Dedifferentiated Liposarcoma Research Articles

Giant Retroperitoneal Dedifferentiated Liposarcoma: A Case Report

Summary Retroperitoneal soft tissue sarcomas comprise a relatively rare entity with incidence rates of less than 1% of all malignancies. The surgical treatment of these tumors is challenging. We present a case of a 70-year-old patient who underwent radical surgery at the Department of Surgical Oncology at the University Hospital in Pleven for giant dedifferentiated liposarcoma. The patient presented with cachexia, anemia, dull abdominal pain, and a huge abdominal mass. After ultrasound and CT, the tumor was assessed as resectable. The removed tumor mass weighed 5.7 kg. Nowadays, complete resection of such tumors remains the most important predictive factor for local recurrence and overall survival.

Broadening the spectrum of NTRK rearranged mesenchymal tumors and usefulness of pan-TRK immunohistochemistry for identification of NTRK fusions

Fusions involving NTRK1, NTRK2, and NTRK3 are oncogenic drivers occurring in a spectrum of mesenchymal neoplasms ranging from benign to highly malignant tumors. To gain further insights into the staining profile with the pan-TRK assay, we analyzed a large number of soft tissue sarcomas and correlated our findings with molecular testing. Additionally, we expand the spectrum of NTRK-fusion tumors by reporting a mesenchymal lesion in the lung as well as a mesenchymal skin lesion in the spectrum of benign fibrous histiocytoma with NTRK—fusion. We retrospectively reviewed soft tissue sarcomas diagnosed at the Diagnostic and Research Institute of Pathology, Medical University of Graz, between 1999 and 2019, and cases from the consultation files of one of the authors (BLA). In total, 494 cases were analyzed immunohistochemically with pan-TRK antibody (clone EPR17341, RTU, Roche/Ventana) and positive cases (defined as any cytoplasmic/nuclear staining in more than 1% of tumor cells) underwent next-generation sequencing (NGS). Immunohistochemical staining was observed in 16 (3.2%) cases. Eleven cases with focal weak and moderate cytoplasmic/membranous or focal moderate to strong nuclear staining did not harbor an NTRK-fusion (three synovial sarcomas, three leiomyosarcomas, two extraskeletal myxoid chondrosarcomas, and one each: dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxofibrosarcoma). Four cases showed strong diffuse nuclear and/or cytoplasmatic staining, and one case showed diffuse, but weak cytoplasmic staining. All these cases demonstrated an NTRK-fusion (LMNA-NTRK1, IRF2BP2-NTRK1, TMB3-NTRK1, ETV6-NTRK3, RBPMS-NTRK3). Pan-TRK assay (clone EPR17341, RTU, Roche, Ventana) immunohistochemistry serves as a reliable diagnostic marker that can also be expressed in non-NTRK-rearranged mesenchymal neoplasms. It can be used as a surrogate marker for identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement, if patients are undergoing targeted therapy. Additionally, we identified NTRK-fusion-positive, primary mesenchymal tumors of the lung and the skin.

MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies.

The MDM2 gene is amplified in dedifferentiated liposarcoma (DDLPS). Treatment with MDM2 antagonists is a promising strategy to treat DDLPS; however, drug resistance is a major limitation when these drugs are used as a single agent. This study examined the impact of MDM2 antagonists on the mitogen-activated protein kinase (MAPK) pathway in DDLPS and investigated the potential synergistic activity of a MAPK kinase (MEK) inhibitor in combination with MDM2 antagonists. We identified a synergistic effect and identified the mechanism behind it. Combination effects of MDM2 antagonists and a MEK inhibitor were analyzed in a patient-derived xenograft mouse model and in DDLPS and leiomyosarcoma cell lines using different cell proliferation assays and immunoblot analysis. MDM2 antagonist (RG7388)-resistant IB115 [P4] cells and p53-silenced DDLPS cells were also established to understand the importance of functional p53. We found that MDM2 antagonists induced an upregulation of phosphorylated extracellular signal-regulated kinase (p-ERK) in DDLPS cells. The upregulation of p-ERK occurred due to mitochondrial translocation of p53, which resulted in increased production of reactive oxygen species, causing the activation of receptor tyrosine kinases (RTKs). Activated RTKs led to the activation of the downstream MEK/ERK signaling pathway. Treatment with a MEK inhibitor resulted in decreased expression of p-ERK, causing significant anti-tumor synergy when combined with MDM2 antagonists. Our results provide a framework for designing clinical studies of combination therapies in DDLPS patients.

MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models.

Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal cancer marked by amplification of MDM2, an inhibitor of the tumor suppressor TP53. DDLPS patients with higher MDM2 amplification have lower chemotherapy sensitivity and worse outcome than patients with lower MDM2 amplification. We hypothesized that MDM2 amplification levels may be associated with changes in DDLPS metabolism. Six patient-derived DDLPS cell line models were subject to comprehensive metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling to assess associations with MDM2 amplification and their responses to metabolic perturbations. Comparing metabolomic profiles between MDM2 higher and lower amplification cells yielded a total of 17 differentially abundant metabolites across both panels (FDR < 0.05, log2 fold change < 0.75), including ceramides, glycosylated ceramides, and sphingomyelins. Disruption of lipid metabolism through statin administration resulted in a chemo-sensitive phenotype in MDM2 lower cell lines only, suggesting that lipid metabolism may be a large contributor to the more aggressive nature of MDM2 higher DDLPS tumors. This study is the first to provide comprehensive metabolomic and lipidomic characterization of DDLPS cell lines and provides evidence for MDM2-dependent differential molecular mechanisms that are critical factors in chemoresistance and could thus affect patient outcome.

Giant paratesticular liposarcoma with lung metastases: a case report and review of the\xa0literature

BackgroundDue to its rarity, little is known about the clinical presentations and responses to systemic chemotherapies in advanced and/or metastatic cases of paratesticular liposarcoma.Case presentationHere, we report the case of a 75-year-old Japanese man with giant paratesticular liposarcoma. Imaging studies revealed a 26 cm tumor in his right scrotum and lung metastases at presentation. He underwent radical orchiectomy followed by systemic chemotherapies. Pathological findings of the resected primary tumor confirmed a dedifferentiated liposarcoma. He then started chemotherapy treatment with gemcitabine plus docetaxel. His disease status was stable for 1 year. Eribulin was used for second-line chemotherapy. He had a relapse at 5 months after eliburin and died at 22 months after diagnosis.ConclusionEarly diagnosis and curative radical surgery are important for treatment of paratesticular liposarcoma. However, a giant paratesticular liposarcoma could cause metastases, and systemic chemotherapy may be helpful for prolonging survival in patients with metastatic paratesticular liposarcoma.

MDM2 amplification and fusion gene ss18-ssx in a poorly differentiated synovial sarcoma: A rare but puzzling conjunction

The detection of specific alterations by genetic analyses has been included in the diagnostic criterions of the World Health Organization’s classification of soft tissues tumors since 2013. The presence of a SS18 rearrangement is pathognomonic of synovial sarcoma (SS). MDM2 amplification is strongly correlated to well-differentiated or dedifferentiated liposarcoma (DDLPS) in the context of sarcoma. We identified one case of poorly differentiated sarcoma harboring both SS18-SSX2 fusion and MDM2 amplification. The review of the literature showed high discrepancies, concerning the incidence of MDM2 amplification in SS: from 1.4% up to 40%. Our goal was to precisely determine the specific clinico-pathological features of this case and to estimate the frequency and characteristics of the association of SS18-SSX fusion/MDM2 amplification in sarcomas. We performed a retrospective and prospective study in 96 sarcomas, (56 SS and 40 DDLPS), using FISH and/or array-CGH to detect MDM2 amplification and SS18 rearrangement. None of the 96 cases presented both genetic alterations. Among the SS, only the index case (1/57: 1.7 %) presented the double anomaly. We concluded that MDM2 amplification in SS is a very rare event. The final diagnosis of the index case was a SS with SS18-SSX2 and MDM2 amplification as a secondary alteration. If the detection of MDM2 amplification is performed first in a poorly differentiated sarcoma, that may lead to not search other anomalies such as SS18 rearrangement and therefore to an erroneous diagnosis. This observation emphasizes the strong complementarity between histomorphology, immunohistochemistry and molecular studies in sarcoma diagnosis.

PET/CT Imaging as a Diagnostic Tool in Distinguishing Well-Differentiated versus Dedifferentiated Liposarcoma.

Distinguishing well-differentiated liposarcoma (WDLPS) from dedifferentiated liposarcoma (DDLPS) is essential given distinct treatment paradigms and chemosensitivity. Percutaneous biopsy has a low sensitivity for detecting DDLPS. We sought to identify the diagnostic utility of positron emission tomography/computed tomography (PET/CT) in identifying WDLPS versus DDLPS. An independent radiologist reviewed PET/CT images to identify target lesions and determine the maximum standardized uptake value (SUVmax). An independent pathologist review confirmed WDLPS or DDLPS histology. A binary cutoff point of SUVmax was identified using a classification and regression trees (CART) algorithm. We identified 20 patients with WDLPS or DDLPS with 26 PET/CTs performed for separate recurrences that were followed by surgical sampling. Of the 26 records, 12 were DDLPS (46%) and 14 were WDLPS (54%). Patients with DDLPS had significantly higher SUVmax than those with WDLPS (p value = 0.0035). A SUVmax of 4 was identified as the cutoff point. Using this cutoff, the sensitivity of SUVmax identifying a case as DDLPS was 83.3% (95% CI: 51.6%, 97.9%) and the specificity was 85.7% (95% CI: 57.2%, 98.2%). PET/CT is a sensitive and specific diagnostic tool to identify the presence of dedifferentiation within the tumor.

Extracellular vesicle cross-talk in the liposarcoma microenvironment.

Liposarcoma (LPS) is the most prevalent soft tissue sarcoma; among the four different LPS subtypes, dedifferentiated liposarcoma (DDLPS) is especially worrisome given its propensity for local and distant recurrence, with an overall survival rate of only 10% at 10 years. Our understanding of the molecular drivers of this disease is rudimentary at best; knowledge about how DDLPS interacts with cells in the tumor microenvironment (TME) is also lacking. Extracellular vesicle (EVs) have been studied in a number of different systems concerning their ability to influence the TME transferring bioactive molecules. In this review, we outline the role of the TME in the DDLPS progression and recurrence, focusing on the interplay between EVs released from the tumor and their target recipient cells in the TME. Success in the understanding of this process will be critical to an enhanced understanding of the underlying biologic drivers at play, potentially leading to new therapeutic strategies of benefit to patients with this disease.

A case of retroperitoneal dedifferentiated liposarcoma successfully treated by neoadjuvant chemotherapy and subsequent surgery

BackgroundRetroperitoneal liposarcoma (RPLS) is the most commonly observed soft tissue sarcoma in the retroperitoneal space. Although the beneficial effect of chemotherapy for RPLS is controversial, there are some reports that have shown a considerable tumor-suppressive effect of chemotherapy in RPLS. We demonstrate a case of dedifferentiated RPLS, which was initially considered inoperable but was successfully treated by neoadjuvant chemotherapy and subsequent curative resection.Case presentationA 59-year-old female was referred to our hospital with a chief complaint of right lower quadrant abdominal pain. Abdominal computed tomography revealed a large retroperitoneal tumor with a maximum diameter of 11 cm. The tumor involved retroperitoneal major vasculatures, such as the right common iliac vein and artery, as well as the right psoas muscle and femoral nerve. The right ureter was also involved and obstructed by the tumor. A biopsy was performed through the retroperitoneal route, and the tumor was diagnosed as a dedifferentiated liposarcoma with the Fédération Nationale des Centres de Lutte Contre le Cancer grade 3. Because the tumor was highly invasive and complete resection was not feasible, we decided to administer neoadjuvant chemotherapy with doxorubicin and ifosfamide (AI). After completing 6 courses of AI, the tumor size was considerably reduced, and we decided to perform surgery with curative intent. Before laparotomy, femoro-femoral arterial bypass was performed to prepare for the right common iliac artery resection. Thereafter, the patient underwent laparotomy and tumor resection combined with right nephrectomy, resection of the right common iliac artery and vein, and resection of the right psoas muscle and femoral nerve. The postoperative course was uneventful, although the patient needed a walking brace to support her gait. The pathological findings indicated a 99% disappearance of tumor cells. The patient was healthy without any complaints after 1 year of surgery, and a follow-up CT scan revealed no tumor recurrence.ConclusionsTo the best of our knowledge, this is the first report that showed a nearly complete pathological response to AI in dedifferentiated RPLS, which was subsequently completely resected.

SAR-096: A phase II trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL), and leiomyosarcoma (LMS).

11544 Background: Inhibition of CDK4 is being studied in a variety of sarcomas, especially dedifferentiated liposarcoma (DDL) where prolonged progression free survival has been noted. Exposure to CDK4 inhibitors in Rb+ leiomyosarcoma (LMS) cell lines leads to decreased cell proliferation, and increased senescence, and G0/G1-phase arrest. When combined, ribociclib a CDK4 inhibitor and everolimus, an mTOR inhibitor show synergistic growth inhibition in multiple tumor models. Methods: Patients (pts) were enrolled to one of two cohorts: DDL or Rb+ LMS. LMS pts were required to have 1 prior line of therapy; DDL pts required no prior therapy. There were no limits to prior therapies in either group. Progression on prior therapy and measurable disease by RECIST 1.1 was also required. Ribociclib was given at 300 mg daily for 21/28 days and everolimus was given continuously at 2.5 mg daily in 28 day cycles. The primary endpoint was progression free rate at 16 weeks. A Simon two-stage design was utilized and if at least 8 out of 24 pts were progression free at 16 weeks, the treatment was declared promising for the cohort. Here in we present data on the LMS cohort. Results: Twenty-four LMS pts, 83% (n = 20) female, 58% (n = 14) uterine primary were treated. Median prior lines of therapy was 3.5 (range 1-9). Of 22 pts with complete data, 6 (27.2%) met the primary endpoint of non-progression at 16 weeks. Median PFS was 19.6 weeks (range 2.8-84), with progression as best response occurring in 13 pts. There were no objective responses. Five pts who had progressive disease on multiple lines of therapy experienced prolonged progression free survival (23-84 weeks). Grade 3-4, toxicities included neutropenia (29%), thrombocytopenia (12.5%) and leucopenia (12.5%) being most common. Tissue samples pre and on therapy as well as blood were collected in 21 and 18 pts respectively to evaluate pharmacodynamic changes. Conclusions: Final data on the primary endpoint for the LMS cohort is pending; it is notable that several heavily pre-treated LMS pts experienced prolonged progression free survival for &gt; 9 months. Updated results and biology correlatives will be presented. Clinical trial information: NCT03114527 .

Preliminary results of a phase II study of neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS).

11505 Background: is a randomized, phase II non-comparative trial evaluating the efficacy of neoadjuvant checkpoint blockade [nivolumab (N) or ipilimumab/ nivolumab (I/N)] in patients (pts) with surgically resectable retroperitoneal DDLPS or extremity/truncal UPS treated with concurrent neoadjuvant radiation therapy (RT, UPS only). Methods: Primary endpoint was pathologic (path) response. Secondary endpoints were safety, RECIST response, recurrence-free survival, overall survival and patient-reported outcomes. Biospecimens (tumor, blood, fecal microbiome) at baseline, on therapy, and at time of surgery were collected and will be assessed for immune-based prognostic biomarkers. We assessed correlation between radiographic and pathologic response by linear regression. Correlative analyses includes assessment of tumor PD-L1 expression, characterization of tumor immune infiltrates by multiplex immunohistochemistry, and transcriptomic and genomic analyses. Results: Of the 25 pts enrolled; 24 are evaluable for response (14 DDLPS, 9 UPS). Clinical activity was variable by histologic subtype and treatment with RT. Median path response in the UPS cohort was 95% [95% CI 85–99] and was similar between the N/RT and I/N/RT groups (Table). Median path response in the DDLPS cohort was 22.5% [95% CI 85–99; Table]. Median change in tumor size (radiographic response) was -4% and +9% in the UPS and DDLPS cohorts, respectively. There was no correlation between path response and radiographic response (R2 0.0309; p = 0.43). Of 8 pts with path response ≥ 85%, there was 1 partial response, 5 stable disease and 2 progressive disease by RECIST criteria. There was 1 delay to surgery due to grade 3 hyperbilirubinemia (Arm B). There was no difference in toxicity between N/RT and I/N/RT. Conclusions: N/RT and I/N/RT have significant clinical activity in UPS; more than expected compared to historic controls. Toxicity profiles were as expected and the majority of patients underwent resection without delay. Larger studies evaluating N/RT in UPS are warranted given the significant path response in this cohort. RECIST was not associated with path response and better markers of on-treatment clinical activity are needed. Correlative analyses that may guide combination strategies are ongoing and will be presented at the meeting. Clinical trial information: NCT03307616 .

Prediction of histologic and molecular subsets of soft tissue sarcoma using deep learning.

e23529 Background: Soft tissue sarcomas (STS) are histologically and molecularly heterogenous with variable biologic behavior and differential therapeutic responses. Molecular analysis of STS is commonly utilized to identify targetable mutations or identify STS subtypes that have predictive and prognostic implications. To address the challenge of rapid, accurate classification of STS subtypes, we sought to develop an approach using a form of artificial intelligence called deep learning to identify meaningful hidden information directly from digital H+E slide images. We trained a deep learning model using genotype and phenotype data from The Cancer Genome Atlas (TCGA) and companion diagnostic digital H+E slide images, in order to identify therapeutic biomarkers and prognostic molecular subtypes. Methods: Digital whole slide images (WSIs) from TCGA were downloaded and regions of tumor were annotated by pathologists. WSIs were carved into 604 um by 604 um square tiles within the tumor region and saved at an image size of 598 px by 598 px for a resolution of ~1um/px. These tiles were used as input to a deep convolution neural network (Xception model pretrained on imagenet). Performance results are reported at the as the average of three-fold cross-validation, averaged at the patient level. Results: 206 sarcomas available through the TCGA were used as training set. Sarcoma histologies include 80 leiomyosarcoma (LMS) (27 uterine LMS and 53 non-uterine LMS), 50 dedifferentiated liposarcoma (DDLPS), 44 undifferentiated pleomorphic sarcoma (UPS), 72 myxofibrosarcoma (MFS), and 10 synovial sarcoma (SS). FNCLCC grade 1 (n = 14), grade 2 (n = 112), and grade 3 (n = 80). Histology could be predicted automatically with very high accuracy for LMS (Area under Receiver-operator curve (AUROC) 0.93 and 0.95 for uterine and non-uterine LMS respectively), DDLPS (AUROC 0.70), UPS (AUROC 0.76), and MFS (AUROC 0.76). FNCLCC grade could be predicted for grade 3, 2, 1 with AUROC of 0.79, 0.73, and 0.81 respectively. High vs. low mitotic rate (threshold 15) could be predicted with AUROC of 0.70. Within non-uterine LMS, prognostic molecular cluster could be predicted with AUC of 0.62 for cluster with worse recurrence-free and disease specific survival. Within DDLPS, DNA methylation cluster 2 associated with worse disease specific survival was predicted with AUC of 0.80. Conclusions: Deep learning algorithm analysis of histologic slides was able to predict clinically meaningful characteristics and molecular clusters with reasonable accuracy. Retrospective and prospective validation is needed.

A multicenter phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma (Alliance A091401): Results of expansion cohorts.

11511 Background: In the open-label multicenter phase II study, A091401, nivolumab (N) and nivolumab+ipilimumab (N+I) demonstrated a confirmed response rate (RR) of 5% and 16%, respectively in patients (pts) with advanced sarcoma (D’Angelo SP et al Lancet Oncology 2018). Responses occurred in undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, leiomyosarcoma, sarcoma not otherwise specified and alveolar soft part sarcoma. Here, we report efficacy of N and N+I, in each of 3 expansion cohorts [gastrointestinal stromal tumor (GIST), UPS and dedifferentiated liposarcoma (DDLS)]. Methods: Pts refractory to ≥ 1 regimen(s) were randomized (non-comparative) to receive either N [N (3 mg/kg q2W)] or N+I [N (3 mg/kg Q3W x4, then Q2W) plus I (3 mg/kg q3W x4)]. The primary endpoint was 6 month confirmed RR (RECIST v1.1). For UPS and DDLS, 2 confirmed responses in the 1st 12 evaluable pts was needed (85% power, 1-sided alpha=0.15, 5 v 25% RR). For GIST, a confirmed response in the 1st 9 evaluable pts expanded enrollment to 24 (80% power, 1-sided alpha=0.10, 5 v 20% RR). Other endpoints: adverse events (AEs, TRAEs), progression-free and overall survival (PFS, OS), and correlatives. Results: See table. Clinical trial information: NCT02500797 . Conclusions: Neither N or N+I lead to confirmed responses in GIST. In DDLS and UPS, the primary response endpoint was met with N+I but not with N alone (RR 14% for N+I vs. 7% and 8% for N alone). For the GIST cohort TRAE was higher with N+I, holding enrollment as required per protocol. There remains a pressing need to determine genomic and clinical biomarkers of response, resistance and toxicity. Correlative analyses (whole exome sequencing, multiplex IHC and RNAseq) are in progress. Support: U10CA180821, U10CA180882; ClinicalTrials.gov Identifier: NCT02500797. [Table: see text]

Activity of cabazitaxel in patients with metastatic or inoperable locally advanced dedifferentiated liposarcoma: European Organization for Research and Treatment of Cancer (EORTC) Phase II trial 1202.

11556 Background: The optimal treatment for patients with advanced dedifferentiated (DD) liposarcoma (LPS) remains uncertain. Single agents which are most effective include doxorubicin and ifosfamide but, as with soft tissue sarcomas (STS) in general, objective response rates (ORR) and progression free survival (PFS) are very modest. Cabazitaxel exerts its effect through inhibition of microtubular disassembly and has been shown to be relatively safe, effective and well-tolerated. EORTC 1202 assessed whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DD LPS to justify further investigation in a phase III setting. Methods: This was an international multi-center, open label single arm phase II trial. Eligible patients with metastatic or inoperable locally advanced DD LPS were treated with cabazitaxel 25mg/m² IV infusion over 1 hour every 21 days. Primary endpoint was PFS rate at 12 weeks assessed by local investigator per RECIST 1.1. Based on a Simon two-stage design, at least 4 out of 17 (Stage 1) and 11 out of 37 (Stage 2) eligible and evaluable patients who are progression-free at 12 weeks were needed. Results: Forty patients were registered by 10 institutions in 4 countries between March 2015 and March 2019, with 2 patients being ineligible. Among the 38 eligible patients who started treatment, 3 (7.5 %) were still on treatment at the time of analysis. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. Among the first 17 (Stage 1) and 37 (Stage 2), 11 and 20 patients were progression-free at 12 weeks respectively, satisfying the study decision rules. The PFS rate at 12 weeks for all 38 eligible patients was 52.6% (conditional 1-sided 95 % CI 38.3 – 100). Two patients (5.3%) achieved a confirmed partial response (PR) and 23 stable disease (SD) (60.5%). Disease control (PR+SD) was achieved in 25 patients (65.8%). Median PFS was 7.4 months (95%CI 2.8-10.3). The most common cabazitaxel -related grade &gt;3 adverse events in all 40 registered patients were neutropenia (60%), febrile neutropenia (25%), fatigue (12.5%), and anemia (10%). There were no cabazitaxel-related deaths. Conclusions: EORTC 1202 met its primary endpoint, with 20/37 pts (54%) being progression-free at 12 weeks. Results of this trial confirm activity of cabazitaxel in patients with metastatic or inoperable locally advanced DD LPS and warrant further exploration of the drug. Clinical trial information: NCT01913652 .

Well-Differentiated/Dedifferentiated Liposarcoma Arising in the Upper Aerodigestive Tract: 8 Cases Mimicking Non-adipocytic Lesions.

Well-differentiated (WDL) and dedifferentiated liposarcomas (DL) of the pharynx, larynx and oral cavity are rare, often mimicking benign lipomatous neoplasms or non-lipogenic mesenchymal tumors. Cases of WDL/DL arising in the upper aerodigestive tract, exclusive of the cervical esophagus, were reviewed. Morphologic features, ancillary studies, including fluorescence in situ hybridization (FISH) studies for CPM/MDM2, and clinical data was catalogued. Eight WDL/DL (4 WDL, 4 DL); were identified in patients ranging from 32 to 77 years (median 52.5 years; 6 males, 2 females) with sites of origin including hypopharynx (5 cases), larynx (2 cases) and oral cavity (1 case). Six of the 8 cases were received for expert consultation, and the remaining 2 cases were initially misdiagnosed as benign lymphangiomatous or fibroepithelial polyps. Morphologically, 4 tumors had areas mimicking various non-lipomatous soft tissue tumors including nodular fasciitis, mammary-type myofibroblastoma, low-grade myofibroblastic sarcoma and undifferentiated pleomorphic sarcoma, 2 cases simulated benign hypopharyngeal polyps, and 1 lesion was notable for a dense lymphoplasmacytic infiltrate suggestive of hematolymphoid neoplasm or IgG4-related sclerosing disease. FISH showed amplification of CPM/MDM2 (8/8 cases). All cases (4/4) with longer than 1-year of follow-up recurred (45-118 months) with 1 tumor showing progression to DL. WDL/DL presenting in the upper aerodigestive tract are rare and diagnostically challenging. Awareness of the morphologic spectrum of WDL/DL coupled with appropriate use of MDM2 FISH is essential for accurate classification and management, as these tumors appear to have a high risk for local recurrence and eventual dedifferentiation in these anatomical locations.

Improved Biopsy Accuracy in Retroperitoneal Dedifferentiated Liposarcoma.

Biopsy sensitivity in retroperitoneal dedifferentiated liposarcoma (DDLPS) is variable. Patients with grade 3 DDLPS face a significant risk of metastatic disease and may potentially benefit from neoadjuvant therapy, making highly accurate pretherapy diagnosis essential. Our study aimed to establish whether diagnostic sensitivity could be improved by targeting solid areas of tumor on percutaneous biopsy. Between 2016 and 2019, data on patients with suspected primary retroperitoneal sarcoma who underwent a biopsy were collected, and diagnostic accuracy was calculated. These data were compared with our previously reported series from 2005 to 2016. For DDLPS tumors, comparisons were then made between biopsies that targeted the solid component and those that did not. Data were available for 121 patients in the current series and 238 from the previous study. The proportion of biopsies returning a histological subtype concordant with postoperative pathology was 83% in the current series, marking a significant improvement over our previous study (67%, p = 0.001). For diagnosis of DDLPS, biopsy sensitivity improved from 40 to 74% (p < 0.001), with an increase from 13 to 50% (p = 0.006) where grade 3 DDLPS was treated as a separate disease. Within the current series, targeted biopsy yielded a sensitivity of 100% for identifying DDLPS, compared with 10% in nontargeted biopsy (p < 0.001). Systematic targeting of solid areas of tumor within suspected retroperitoneal liposarcoma has improved sensitivity for detection of both DDLPS and grade 3 DDLPS on biopsy. This approach minimizes the risk of underdiagnosis of patients with DDLPS who could benefit from neoadjuvant chemotherapy.

Evaluation of Cancer-testis Antigens in Osteosarcoma and Dedifferentiated Liposarcoma as Targets for Immunotherapy

Abstract T cell based immunotherapies targeting tumor antigens are a promising alternative to traditional cancer treatments due to their ability to eliminate malignant cells, but require highly immunogenic tumor-associated proteins as targets for CD8+ T cell recognition. Additional parameters to consider in a T cell based immunotherapy include tumor T cell infiltration and expression of HLA-peptide complexes on the surface of cancer cells. The goal of this study is to identify targetable immunogenic tumor antigens and to characterize the immune profile of human dedifferentiated liposarcoma (DDLPS) and osteosarcoma (OS) sarcoma subtypes by screening for cancer-testis antigen (CTA) expression, HLA expression, and tumor T cell infiltration by immunohistochemistry (IHC). Human tissue micro-arrays composed of 80 cores of OS and 49 cores of DDLPS were obtained and stained by IHC for selected CTAs (MAGE-A3, NY-ESO-1 and SSX2) and various immune markers. In DDLPS, 11% of samples express MAGE-A3 and 2% express SSX2 and NY-ESO-1 in low percentages of tumor cells. In OS, 100% of samples express MAGE-A3 and 89% express SSX2, both with &amp;gt;80% of positive cases showing moderate to high expression. NY-ESO-1 is expressed in 78% of OS samples, predominantly at low levels. Brisk infiltration of CD8+ T cells is observed in over 70% of both sarcoma types. Furthermore, all sarcoma samples tested are positive for HLA expression. These results show promising expression of CTAs MAGE-A3 and SSX2 in OS, which may be used as targets for immunotherapy for OS. The data generated throughout this study will provide insight into the immune profile of these sarcomas - information that is critical for immunotherapy design.

Recombinant Methioninase Combined With Tumor-targeting Salmonella typhimurium A1-R Induced Regression in a PDOX Mouse Model of Doxorubicin-resistant Dedifferentiated Liposarcoma.

Dedifferentiated liposarcoma (DDLPS) is associated with a poor survival rate even with multi-modality treatment. In the present study, we evaluated the efficacy of recombinant methioninase (rMETase) combined with tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R against a doxorubicin-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) mouse model. A recurrent high-grade DDLPS from the right retroperitoneum of a patient was grown orthotopically in the retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomly divided into the following groups: Control, no treatment; doxorubicin monotherapy; rMETase monotherapy; S. typhimurium A1-R monotherapy; S. typhimurium A1-R and rMETase combination therapy. Tumor length and width were measured before and after treatment. On day 14 after treatment, all treatments significantly inhibited DDLPS PDOX tumor growth compared to the untreated control except for doxorubicin monotherapy. rMETase combined with S. typhimurium A1-R was significantly more effective and regressed tumor volume compared to either rMETase or S. typhimurium A1-R alone. The relative body weight did not significantly differ between days 0 and 14 for individual groups. The combination of rMETase and S. typhimurium A1-R has important clinical potential for this recalcitrant sarcoma.

From head and neck lipoma to liposarcoma: a wide spectrum of differential diagnoses and their therapeutic implications.

To overview the array of differential diagnoses among lipomatous tumours of the head and neck with special focus on their evaluation, three-dimensional assessment, and their available treatments. The head and neck is an infrequent localization for lipomatous tumours, even though they represent the most common mesenchymal lesions. Lipoma, spindle cell/pleomorphic lipoma (SC/PL), atypical lipomatous tumour/well differentiated liposarcoma (ALT/WDLPS), de-differentiated liposarcoma (DDLPS), myxoid liposarcoma (MLPS), and pleomorphic liposarcoma (PLPS) are the most distinctive histotypes. Lipoma and SC/PL present alterations of chromosomes 12 and 13, ALT/WDLPS and DDLPS both show the Mouse Double Minute 2 amplification, whereas MLPS presents a CHOP gene fusion. Diagnosis of PLPS is purely morphological as there is no pathognomonic genetic alteration identified to date. Radiological assessment can be challenging for the presence of nonadipose components within the lesion. Surgery is the mainstay of treatment, even though achieving true radicality in terms of a large cuff of healthy tissue surrounding the tumour is not always realistic in the head and neck. Adjuvant radiation, eventually in combination with systemic chemotherapy, has been shown to improve overall survival in patients with positive margins, high-grade, deep, and more than 5 cm lesions. Further studies should be aimed at the evaluation of the role of hadron therapy, as well as targeted drugs against overexpressed proteins. Adequate differential diagnosis of the histotypes collected under the umbrella term of head and neck lipomatous tumours plays a fundamental role in treatment and follow-up of these lesions and requires specific expertise with referral to high-volume centres.

Comprehensive Review of Abdominopelvic Mesenchymal Tumors With Radiologic Pathologic Correlation and Update on Current Treatment Guidelines—Part 2

Soft-tissue sarcomas are a diverse group of rare mesenchymal malignancies accounting for only 1% of all solid adult malignancies. These have been categorized in 12 broad groups by the World Health Organization (WHO) with their recent update in 2013. Majority of them lack specific imaging features serving as imaging conundrums for a radiologist. These are often large masses at presentation as they are asymptomatic or cause vague clinical symptoms. These tumors are challenging for surgeons as well as they find it difficult to achieve complete resection because of complex intra-abdominal anatomy and their close relationship with critical structures. Often, a multidisciplinary approach is required to decide on the most appropriate management for these complex cases so as to provide optimal patient care. Knowledge of the WHO classification, pathologic features, and treatment options available helps the radiologist make a meaningful contribution in multidisciplinary discussions of such cases and overall patient care. Liposarcoma (well-differentiated and dedifferentiated liposarcomas), leiomyosarcoma, and gastrointestinal stromal tumor are the 3 most common primary intra-abdominal sarcomas. In part 1 of this article, general features of soft-tissue sarcomas and some of the common tumors from WHO category 1-4 found in abdomen and pelvis are discussed. Part 2 will focus on common tumors from remainder of the WHO categories.