Liposarcoma Research Articles

Atypical Pleomorphic Lipomatous Tumor: Expanding Our Current Understanding in a Clinicopathologic Analysis of 64 Cases.

Atypical pleomorphic lipomatous tumor (APLT) is a recently recognized adipocytic neoplasm that lies on a spectrum with atypical spindle cell lipomatous tumor (ASCLT). APLT/ASCLT are included together in the fifth edition World Health Organization Classification of Soft Tissue and Bone Tumours; however limited data on APLT have emerged since its first description in 2017. This study aims to further define the clinicopathologic features of APLT in a large series of 64 cases. Histologic features and ancillary studies were reviewed, and clinical and follow-up data were obtained from referring institutions. Immunohistochemistry for MDM2, CDK4, CD34, Rb, S100, and desmin was performed in cases with available material. Patients were 24 females and 40 males, and the median age was 61 years (range, 20 to 89 y). Tumors arose in upper limb (33%), lower limb (31%), trunk (23%), head and neck (8%), breast (3%), and inguinal region (2%), with a median size of 5.4 cm (range, 1.5 to 14.5 cm). Tumor depth was mostly subcutaneous or deep/subfascial. Microscopically, APLTs were variably composed of atypical spindle and pleomorphic cells, adipocytes, and lipoblasts, often showing infiltrative growth, myxoid or collagenous stroma, and multinucleate floret cells. Mitoses were infrequent and necrosis was consistently absent. By immunohistochemistry, tumors expressed CD34 (63%), S100 (19%), and desmin (28%). APLT showed frequent loss of Rb (79%; 46/58). Rare cases showed staining for MDM2 (2%) or CDK4 (12%); however, fluorescence in situ hybridization was negative for MDM2 amplification in all cases tested (0/22). Follow-up in 28 patients (median duration: 21 mo) revealed a single patient with local recurrence (4%); no patient developed metastatic disease. Despite its frequently infiltrative growth, nuclear pleomorphism, and hypercellularity which can mimic sarcoma, APLT behaves in an indolent manner and should be distinguished from its more aggressive mimics, including atypical lipomatous tumor/well-differentiated liposarcoma and pleomorphic liposarcoma. Immunohistochemistry for CD34, S100, desmin, and Rb (demonstrating loss), as well as exclusion of MDM2 amplification, can support the diagnosis.

54. Genome-wide copy number abnormalities in lipomatous neoplasms detected with chromosomal microarray: Is gain of MDM2 necessary for 12q amplification characterization and prognostication?

Lipomatous neoplasms (LN) are a heterogeneous group of adipocytic tumors, including benign lipomas, low-grade atypical lipomatous tumors (ALT), and high-grade liposarcomas [sub-grouped into de-differentiated liposarcomas (DDLS) evolved from ALT and pleomorphic liposarcomas]. Using histological (H&E) approaches, ALT are often difficult to distinguish from benign lipomas, while DDLS are challenging to differentiate from other high-grade sarcomas. Given this diagnostic challenge, molecular signatures can aid in the characterization/prognostication of these tumors and have shown MDM2 and/or CDK4 amplification in ALT and DDLS tumors, with MDM2 being recognized as the likely “driver” gene, based on fluorescence in situ hybridization (FISH) studies. We describe an atypical lipomatous tumor having features of spindle cell lipoma. A genome-wide copy number microarray (MA) assessment showed amplification on 3q (6-10 copies; 4 contiguous regions) and 12q (6-11 copies; 7 contiguous regions), with the 12q amplification regions being juxtaposed to, but not encompassing, the MDM2 gene. A FISH test for this specimen, using a commercial probe, yielded an “MDM2” positive result (albeit with smaller signals). This “discrepant” finding is not unexpected since the 209 kb FISH probe encompasses loci other than MDM2, including the CPM gene (which is amplified in the MA). To our knowledge, this is the first documented case of 12q amplification in a LN that does not encompass the MDM2 gene. Moreover, in our experience (n= 44 tumors), 100% of the 12q (MDM2/CPM) amplified LN have shown additional imbalances using MA methods [including, but not limited to, amplifications of 1q (60%); CDK4 and/or HMGA2 (58%), & HMGA2 (25%)]. In summary, our data underscore the advantages of using MA to evaluate LN. Moreover, this rare tumor having 12q15 amplification that does not encompass the MDM2 gene may provide new insight as to the role of MDM2 (versus possibly CPM) as a “driver” for ALT/DDLS tumor formation/progression.

Recent Advancement in Atypical Lipomatous Tumor Research.

After Evans and colleagues identified the lipomatous tumor with a well-differentiated liposarcoma in a subcutaneous location or within a muscle layer, namely, atypical lipomatous tumor (ALT), this malignancy has been investigated to clarify the characteristics of clinical behavior and genomic changes. As one of the important issues for clinicians, it is a hot topic of how to distinguish ALT from benign lipoma in the clinical aspect. Recent studies revealed novel findings to clarify the risk factor for the diagnosis of ALT and molecular targets for the treatment of ALT. Clinical characteristics of superficial-type ALT well reflect the subcutaneous location of the tumor and are slightly different compared to deep-type ALT, such as tumor size. In addition, there has been a recent discovery of novel findings in ALT-related genes, namely, HMG2A (high mobility group protein 2a), YEATS4 (YEATS domain containing 4), and CPM (Carboxypeptidase M). Recent updates on treatment for advanced ALT are well developed including immunotherapy and conducting clinical trials. Finally, this review introduces one of the hot topics of ALT research focused on epigenetic changes: their attention in recent updates on clinical characteristics and the novel discovery of related genes, treatment, and epigenetic modifications in atypical lipomatous tumors.

Recent advances in the understanding and management of liposarcoma.

Liposarcomas are a common subfamily of soft tissue sarcoma with several subtypes recognized by the World Health Organization: atypical lipomatous tumors (ALT)/well-differentiated liposarcoma (WDLPS), dedifferentiated liposarcoma (DDLPS), myxoid liposarcoma (MLPS), pleomorphic liposarcoma (PLPS), and myxoid pleomorphic liposarcoma (MPLPS). Despite shared adipocytic features among liposarcomas, the clinical approach to each subtype differs based on histology, location, clinical behavior, and specific oncogenic drivers. In this review, we highlight subtype-specific molecular features with the potential to generate novel therapies. We discuss recent clinical trials investigating the use of preoperative radiation therapy for retroperitoneal liposarcoma, chemotherapy, small molecule inhibitors, and innovative immunotherapy approaches and describe how we incorporate these advancements into the management of liposarcoma.

Atypical lipomatous tumor with osteoid metaplasia – a rare occurrence

The presence of metaplastic ossification within a atypical lipomatous tumour /well differentiated Liposarcoma (ALT/WDLPS) is a rare occurrence. We report a case ALT/WDLPS with unusual extensive metaplastic bone formation in a 30 years female who complained of swelling in the right shoulder for the past one and a half years.
 Bangladesh Journal of Medical Science Vol.20(1) 2021 p.197-199

Common Differential Diagnostic Issues in Soft Tissue Pathology

Abstract In this review, we discuss 4 differential diagnostic considerations that commonly arise in soft tissue pathology, namely, separating myxoid liposarcoma from myxofibrosarcoma, nodular fasciitis from a host of spindle cell sarcoma types, fibrous histiocytoma from dermatofibrosarcoma protuberans, and atypical lipomatous tumor from several nonneoplastic congeners. These topics were chosen as means to highlight several areas of soft tissue pathology, focusing on some of the most common issues in soft tissue pathology.

Mediastinal Liposarcoma: Case Report and Literature Review

Liposarcomas (LS) are the second most common type of soft tissue malignancies in adults; they arise from mesenchymal cells and account for 1% of all adult cancers and 15% of all pediatric cancers. The site of origin can be from anywhere there is fat in the human body. LS are classified based on the primary site of origin, and mediastinal LS are extremely rare. When mediastinal neoplasms are stratified based on histology, they represent less than 1% of all mediastinal tumors. To date, less than 150 cases have been reported in the English literature. This article aims to present an unusual case of an extremely rare malignancy and perform a systematic review of the latest literature. In this report, our group is documenting the presentation, management, and outcome of a 65-year-old male patient with a massive anterior mediastinal primary LS. The tumor was displacing the mediastinum into the right chest, occupying most of the left chest, and pushing the diaphragm into the abdomen. Mediastinal liposarcomas are extremely rare malignancies and can prove to be challenging to diagnose and treat. Aggressive surgical treatment with R0 resection is the gold standard, however, tumor biology in many cases is associated with variable growth rates and encroachment of adjacent vital structures and blood vessels. When complex anatomical structures preclude an R0 resection, there is a high incidence of local recurrence. In cases where there is a high risk of recurrence, radiotherapy is indicated and chemotherapy has a more limited role.

Diagnostic Significance of Fine Needle Aspiration Smear and Cell Block Study in Skin and Subcutaneous Nodules

Background: Evaluation of patients with skin or subcutaneous nodules, especially if it was multiple represents a major problem for the clinicians. But with full investigations, the problem becomes easier. However, the final diagnosis depends on pathological reports of tissue biopsy [1]. The easy access of the skin nodule provides the soil for performance fine needle aspiration cytology and taking the samples by the pathologists, or the clinicians. Smear cytology gives many defaults[2]. Performance of cell blocks was a trial to avoid these defaults and improve the diagnosis. The results of smear and cell block examinations were compared with examination of tissue biopsies. Methodology: Two hundred twenty five skin and subcutaneous nodules from 225 patients underwent the material of this study. The patients were selected from those referred topathology department, faculty of medicine Zagazig University, through the period between January 2018 and December 2020. Fine needle aspirations were performed utilizing the ordinary 22-gaugeneedle 10 cc syringes. Cell blocks were done utilizing the remnants in the syringe after performance of the smears. Histopathological examination was done using biopsies taken later on. Results: According to tissue biopsy examination: Benign lesions constitute the commonest findings (180 cases) 80% 0f cases: Lipoma35 cases (15.5%), Adipose tissue30 cases (13.3%), Fibrolipoma 20 cases (8.8%), Fibroma20 cases (8.8%), Juvenile fibroma 5 cases (2.2%), Neurofibroma 5 cases (2.2%), Sebaceous cyst in 25 cases (11.1%), Implantation cyst, or dermoid cyst 20 cases (8.8%), Pilomatrixoma 5 cases (2.2%), Seborrheic keratosis 10 cases (4.4%), Madura foot (actinomycosis) 5 cases (2.2%). Intermediate lesions: Atypical lipoma 5 cases (2.2%). Malignant lesions 25 cases (11.11%): Basal cell carcinoma10 cases (4.4%), squamous cell carcinoma 10 cases (4.4%), Basosquamous cell carcinoma 5cases (2.2%). For the FNAC smear examination, the sensitivity test was: 83.01%, the specificity test was: 16.66%. For the cell blocks examination, the sensitivity test was: 97.77%, specificity test was: 100%. Conclusion: Smear cytology is an easy, rapid test for diagnosis of skin nodule and performance of cell blocks improves its sensitivity and specificity outcome, but both must be attempted, because smear may be inefficient for some cases while cell block cannot be performed others.

A Retrospective Study of Superficial Type Atypical Lipomatous Tumor.

Atypical lipomatous tumor (ALT) has been defined as a well-differentiated liposarcoma exhibiting a higher frequency of a local recurrence after surgical resection. ALT is mainly classified into deep type and superficial type. Compared with deep type ALT, superficial type ALT is rarely observed. One of the most important issues is that little has been known about superficial type ALT and it is not easy to predict the presence of superficial type ALT before surgical resection. To clarify the clinical manifestations of superficial type ALT, we examined 15 cases with superficial type ALT and 118 cases with benign lipoma, and analyzed their differences in clinical characteristics and the findings of MRI test. In clinical characteristics, the tumor size of superficial type ALT was significantly greater than that of benign lipoma, and superficial type ALT showed a significantly higher frequency of the tumor size of more than 4 cm. Superficial type ALT exhibited poor tumor mobility and hardness with elastic soft. In addition, a significantly higher frequency of tumor location of superficial type ALT was observed in extremities. Among tumor sites at the trunk, buttocks, and shoulder were high frequent location in superficial type ALT. In an MRI examination, superficial type ALT exhibited a significantly higher frequency of the septal structures compared with benign lipoma. The combinations of clinical characteristics, including physical examinations, MRI, and histological examinations, are helpful for the diagnosis of superficial type ALT.

Development and validation of a novel prognostic model for long-term overall survival in liposarcoma patients: a population-based study.

ObjectiveTo construct and validate a clinically accurate and histology-specific nomogram to predict overall survival (OS) among liposarcoma (LPS) patients.MethodsWe retrospectively screened eligible patients with LPS diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results database. We screened independent predictors for the nomogram using univariate and multivariate analyses. We then evaluated the prognostic accuracy of the nomogram by receiver operating characteristic (ROC) curve analysis and Harrell’s concordance index. The prognostic performances of the nomogram and the American Joint Committee on Cancer (AJCC) seventh edition staging system were compared using integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision curve analyses (DCA).ResultsA novel nomogram was developed using independent prognostic variables, which exhibited excellent predictive performances for 3- and 5-year OS according to ROC curves. The C-index proved that the proposed nomogram had better prognostic accuracy for LPS than the traditional AJCC system, while the NRI, IDI, and DCA of the nomogram indicated better clinical net benefit.ConclusionsThe proposed nomogram can predict 3- and 5-year OS of LPS patients with reliable accuracy and may thus help clinicians to develop appropriate clinical therapies and counseling strategies to prolong the life expectancy of these patients.

A single institutional experience treating adipocytic tumors: incidence, disease-related outcomes, and the clinical significance of MDM2 analysis.

Adipocytic tumors exist either as a benign or malignant form. The benign variant, lipoma, is composed of normal fat tissue. Lipomas typically develop from superficial fat cells beneath the skin or mucous membranes. Liposarcoma, the malignant counterpart, often develops in deeper tissues and is the most commonly diagnosed Soft Tissue Sarcoma (STS), comprising at least 20% of adult STS. However, malignant tumors of fatty origin exist as a spectrum of diagnoses, each carrying a unique risk of recurrence, metastasis, and longterm survival. The World Health Organization classifies liposarcomas into five categories: i) Atypical Lipomatous Tumors/Well Differentiated (ALT/WD); Ii) Dedifferentiated (ALT/DD); Iii) Myxoid; Iv) Round cell; and v) Pleomorphic. Lipomatous tumors often exhibit different immunohistochemical patterns. Benign lipomas are distinguished by the absence of Murine Double-Minute 2 (MDM2) amplification. Similarly, ALT/WD, classically defined as a low-grade and locally aggressive tumor, demonstrates consistent patterns of MDM2 amplification. Some studies suggest 10% of ALT/WD progress to the highgrade DD form, with others report a dedifferentiation rate of as high as 20% for primary ALT/WD based on location. The ALT/DD subtype is aggressive and has a high capacity to metastasize. While the mechanism of pathogenesis of ALT/DD metastasis is unknown, previous studies suggest that increased MDM2 amplification may play a role. This study sought to evaluate a single institutional experience treating the entire spectrum of lipomatous tumors and describe utilization patterns of MDM2 testing. The group hypothesized: i) Atypical Lipomatous Tumors (ALT), which include ALT/DD and ALT/WD, would exhibit a higher rate of local recurrence than lipomas with no significantly increased incidence of metastases; and ii) at least 50% of our MDM2 testing of ALT would prove positive for the MDM2 overamplification. This study retrospectively reviewed 105 cases (66 lipomas, 27 ALTs, 12 liposarcomas) of patients who underwent lipomatous tumor excision at our institution from 2013 to 2017. Twenty-five tumors (6 lipomas, 18 ALT, 1 liposarcoma) were tested for MDM2 amplification. Three of the tested tumors recurred (2 ALT, 1 liposarcoma), and each exhibited MDM2 overamplification. Five tumors (5 liposarcoma) developed late metastases. These data suggest that although ALT is associated with a higher rate of local recurrence, metastases are quite rare. Additionally, the data demonstrate a high rate of positive MDM2 testing (76%) based on clinical and imaging characteristics of the tumors.

MRI-based radiomics to predict lipomatous soft tissue tumors malignancy: a pilot study

ObjectivesTo develop and validate a MRI-based radiomic method to predict malignancies in lipomatous soft tissue tumors.MethodsThis retrospective study searched in the database of our pathology department, data from patients with lipomatous soft tissue tumors, with histology and gadolinium-contrast enhanced T1w MR images, obtained from 56 centers with non-uniform protocols. For each tumor, 87 radiomic features were extracted by two independent observers to evaluate the inter-observer reproducibility. A reduction of learning base dimension was performed from reproducibility and relevancy criteria. A model was subsequently prototyped using a linear support vector machine to predict malignant lesions.ResultsEighty-one subjects with lipomatous soft tissue tumors including 40 lipomas and 41 atypical lipomatous tumors or well-differentiated liposarcomas with fat-suppressed T1w contrast enhanced MR images available were retrospectively enrolled. Based on a Pearson’s correlation coefficient threshold at 0.8, 55 out of 87 (63.2%) radiomic features were considered reproducible. Further introduction of relevancy finally selected 35 radiomic features to be integrated in the model. To predict malignant tumors, model diagnostic performances were as follow: AUROC = 0.96; sensitivity = 100%; specificity = 90%; positive predictive value = 90.9%; negative predictive value = 100% and overall accuracy = 95.0%.ConclusionThis work demonstrates that radiomics allows to predict malignancy in soft tissue lipomatous tumors with routinely used MR acquisition in clinical oncology. These encouraging results need to be further confirmed in an external validation population.

A case of atypical lipomatous tumor with MDM2 gene amplification in the submandibular region

A case of atypical lipomatous tumor with MDM2 gene amplification in the submandibular region

What Are the Results of Resection of Localized Dedifferentiated Liposarcomas in the Extremities?

Dedifferentiated liposarcoma (DDLPS) is a rare malignancy that transitions from an atypical lipomatous tumor to a sarcoma with a variable morphologic appearance. The behavior of this tumor in the retroperitoneum is aggressive, but the behavior of DDLPS in the extremities is less well-defined because it is rare. Few reports have assessed the imaging features and clinical outcomes of primary DDLPS in the extremities. In patients with primary DDLPS of the extremity, we asked the following questions: (1) How frequently do additional primary malignancies occur in patients with DDLPS? (2) What is the rate of overall survival, metastases, and local recurrence in DDLPS? (3) What factors are associated with metastasis-free survival and local recurrence in DDLPS? We defined DDLPS as a biphasic neoplasm that transitions from an atypical lipomatous tumor (ALT) to a sarcoma of variable morphologic appearance and histologic grades. We retrospectively evaluated the medical records of patients with DDLPS of the extremities who underwent surgery in our institution between 2003 and 2017. During that time, 16 patients were treated for this diagnosis; one was excluded from this study because the patient did not have an MRI, leaving 15 patients (nine men, six women; their median [range] age was 67 years [42 to 87]) for evaluation. All had a minimum of 2 years follow-up (median [range] 54 months [25 to 136]); 14 of 15 have been seen in the last 5 years (one patient, who was doing well at the time, was lost after 9 years of follow-up). In 11 patients, MRI demonstrated two components: an ALT component with high intensity on both T1-weighed and T2-weighted sequences and a dedifferentiated component low-to-intermediate intensity on T1-weighed and heterogeneous hyperintensity on T2-weighted sequence. Nine patients were evaluated using 2-deoxy-2-18F-fluoro-D-glucose positron emission tomography (FDG-PET) combined with CT (PET/CT). PET/CT showed a biphasic pattern with a close relationship to MRI findings. The dedifferentiated component presented with high FDG uptake (median [range] maximum standardized uptake value 5.1 [1.9 to 22.6]), while the atypical lipomatous tumor component showed almost no FDG uptake. In all patients, immunohistochemical studies of p16 and cyclin-dependent kinase-4 (CDK4) were investigated. Positive staining for both p16 and CDK4 were seen in 13 of 15 patients.We retrospectively evaluated the electronic medical records of all patients in our institution for the presence of additional primary malignancies, local recurrence-free survival, metastasis-free survival, and overall survival. The survival rate was estimated using the Kaplan-Meier method. The Wilcoxon exact test was used to determine the prognostic importance of the following survival variables: age, sex, maximum tumor size, radiotherapy, and surgical margin. Seven additional primary malignancies developed in five of 15 patients (two lung cancers, two sarcomas, one renal cell cancer, one uterine cancer, and one non-Hodgkin lymphoma). The 3- and 5-year metastasis-free survival rates were 86% (95% CI 0.67 to 1.00) and 75% (95% CI 0.49 to 1.00), respectively. With the numbers available, we found no factors associated with metastasis-free survival. The 3- and 5-year overall survival rates were 100% (95% CI 1.00 to 1.00) and 88% (95% CI 0.65 to 1.00), respectively. Three of 15 patients had local recurrence. The 3- and 5-year local recurrence-free survival rates were 86% (95% CI 0.67 to 1.00) and 75% (95% CI 0.49 to 1.00), respectively. Large (> 15 cm) tumors were more likely to have a local recurrence (p = 0.04). In this small series, we found that the extremities are a favorable site for DDLPS compared with the retroperitoneum, although we did not directly compare the two sites. This rare tumor has a relatively high likelihood of being associated with other malignancies. We believe patients should be assessed and monitored carefully for this possibility. In the future, larger studies are needed to better define predictors of local recurrence, although the tumor's size may be associated with a greater propensity for local recurrence. Level II, prognostic study.

Primary Myxoid Liposarcoma of the Lower Back in an Adult Female Patient: An Extremely Rare Presentation

Myxoid liposarcoma is the second most common type of liposarcoma that typically presents in the lower extremities and has a predilection for men. Manifestation of this tumor in the lower back is rare. We report the first known case of an adult woman presenting with a soft tissue mass in her lower back. Following excision and further workup, the mass was positive for rearrangements of the DDIT3 ( CHOP ) gene at the 12q13 locus, consistent with the diagnosis of a myxoid liposarcoma. The tumor was noted to be intramuscular and extended into the margins, requiring re-excision at the previous resection site. Biopsy of the re-excised area was negative for evidence of residual myxoid liposarcoma. We report this case to highlight the importance of considering myxoid liposarcoma as a differential diagnosis in soft tissue masses presenting in the lower back. J Med Cases. 2020;11(11):342-344 doi: https://doi.org/10.14740/jmc3558

Cytopathology of myxofibrosarcoma: a study of 66 cases and literature review

Myxofibrosarcoma is one of the more common sarcomas encountered in adults. A search was made of our cytopathology and surgical pathology databases for cases diagnosed as myxofibrosarcoma (MyxoFS). FNA biopsy smears and cell block were performed and examined using standard techniques. Sixty-six cases were retrieved from patients aged 40 to 94 years (mean: 67 years), with a male:female ratio of 1.4:1. Forty-seven (71%) were primary neoplasms, 13 (20%) locally recurrent, and 6 (9%) metastasis. Lower extremity was the most common site 38 (58%) cases, followed by upper extremity and trunk (each 13 [20%] cases), 1 head/neck, and 1 pleural-based mass. Forty-two (64%) cases were specifically/correctly diagnosed as MyxoFS. Thirteen (20%) were diagnosed as undifferentiated pleomorphic sarcoma (UPS), 3 (4.5%) as myxoid neoplasm, 2 (3%) as myxoid sarcoma, and 1 (1.5%) sarcoma, not otherwise specified. As most were examples of high-grade (HG) MyxoFS, cytomorphology contained pleomorphic and spindled cells set in a variable amount of myxoid stroma. Arborizing capillaries were common, and pseudolipoblasts were uncommon. All cases interpreted as UPS were HG MyxoFS histologically. Five (7.5%) cases-pleomorphic liposarcoma (3), solitary fibrous tumor (1), and atypical lipoma (1)-were mistakenly diagnosed. Ancillary immunohistochemistry played a minor role in diagnostic assessment. MyxoFS was accurately interpreted using FNA biopsy in about two thirds of cases. One fifth were misinterpreted as UPS due to the absence/near absence of myxoid stroma, which varies considerably in the definition of this neoplasm.

Angiolipoma-like Atypical Lipomatous Tumor/Welldifferentiated Liposarcoma

Angiolipoma-like Atypical Lipomatous Tumor/Welldifferentiated Liposarcoma

Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas

Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib’s efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management.

Abstract 5185: Analysis of the role of FGFR signaling in liposarcomas: Dual targeting of FGFR and MDM2 is synergistic

Abstract Clinical trials have shown the benefits of FGFR inhibitors; notably, the oral pan-FGFR inhibitor JNJ-42756493 (erdafitinib) has recently been the first FGFR kinase inhibitor to receive US FDA approval for the treatment of patients with advanced or metastatic urothelial carcinoma. Our objectives were to show that the FGFR pathway is involved in liposarcoma (LPS) pathogenesis and to investigate the therapeutic potential of erdafitinib for LPS patients. LPS is the most common soft tissue sarcoma. Among LPS, well-differentiated/dedifferentiated LPS (WD/DDLPS) are the most frequent types. DDLPS have metastatic potential and a poor prognosis with a five-year mortality rate of 30%. Standard chemotherapies are inefficient and new therapeutic options are needed. FRS2, a crucial adaptor protein of the FGFR signaling pathway is overexpressed in most WD/DDLPS suggesting involvement of the FGFR pathway in LPS tumorigenesis. Immunohistochemistry was used to perform an exhaustive analysis of the expression pattern of FGFR1-4 in WD/DDLPS both in a large collection of 421 primary tumors and in our in-house panel of validated human WDLPS and DDLPS cell lines. Cells were exposed to erdafitinib - as a single agent or in combination - and apoptosis and signalling pathway perturbations were monitored by flow cytometry and western blotting. Xenograft mouse models were used to confirm our in vitro results in the in vivo setting. We have detected a high expression of FGFR1 and/or FGFR4 in a significant percentage of WDLPS and DDLPS and demonstrated that this expression is correlated with poor prognosis. Exposure of LPS cells to erdafitinib induced a decrease in cell viability, cell cycle arrest in G1 and apoptosis. Erdafitinib treatment had a strong inhibitory effect on the ERK1/2 pathway whereas the PI3K/AKT pathway was less affected. The PI3K/mTOR antagonist BEZ235 was not synergistic with erdafitinib in DDLPS cells. MDM2 overexpression being the hallmark of WD/DDLPS, we investigated the effects of the MDM2-TP53 interaction inhibitor RG7388 (idasanutlin) in combination with erdafitinib. Interestingly, we found that the combination of RG7388 and erdafitinib exerts a highly synergistic effect on both viability and apoptosis in all our WDLPS and DDLPS cell lines. We are currently investigating the mechanics of the synergy between the FGFR and the MDM2 antagonists. We confirmed the inhibitory effect of erdafitinib on tumor growth using a DDLPS xenograft model. Finally and importantly, we report the efficacy of FGFR inhibition in two metastatic DDLPS patients heavily pretreated and refractory to several lines of treatment with notably one patient on erdafitinib showing stable disease for 15 weeks. In conclusion, we have shown that the FGFR pathway has therapeutic potential for a subset of DDLPS patients and that FGFR expression might constitute a powerful biomarker to select patients for clinical trials testing FGFR inhibitors. Citation Format: Bérengère Dadone-Montaudié, Audrey Laroche-Clary, Aline Mongis, Vanessa Chaire, Ilaria Di Mauro, Renaud Schiappa, Emmanuel Chamorey, Bertucci François, Florence Pedeutour, Finetti Pascal, Jean-François Michiels, Antoine Italiano, Laurence Bianchini. Analysis of the role of FGFR signaling in liposarcomas: Dual targeting of FGFR and MDM2 is synergistic [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5185.

Abstract 3864: A single-center retrospective study of the immune landscape in patients with untreated liposarcoma (LS) with long-term follow-up

Abstract Background: Liposarcoma (LS) is one of the most common soft tissue sarcoma subtypes. The aim of this study was to evaluate the immune landscape along with potential biomarkers in untreated LS tumors from University of Washington (UW) prior to 2018 in relation to patient outcomes. Methods: We performed a retrospective search of UW/Fred Hutchinson Cancer Research Center (FHCRC) CASIS database to identify patients with available untreated formalin fixed paraffin embedded (FFPE) LS tumor samples who were diagnosed prior to 2018. Using the immunoSEQ® Assay (Adaptive Biotechnologies, Seattle, WA), we analyzed the T-cell receptor (TCR) Vβ to describe T-cell repertoire properties. We also used the ImmunoPrism platform (Cofactor Genomics, San Francisco, CA) to quantify the immune cell composition in these tumors. Results: 61 patients with appropriate and available tumors were identified. The median age was 71yrs, and the mean tumor size was 21.18 cm. Tumors were high grade in 34.4% and low grade in 26.2% of cases. Recurrences were seen in 60.7% of patients with a mean recurrence free survival of 41.48 months. 47.5% of patients were alive at the time of our data cutoff with a mean overall survival of 45.83 months. Survival was negatively associated with age and the presence of multiple tumors at the time of surgery. Using the immunoSEQ Assay, we found that the number of infiltrating T cells amongst samples was variable, with a mean T-cell fraction of 9.5% (±11.9). The clonality of the T-cell repertoire was low in most cases, with a mean score of 0.066 (±0.0366). Interestingly, below median T-cell fraction with above median repertoire of clonality together were associated with worse patient outcomes (HR p-value=2.74e-04). Using the ImmunoPrism platform, we found the mean percentage of immune cell subsets in the samples (±std): CD4+ 5.5%(±4.5), CD8+ 7.1% (±10.3), CD19+ 4.7% (±10.4), CD14+ 7.6% (±7.6), CD56+ 5.4% (±4.5), M1 macrophage 0.1% (±0.3), M2 macrophage 2.3% (±1.6), and Treg 4.2 (±6.2%). The mean percentage of immune cells overall was 36.9% (±21.8). Gene expression was statistically lower in patients who recurred before three years: PD-1 (p=0.003), ICOS (p=0.006), BTLA (p=0.033), and CTLA-4 (p=0.018); suggesting a protective effect of a naturally occurring immune response. Further, hierarchical clustering showed the relationship in expression between PD-1, ICOS, BTLA, and ICOS. Variable selection and shrinkage (to account for possible overfitting) using the lasso showed that increased infiltration by CD14+ monocytes and M2-macrophages predicted worse outcomes. Conclusions: LS often has a low T-cell clonality. Low T-cell fraction with high clonality corresponds to worse patient outcomes. Patients with higher expression of PD-1, ICOS, BTLA, and CTLA-4 were more likely to recur after three years vs. patients with lower expression levels. Patients with fewer monocyte and macrophage tumor infiltrates have better outcomes. Citation Format: Brett A. Schroeder, Natalie A. LaFranzo, Bonnie J. LaFleur, Kevin C. Flanagan, Rachel M. Gittelman, Julie Rytlewski, Seth M. Pollack. A single-center retrospective study of the immune landscape in patients with untreated liposarcoma (LS) with long-term follow-up [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3864.