Recurrent Dedifferentiated Liposarcoma Research Articles

En Bloc Resection of a 60cm Recurrent Dedifferentiated Liposarcoma Involving the Liver, Right Kidney and Ascending Colon

This case report was about a giant recurrent dedifferentiated liposarcoma which invaded the intraperitoneal space to the posterior sector of liver, attaching the right hepatic vein (RHV) and inferior vena cava (IVC). It had already encased the right kidney, right ureter, right colon and mesocolon. The whole IVC was compressed and pushed to the left side and ventral side of the abdominal space by this giant tumour. The posterior approach cannot be done due to the heavy giant tumour (about 28 Kg) and change of anatomy landmarks. By anterior approach to cut into the liver parenchyma, dissection and exposure along the surface of RHV can advance to the IVC surface. Small venous outflow tracts from the tumour to the surface of RHV and IVC were exposed, ligated and separated. After the junction of RHV and retrohepatic IVC was exposed, cranial to caudal dissection using an ultrasonic aspirator along the ventral, lateral and posterior surface of IVC can separate the IVC wall from the tumour clearly. Further dissection downward along the surface of the twisted IVC was useful to separate the tumour from the posterior side of pancreatic head, portal vein, superior mesentery vein (SMV), and the root of right renal vein. In conclusion, an anterior approach of hepatotomy for RHV first and then IVC is a useful method for this giant tumour if the posterior approach for IVC exposure cannot be done.

Multifocal Giant Retroperitoneal Dedifferentiated Liposarcoma with dual heterologous dedifferentiation– a diagnostic and therapeutic challenge

Dedifferentiated liposarcoma (DDL) with divergent dedifferentiation is uncommonly reported with variable incidences. Liposarcomas, particularly those manifesting dedifferentiation, occur in the retroperitoneum. They grow into large size, present at very late stages, and can have a poor clinical outcome. Here we present a rare case of recurrent dedifferentiated liposarcoma with dual heterologous differentiation with osteosarcoma and Chondrosarcoma in an elderly male who had initially presented wi

The Oncolytic Activity of Myxoma Virus against Soft Tissue Sarcoma Is Mediated by the Overexpression of Ribonucleotide Reductase.

Background:Myxoma virus (MYXV) is an oncolytic poxvirus that lacks the gene for 1 of the subunits of ribonucleotide reductase (RR), a crucial DNA synthesis and repair enzyme. The overexpression of RR has been implicated in the invasiveness of several cancers, including soft tissue sarcomas (STS). The purpose of the study was to investigate the oncolytic efficacy of MYXV in STS with different levels of RR expression.Methods:The oncolytic effect of recombinant MYXV was evaluated in 4 human STS cell lines, LS141 (a dedifferentiated liposarcoma), DDLS8817 (a dedifferentiated liposarcoma), RDD2213 (recurrent dedifferentiated liposarcoma), and HSSYII (a synovial sarcoma) using infectivity and cytotoxicity assays. Following the overexpression of RRM2 by cDNA transfection and silencing of RRM2 by siRRM2 in these STS cell lines, the RRM2 expression levels were analyzed by Western blot.Results:We observed a direct correlation between viral oncolysis and RRM2 mRNA levels (R = 0.96) in STS. Higher RRM2 expression was associated with a more robust cell kill. Silencing the RRM2 gene led to significantly greater cell survival (80%) compared with the control group (P = .003), whereas overexpression of the RRM2 increased viral oncolysis by 33% (P < .001).Conclusions:Our results show that the oncolytic effects of MYXV correlate directly with RR expression levels and are enhanced in STS cell lines with naturally occurring or artificially induced high expression levels of RR. Myxoma virus holds promise in the treatment of advanced soft tissue cancer, especially in tumors overexpressing RR.

The combination of gemcitabine and docetaxel arrests a doxorubicin-resistant dedifferentiated liposarcoma in a patient-derived orthotopic xenograft model

Liposarcoma (LS) is a chemotherapy-resistant disease. The aim of the present study was to find precise therapy for a recurrent dedifferentiated liposarcoma (DDLS) in a patient-derived orthotopic xenograft (PDOX) model. The DDLS PDOX models were established orthotopically in the right inguinal area of nude mice. The DDLS PDOX models were randomized into five groups: untreated; doxorubicin (DOX); gemcitabine (GEM) combined with docetaxel (DOC); pazopanib (PAZ); and yondelis (YON). On day 15, all mice were sacrificed. Measurement of tumor volume and body weight were done two times a week. The DDLS PDOX was resistant to DOX (P > 0.184). YON suppressed tumor growth significantly compared to control group (P < 0.027). However, only GEM combined with DOC arrested the tumor growth (P < 0.001). These findings suggest that GEM combined with DOC has clinical potential for this and possibly other DDLS patients.

Phase II study of neoadjuvant checkpoint blockade in patients with surgically resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma

BackgroundSoft tissue sarcomas are a heterogeneous and rare group of solid tumors of mesenchymal origin that can arise anywhere in the body. Although surgical resection is the mainstay of treatment for patients with localized disease, disease recurrence is common and 5-year overall survival is poor (~ 65%). Both radiation therapy and conventional chemotherapy are used to reduce local and distant recurrence. However, the utility of radiation therapy is often limited by disease location (in the case of retroperitoneal sarcomas, for instance) while systemic therapy with conventional lines of chemotherapy offer limited efficacy and are often poorly tolerated and associated with significant toxicity. Within the past decade, major advances have been made in the treatment of other malignancies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma with the advent of immune-checkpoint inhibitors such as ipilimumab (anti-CTLA4), pembrolizumab (anti-PD1), and nivolumab (anti-PD1). The recently published SARC028 (NCT02301039), an open label, phase II, multicenter trial of pembrolizumab in patients with advanced bone and soft tissue sarcomas reported promising activity in select histologic subtypes of advanced STS, including undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.MethodsThere is a clear need for novel and effective adjuncts in the treatment of STS. We hypothesize that immune checkpoint blockade will be effective in patients with surgically resectable primary or locally recurrent dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma when administered in the neoadjuvant setting. The primary aim of this phase II, single-center, open label, randomized non-comparative trial is to determine the pathologic response to neoadjuvant nivolumab monotherapy and combination nivolumab/ipilimumab in patients with resectable dedifferentiated liposarcoma of the retroperitoneum or undifferentiated pleomorphic sarcoma of the trunk or extremity treated with concurrent standard of care neoadjuvant radiation therapy.DiscussionThis study will help define the role of single agent anti-PD1 and combination anti-CTLA4 and anti-PD1 therapy in patients with surgically resectable dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma.Trial registrationClinicalTrials.govNCT03307616, registered October 12, 2017.

Frequent Alterations and Epigenetic Silencing of Differentiation Pathway Genes in Structurally Rearranged Liposarcomas

We explored diverse alterations contributing to liposarcomagenesis by sequencing the genome, exome, transcriptome, and cytosine methylome of a primary and recurrent dedifferentiated liposarcoma (DLPS) from distinct chemotherapy/radiotherapy-naïve patients. The liposarcoma genomes had complex structural rearrangements, but in different patterns, and with varied effects on the structure and expression of affected genes. While the point mutation rate was modest, integrative analyses and additional screening identified somatic mutations in HDAC1 in 8.3% of DLPS. Liposarcoma methylomes revealed alterations in differentiation pathway genes, including CEBPA methylation in 24% of DLPS. Treatment with demethylating agents, which restored CEBPA expression in DLPS cells, was anti-proliferative and pro-apoptotic in vitro and reduced tumor growth in vivo. Both genetic and epigenetic abnormalities established a role for small RNAs in liposarcomagenesis, typified by methylation-induced silencing of microRNA-193b in DLPS but not its well-differentiated counterpart. These findings reveal an unanticipated role for epigenetic abnormalities in DLPS tumors and suggest demethylating agents as potential therapeutics. Multimodality sequence analysis of DLPS revealed recurrent mutations and epigenetic abnormalities critical to liposarcomagenesis and to the suppression of adipocyte differentiation. Pharmacologic inhibition of DNA methylation promoted apoptosis and differentiated DLPS cells in vitro and inhibited tumor growth in vivo, providing a rationale for investigating methylation inhibitors in this disease.

Recurrent dedifferentiated liposarcoma of mediastinum involving lung and pleura

We report a case of primary recurrent mediastinal dedifferentiated liposarcoma with unusual long-term survival. A woman who complained of dyspnea showed on imaging features a bulky posterior mediastinal mass which was completely excised and initially misdiagnosed as an angiomyolipoma. She recurred 15 months later and histological examination showed a dedifferentiated liposarcoma. Resection was incomplete and the patient received adjuvant therapy. Eight years later a second recurrence occurred in the right pleura and lung. The patient died three months later.

Dedifferentiated liposarcoma with rhabdomyoblastic differentiation

Dedifferentiated areas of dedifferentiated liposarcoma (DDL) usually show malignant fibrous histiocytoma (MFH)- or fibrosarcoma-like features and lack any histologic signs of specific differentiation. However, some reports have demonstrated specific differentiation in these areas, with histologic features resembling those of rhabdomyosarcoma, leiomyosarcoma, and osteosarcoma. We report here a pathologic and genetic analysis of three cases of DDLs with rhabdomyosarcomatous areas. MFH- or fibrosarcoma-like areas of one primary DDL and two recurrent DDLs contained various amounts of rhabdomyoblasts, which were immunoreactive for desmin, myoglobin, muscle actin (HHF-35), and myogenin. An ultrastructural examination demonstrated rhabdomyoblasts with abundant cytoplasm containing thin and thick filaments and Z-bands. By real-time PCR, amplification of mdm2 and cdk4 was confirmed in both well-differentiated and dedifferentiated areas with rhabdomyoblasts of all cases. To our knowledge, only seven cases of DDLs with rhabdomyosarcomatous components have been reported, and furthermore, the genetic profiles of the rhabdomyosarcomatous components in DDLs have not been investigated. This study demonstrates that DDLs with rhabdomyosarcomatous areas have genetic alterations that are common to well-differentiated/dedifferentiated liposarcomas.

Recurrent dedifferentiated liposarcoma of the spermatic cord simulating malignant fibrous histiocytoma: An immunohistochemical and ultrastructural study

A case of recurrent dedifferentiated liposarcoma simulating malignant fibrous histiocytoma, with complete absence of lipoblastic differentiation, is described. The tumour cells showed strongly positive immunostaining for alpha-1-antichymotrypsin. Electron microscopy revealed a mixture of fibroblasts and histiocytes. Our findings suggest that the dedifferentiated component reflects an altered differentiation pathway of the primitive mesenchymal cells in the original liposarcoma.