline SUV/HU ratios as a valuable diagnostic tool in predicting liposarcoma treatment outcomes. This ability was not revealed by classic semiquantitative PET or CT parameters at baseline. Full article