Liposarcoma Research Articles

Atypical Lipomas of the Hand and Forearm

Three lipomas are presented: lipoma arborescens of the long flexor tendons, a forearm lipoma traversing the interosseous membrane and a thenar eminence lipoma with median nerve compression. Pre-operative magnetic resonance imaging defined the extent of lipomatous infiltration in each case. Excellent outcomes were observed after complete excision.

Atypical Lipomas of the Hand and Forearm

Atypical Lipomas of the Hand and Forearm

Atypical young presentation of lipoma arborescens of knee with USG and MRI correlation.

Lipoma arborescens of the knee joint is a rare entity and only a few cases have been documented in literature. It is described as an idiopathic rare joint disease in which benign fatty deposits replace and distend the synovium. Incidence rate of 0.12-0.25% has been evaluated by Vilanova et al with slight male preponderanceand mean age of presentation 45.6 years. Clinically patient may present with diffuse painless gradually progressive swelling of the knee joint. MRI and High Resolution Ultrasonography are the diagnostic imaging modalities. Here, we present a case report of an atypical lipoma arborescens in a young adult.

Myxoid liposarcoma: Fine-needle aspiration cytopathology in the molecular era. A report of 24 cases

Application of fine-needle aspiration (FNA) biopsy to soft tissue tumors remains underutilized in North America. Myxoid liposarcoma (LPS), the second most common subtype of LPS, is characterized primarily by t(12;16)(q13;p11) which is amenable to FISH analysis using a break-apart probe for DDIT3. Little is known regarding FISH testing for DDIT3 on cytologic specimens. We report our FNA experience with myxoid LPS and application of this molecular probe. Specimens retrieved from our cytology database used search codes for myxoid LPS. Tissue files were searched for any cases with corresponding FNA biopsies. FNA biopsy was performed using a standard technique. From 24 FNA cases of myxoid LPS (mean age = 52 years), a specific diagnosis was made in 87.5%. Two cases were diagnosed as spindle/round cell neoplasm, and 1 as suspicious for myxoid LPS. There were 2 false positive diagnoses and no false negatives. Nearly all cases arose in the extremities; thigh being most common. Principal cytologic features consisted of discrete myxocellular microfragments, a plexiform capillary pattern, and variable number of univacuolated lipoblasts. Uniformly banal ovoid nuclei were randomly scattered within myxocellular microfragments. FISH analysis for DDIT3 rearrangement from unstained smears and/or cell-block was positive in 13 cases, and unsuccessful in 3, with no false positive/false negative results. Myxoid LPS is diagnosable in a high percentage of cases using FNA biopsy alone. Confirmatory FISH analysis for DDIT3 is not only possible, but also valuable for correctly recognizing this neoplasm.

1321 Efficacy and safety of trabectedin (T) or dacarbazine (D) in an elderly patient subgroup (65 years) with advanced leiomyosarcoma (LMS) or liposarcoma (LPS) after prior chemotherapy

1321 Efficacy and safety of trabectedin (T) or dacarbazine (D) in an elderly patient subgroup (65 years) with advanced leiomyosarcoma (LMS) or liposarcoma (LPS) after prior chemotherapy

3403 Final overall survival (OS) analysis of the randomized phase 3 study of trabectedin (T) or dacarbazine (D) for the treatment of patients (pts) with advanced leiomyosarcoma (LMS) or liposarcoma (LPS)

3403 Final overall survival (OS) analysis of the randomized phase 3 study of trabectedin (T) or dacarbazine (D) for the treatment of patients (pts) with advanced leiomyosarcoma (LMS) or liposarcoma (LPS)

3436 Efficacy and safety of trabectedin (T) or dacarbazine (D) for treatment of patients (pts) with advanced leiomyosarcoma (LMS) or liposarcoma (LPS) after prior chemotherapy

3436 Efficacy and safety of trabectedin (T) or dacarbazine (D) for treatment of patients (pts) with advanced leiomyosarcoma (LMS) or liposarcoma (LPS) after prior chemotherapy

Neoadjuvant radiation in primary extremity liposarcoma: correlation of MRI features with histopathology.

To evaluate MRI features of response of primary extremity liposarcoma (LPS) to neoadjuvant radiation therapy (RT) with histopathologic correlation. In this IRB-approved study including 125 patients with extremity LPS treated with neoadjuvant RT from 2000 to 2013, MRI of the primary tumour in 18 patients (5 pleomorphic LPS, 13 myxoid LPS) before and after RT were reviewed by two radiologists by consensus. Histopathology of the surgical specimens was reviewed by a pathologist with expertise in sarcomas. In the pleomorphic LPS cohort, 3/5 tumours increased in size; 3/5 decreased in enhancing component; and 3/5 increased in peritumoral oedema, intratumoral haemorrhage, and necrosis. In the myxoid LPS cohort, 12/13 tumours decreased in size, 8/13 decreased in enhancing component, and 5/13 increased in internal fat following RT. Histopathology showed ≥50% residual tumour in 1/5 pleomorphic LPS and 2/13 myxoid LPS. Hyalinization/necrosis of ≥75% was noted in 4/5 pleomorphic LPS and 11/13 myxoid LPS. Cytodifferentiation was noted in 1/5 pleomorphic and 9/13 myxoid LPS. While pleomorphic LPS showed an increase in size, peritumoral oedema, intratumoral haemorrhage, and necrosis on MRI following neoadjuvant RT, myxoid LPS showed a decrease in size and enhancement with an increase in internal fat. • Pleomorphic LPS commonly increase in size and necrosis on MRI following RT. • Myxoid LPS commonly decrease in size and enhancement on MRI following RT. • Myxoid LPS often increase in fatty component on MRI following RT.

Abstract 4819: Differential evolution of tumor heterogeneity in leiomyosarcomas and liposarcomas suggested by genomic profiling

Abstract Sarcomas represent a heterogeneous set of malignant tumors originating from mesenchymal cells. Liposarcomas (LPS) and Leiomyosarcomas (LMS) are two of the most common histotypes, accounting for approximately 25% and 30% of all soft tissue sarcomas, respectively. The most frequent form of LPS is represented by a spectrum of disease including well-differentiated LPS (WDLPS), a non-metastasizing but locally recurrent disease with adipocytic differentiation, and de-differentiated LPS (DDLPS), an aggressive, frequently metastasizing high grade sarcoma which can arise in conjunction with elements of WDLPS. Besides the known oncogenic KIT or PDGFRA driver mutations in GIST, somatic alterations in RB1, deletions in PTEN, MDM2 amplifications in LPS, and TP53 mutations in LMS are the most commonly reported genomic aberrancies identified in sarcomas. Both WDLPS and DDLPS share amplification of 12q13-15, a genomic region containing the MDM2 and CDK4 loci, yet little is understood about the other genetic processes that yield such different phenotypes. In LMS, recurrent mutations in TP53 have been identified, but a detailed analysis of primary and metastatic tumors has not previously been described. To evaluate genetic events in these transitions, we performed whole exome sequencing (WES) on trios comprising normal tissue, WDLPS, and DDLPS obtained from individual patients (n = 19), as well as on trios of normal tissue, primary and metastatic LMS tumors obtained from separate individual patients (n = 8). Consistent with prior reports of the molecular characterization of LPS, we observed arm-level amplifications in Chr 12 in all LPS samples, and Chr 17 amplification in many LMS cases. There were no shared somatic alterations across paired WDLPS and DLPS pairs from individual patients aside from the common Chr 12 amplification (MDM2 & CDK4). A higher mutation rate was observed in LMS, and there were many clonal somatic alterations shared between the primary and metastatic lesions of individuals. This study demonstrates the heterogeneity of evolution between different subtypes of sarcomas using whole exome sequencing of clinical specimens. This finding has implications for better understanding of the molecular drivers of these tumors and opportunities to identify subtype-specific therapeutic targets. Citation Format: Ali Amin-Mansour, Stefano Sioletic, Scott L. Carter, Levi A. Garraway, George D. Demetri, Suzanne George, Eliezer M. Van Allen, Andrew J. Wagner. Differential evolution of tumor heterogeneity in leiomyosarcomas and liposarcomas suggested by genomic profiling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4819. doi:10.1158/1538-7445.AM2015-4819

Abstract 1759: Preclinical activity of selinexor, an inhibitor of XPO1/CRM1, in sarcoma

Abstract Objective Exportin 1/Chromosomal Region Maintenance Protein 1 (XPO1/CRM1) transports proteins bearing nuclear export signals from the cell nucleus to the cytoplasm. SINE are a family of small-molecules that selectively inhibit nuclear export through covalent binding to Cysteine 528 (Cys528) in the cargo binding pocket of XPO1. This leads to forced nuclear retention of cargo proteins that include major tumor suppressor proteins such as p53, FOXO, pRB and IkB. Preclinical and clinical studies have demonstrated selinexor activity in hematologic malignancies as well as in certain solid tumors, and it is currently in Phase I and II clinical trials for advanced cancers. In this study, we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes. Materials and Methods The efficacy of selinexor was tested in vitro and in vivo using 17 cell lines and 10 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Following exposure of cell lines to selinexor, effects on cell viability, cell cycle, and RNA and protein expression were determined. In sarcoma xenograft studies, selinexor was administered twice a week by oral gavage and changes in tumor size were recorded. Results Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). The ASPS cell lines were exceptionally resistant to selinexor with IC50 greater than 2 μM. Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. Cell lines from several sarcoma subtypes with defined molecular backgrounds, such as GIST with KIT mutations and dedifferentiated LPS with MDM2 and CDK4 amplification, were treated with selinexor to investigate its mechanism of action. Selinexor induced G1 arrest in GIST cells without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation status and induced G1-arrest irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA levels, indicating a post-transcriptional effect. Conclusions Selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models. Selinexor induced G1-arrest independent of known molecular mechanisms in GIST and LPS. These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes. Citation Format: Robert Nakayama, Yi-Xiang Zhang, Alex Anatone, Ewa Sicinska, George Demetri, Andrew Wagner. Preclinical activity of selinexor, an inhibitor of XPO1/CRM1, in sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1759. doi:10.1158/1538-7445.AM2015-1759

Pleomorphic lipoma- A rare pseudosarcomatous lesion

Pleomorphic lipoma is a rare benign tumor that can resemble a variety of malignant tumors, most commonly liposarcoma. This pseudosarcomatous lesion is an uncommon variant of lipoma, which has beningn behaviour. Two cases of this lesion arising on thigh and posterior aspect of neck respectively along with summarising the principal clinical and morphological characterstic of this rare tumor are presented here. For diagnosis FNAC is the initial investigation followed by confermation by histology.

Induction of p53-independent apoptosis by ectopic expression of HOXA5 in human liposarcomas.

Dedifferentiated liposarcoma (DDLPS) is a highly malignant subtype of human liposarcoma (LPS), whose genomic profile is characterized by chromosomal amplification at 12q13-q22. miR-26a-2 is one of the most frequently amplified genes in the region, and inhibition of its downstream target genes likely contributes to LPS tumorigenesis. Our previous study of LPS predicted homeobox protein A5 (HOXA5) as a target of miR-26a-2, and here we explored further the function of HOXA5, and its relationship with miR-26a-2 in DDLPS cells. Compared to normal human adipocytes, all LPS cell lines showed significant downregulation of HOXA5 (p = 0.046), and inhibition of miR-26a-2 using anti-miR-26a-2 substantially upregulated HOXA5 expression in these LPS cells. Interestingly, overexpression of HOXA5 alone induced very strong apoptotic response of LPS cells. HOXA5-induced apoptosis was p53-independent and caspase-dependent. Surprisingly, overexpression of HOXA5 induced nuclear translocation of RELA (p65), which was not associated with the transcriptional activity of RELA. Rather, nucleolar sequestration of RELA was observed. Overall, our study demonstrated for the first time that the downregulation of HOXA5 in LPS cells, partly by overexpression of miR-26a-2 in DDLPS, confers LPS cells resistance to apoptotic death. Further studies are required to understand the relationship of HOXA5 and the NFκB pathway in LPS cells.

Increased H3K9me3 drives dedifferentiated phenotype via KLF6 repression in liposarcoma.

Liposarcoma (LPS) can be divided into 4 different subtypes, of which well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) are the most common. WDLPS is typically low grade, whereas DDLPS is high grade, aggressive, and carries a worse prognosis. WDLPS and DDLPS frequently co-occur in patients. However, it is not clear whether DDLPS arises independently from WDLPS, or whether epigenomic alterations underly the histopathological differences of these subtypes. Here, we profiled 9 epigenetic marks in tumor samples from 151 patients with LPS and showed elevated trimethylation of histone H3 at Lys9 (H3K9me3) levels in DDLPS tumors. Integrated ChIP-seq and gene expression analyses of patient-derived cell lines revealed that H3K9me3 mediates differential regulation of genes involved in cellular differentiation and migration. Among these, Kruppel-like factor 6 (KLF6) was reduced in DDLPS, with increased H3K9me3 at associated regulatory regions. Pharmacologic inhibition of H3K9me3 with chaetocin decreased DDLPS proliferation and increased expression of the adipogenesis-associated factors PPARγ, CEBPα, and CEBPβ, suggesting that increased H3K9me3 may mediate DDLPS-associated aggressiveness and dedifferentiation properties. KLF6 overexpression partially phenocopied chaetocin treatment in DDLPS cells and induced phenotypic changes that were consistent with adipocytic differentiation, suggesting that the effects of increased H3K9me3 may be mediated through KLF6. In conclusion, we provide evidence of an epigenetic basis for the transition between WDLPS and DDLPS.

SRC inhibition represents a potential therapeutic strategy in liposarcoma

Liposarcomas (LS) are the most common malignant mesenchymal tumors, with an overall long-term mortality rate of 60%. LS comprise three major subtypes, i.e., well-differentiated/dedifferentiated liposarcoma (WDLS/DDLS), myxoid/round cell liposarcoma (MLS) and pleomorphic liposarcoma (PLS). Aiming at the preclinical identification of novel therapeutic options, we here investigate the functional significance of SRC in primary human LS and in LS-derived cell lines. Immunohistochemical and Western blot analyses reveal relevant levels of activated p-(Tyr416)-SRC in LS of the different subtypes with particular activation in MLS and PLS. Dysregulation of the SRC modifiers CSK and PTP1B was excluded as major reason for the activation of the kinase. Consistent siRNA-mediated knockdown of SRC or inhibition by the SRC inhibitor Dasatinib led to decreased proliferation of LS cell lines of the different subtypes, with MLS cells reacting particularly sensitive in MTT assays. Flow cytometric analyses revealed that this effect was due to a significant decrease in mitotic activity and an induction of apoptosis. SRC inhibition by Dasatinib resulted in dephosphorylation of SRC itself, its interacting partners FAK and IGF-IR as well as its downstream target AKT. Consistent with a particular role of SRC in cell motility, Dasatinib reduced the migratory and invasive potential of MLS cells in Boyden chamber and Matrigel chamber assays. In summary, we provide evidence that SRC activation plays an important role in LS biology and therefore represents a potential therapeutic target, particularly in MLS and PLS.

Liposarcoma of the spermatic cord: A case report and review of the literature

Liposarcomas (LPS) are malignant tumours of mesodermal origin that can develop at any site where fatty tissue is present. Liposarcomas of the spermatic cord have been classified as part of the “paratesticular” tumours which mostly originate in the spermatic cord and are found anywhere along its course. They are rare, but well-described neoplasms which present as painless swellings, most often in the groin or scrotal areas. They mimic common surgical conditions, such as hydroceles, hernias or testicular tumours, thus attracting surgical and urologic interest as they are occasionally the culprit of misdiagnoses. We present the case of a liposarcoma of the spermatic cord mimicking inguinal hernia along with a brief review of the literature.

Surgical resection of massive liposarcomas at the extremities: a 10-year experience in a referral musculoskeletal sarcoma unit.

BackgroundThere is still no consensus regarding the management of patients with massive liposarcomas located in the extremities. Several discrepancies related to the aggressiveness of the surgery and the application of concomitant radiotherapy and chemotherapy treatments remain controversial. The purpose of this study was to analyse the clinicopathological characteristics, prognostic factors and outcomes of a series of patients with massive liposarcomas of the extremities who were treated at a referral hospital specializing in musculoskeletal oncology.MethodsThis was an observational, descriptive and retrospective case series covering 10 years of clinical practice. The records of 26 adults, 14 men and 12 women, with localized massive liposarcomas in the extremities were studied. The average age was 53 years. The patients were treated from January 2003 until January 2012. Wide surgical resections with limb-sparing surgeries were performed for most patients (96.2 %).ResultsThe average tumour size was 15.1 ± 6.8 cm in the greatest dimension. Regarding the histological subtypes, there were 11 well-differentiated or atypical lipomatous tumours (42.3 %), 10 myxoid (38.5 %) and 5 (19.2 %) round cell and pleomorphic liposarcomas. Regarding the malignancy grades, 19 cases (73 %) were classified as low grade. Among these low-grade tumours predominated the well-differentiated subtype (57.9 %). Within high-grade tumours, the round cell and pleomorphic subtype was most frequent (57.1 %; p = 0.011). Radiotherapy was additionally applied to 12 patients (46.2 %) and adjuvant chemotherapy to 5 (19.3 %). Tumour recurrence was observed in only 2 cases (7.7 %). Only 1 of these cases developed lung metastatic dissemination.ConclusionsAcross the entire series, these massive tumours did not compromise the survival of the patients. The histologic subtype and the malignancy degree were closely related. Proper and early diagnosis and therapeutic management of these patients via the application of wide-margin surgical excision are essential to ensure long-term survival.

The role of AURKA in liposarcoma.

e21512 Background: Liposarcoma (LPS) is one of the most frequently found soft tissue sarcoma (STS). Among them, well-differentiated (WD) and dedifferentiated (DD) LPS are two the most common subtyp...

A randomized phase III study of trabectedin (T) or dacarbazine (D) for the treatment of patients (pts) with advanced liposarcoma (LPS) or leiomyosarcoma (LMS).

10503 Background: This phase III multicenter trial compared T with D in pts with advanced LPS or LMS previously treated with an anthracycline and at least one additional systemic therapy. Methods: Pts were randomized to T or D in a 2:1 ratio. Dosing of T and D were q 3 wks IV infusion: T (1.5 mg/m2 over 24 hr) vs D (1 g/m2 over 20-120 min). The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), time to progression (TTP), objective response rate (ORR), duration of response (DOR), symptom severity and safety. Cross-over to T after disease progression (PD) on D was not allowed until revision after this planned interim analysis (IA) of OS (50% events). The study is ongoing for final OS. Final results of secondary endpoints are presented. Results: The IA included 518 pts (T = 345, D = 173), 73% with LMS and 27% with LPS. Treatment with T resulted in a 45% reduction in the risk of PD or death compared with D (hazard ratio [HR] = 0.550; P < 0.0001; Median [M] 4.2 vs 1.5 months [mo], respectively), with benefit observed across all subgroups, and validated by independent radiologists audit. Other end points demonstrated improved efficacy of T: TTP (HR = 0.522, p < 0.0001; M = 4.2 vs 1.5 mo), clinical benefit rate (CR+PR+SD ≥ 18wks) (34.2% vs 18.5%; Odds Ratio[OR] = 2.291; p = 0.0002), ORR (9.9% vs 6.9%; OR = 1.467; p = 0.3269), DOR (HR=0.471, p = 0.1415; M = 6.5 vs 4.2 mo). The IA of OS (64% censored) demonstrated a 13% reduction in risk of death in T arm compared with D (HR = 0.872, p = 0.3741; M = 12.4 vs 12.9 mo). 34% of T and 17% of D pts received ≥ 6 cycles. The safety profiles were consistent with the well-characterized toxicities of both agents, with the most common grade 3-4 toxicities in T vs. D arm being ANC (40% vs 25%), platelets (19% vs 20%), increased ALT (29% vs 1%), and drug-related death (2.1% vs 0%). Patient-reported outcomes were similar across the arms, with low symptom scores during treatment. Conclusions: This phase III trial demonstrates improved disease control with T vs. D in advanced LPS and LMS, and confirms the acceptable benefit-risk profile of T from the prior randomized Phase 2 study (STS-201). T is a meaningful treatment option for pts with advanced LPS and LMS. Clinical trial information: NCT01343277.

Retroperitoneal Sarcoma Target Volume and Organ at Risk Contour Delineation Agreement Among NRG Sarcoma Radiation Oncologists

The purpose of this study was to evaluate the variability in target volume and organ at risk (OAR) contour delineation for retroperitoneal sarcoma (RPS) among 12 sarcoma radiation oncologists. Radiation planning computed tomography (CT) scans for 2 cases of RPS were distributed among 12 sarcoma radiation oncologists with instructions for contouring gross tumor volume (GTV), clinical target volume (CTV), high-risk CTV (HR CTV: area judged to be at high risk of resulting in positive margins after resection), and OARs: bowel bag, small bowel, colon, stomach, and duodenum. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. Ten radiation oncologists contoured both RPS cases, 1 contoured only RPS1, and 1 contoured only RPS2 such that each case was contoured by 11 radiation oncologists. The first case (RPS 1) was a patient with a de-differentiated (DD) liposarcoma (LPS) with a predominant well-differentiated (WD) component, and the second case (RPS 2) was a patient with DD LPS made up almost entirely of a DD component. Contouring agreement for GTV and CTV contours was high. However, the agreement for HR CTVs was only moderate. For OARs, agreement for stomach, bowel bag, small bowel, and colon was high, but agreement for duodenum (distorted by tumor in one of these cases) was fair to moderate. For preoperative treatment of RPS, sarcoma radiation oncologists contoured GTV, CTV, and most OARs with a high level of agreement. HR CTV contours were more variable. Further clarification of this volume with the help of sarcoma surgical oncologists is necessary to reach consensus. More attention to delineation of the duodenum is also needed.

Deregulation of dicer and mir-155 expression in liposarcoma.

Liposarcoma (LPS) is the most common soft tissue sarcoma. It has been demonstrated that mir-155 was the most overexpressed miRNA in well-differentiated LPS(WDLPS)/dedifferentiated LPS (DDLPS). The aim of this study is to evaluate the involvement of Dicer, Drosha and mir-155 in development of LPS and their possible role in stratification of different histological subtypes. Dicer, Drosha and mir-155 mRNA levels were analyzed in formalin-fixed paraffin-embedded specimens from patients diagnosed with 62 LPS and compared with samples of adipose tissues of healthy donors. The experimental data were obtained using qRT-PCR comparing Dicer, Drosha and mir-155 expression levels in tumor samples versus normal fat. The tumor samples from LPS patients showed a significantly lower Dicer expression versus normal adipose tissue, while Drosha levels did not differ. Concerning mir155 expression levels, our results demonstrated a significant mir-155 up-regulation in all LPS subtypes versus normal adipose tissue except for WDLS. These findings demonstrate for the first time that Dicer is deregulated in LPS and show that mir-155 is differentially expressed in LPS subgroups and it could be a promising tool to improve LPS disease stratification and differential diagnosis.