High dose (54 Gy) pre-operative helical tomotherapy for retroperitoneal liposarcoma: Results of a phase II multicenter study.

PURPOSE: To evaluate efficacy and feasibility of high-dose intensity-modulated radiotherapy (RT) with pre-operative helical tomotherapy, delivering 54 Gy/30 fractions in patients with retroperitoneal liposarcomas (RPLS). MATERIALS AND METHODS: Patients with operable, biopsy-proven, RPLS were included in this phase II multicenter study (ClinicalTrials.gov: NCT01841047). The primary objectives were to analyze loco-regional relapse free survival (LRFS), overall survival (OS) and toxicities, graded according to CTCAE V3.0. RESULTS: From April 2009 to September 2013, 48 patients were included. Histological types were: 20 well differentiated and 28 dedifferentiated liposarcomas. Median clinical target volume (CTV) was 2570 cc (range, 230-8734 cc). The radio-surgical schedule was completed as planned in all patients apart from one. A monobloc wide excision was achieved for all patients. Surgical margins were R0 (16; 34%), R1 (28; 60%), R2 (2; 4%) or missing (1, 2%).With a median follow-up of 5.5 years, 3-year LRFS rate was 74.2% (95%CI: [59.1%; 84.5%]). At 5 years, cumulative incidence of loco-regional relapse for well differentiated and dedifferentiated RPLS was 10% and 18%, respectively. The 5-year OS was 73.9% [95%CI: 58.7-84.3%]. During RT, the most common grade 3-4 adverse events were hematological (N = 20; 41.6%). After surgery and during follow-up, 17 patients (35.4%) presented a grade 3-4 toxicity. Two patients (4.1%) died due to a duodenal toxicity. Nine second cancers were observed. CONCLUSION: From this phase II trial of preoperative RT in RPLS patients, the dose level proposed cannot be considered safe, leading to non-negligible toxicity and second cancers rates. Our results, combined with STRASS-1 study, suggest that the ideal indication of RT for patients with RPLS still remains to be determined.

Extraordinarily long-inactive solitary fibrous tumor transformed to produce big insulin-like growth factor-2, leading to hypoglycemia and rapid liposarcoma growth: a case report.

BACKGROUND: A high-molecular-weight form of insulin-like growth factor-2 (IGF-2), known as "big" IGF-2, is occasionally produced by various tumor types, leading to hypoglycemia. Although solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm, it has been estimated that 4-6% of SFT patients develop hypoglycemia due to circulating big IGF-2. The mean time elapsed from tumor detection until the onset of hypoglycemia is reportedly less than one year (8.5 ± 1.9 months). CASE PRESENTATION: A 68-year-old man was hospitalized for exacerbation of recurring hypoglycemic episodes. He had been diagnosed with an SFT 17 years before the onset of hypoglycemia, and the SFT had already been very large at that time. The tumor, which was non-resectable and refractory to chemotherapies, had slowly increased in size since the initial diagnosis. Half a year before the hypoglycemic episodes manifested, another tumor, adjacent to the left kidney, was newly identified. Fluorodeoxyglucose positron emission tomography-computed tomography scanning, revealed the left peri-renal tumor to show much higher fluorodeoxyglucose uptake than the preexisting SFT, suggesting that it was unlikely to be a metastasis from the SFT. Abundant serum big IGF-2 was detected by western immunoblot analysis, indicating it to be the cause of the hypoglycemia. Since the 17 years between SFT detection and the onset of IGF-2-induced hypoglycemia was an extremely long period as compared with those in previous reports, we initially suspected that the new, peri-renal tumor had produced big IGF-2, but transcatheter arterial embolization of its feeding arteries did not suppress hypoglycemia. Notably, by measuring the tumor volume doubling time, the peri-renal tumor growth was shown to be markedly accelerated in parallel with exacerbation of the hypoglycemia. The patient died of heart failure 21 months after the onset of hypoglycemia. Unexpectedly, autopsy revealed that big IGF-2 had been produced only by the preexisting SFT, not the peri-renal tumor, and that the peri-renal tumor was a dedifferentiated liposarcoma. CONCLUSIONS: We should keep in mind that even a long-inactive SFT can undergo transformation to produce big IGF-2, which then acts on both insulin and IGF-1 receptors, possibly leading to both hypoglycemia and the development/growth of another tumor, respectively.

Understanding sarcomas and other rare tumors: an interview with Robin L Jones.

Robin L Jones speaks to Jade Parker, Commissioning Editor: Robin Jones is a medical oncologist specializing in the treatment of bone and soft tissue sarcomas and Head of the Sarcoma Unit at The Royal Marsden. He completed his medical training at Guy's and St Thomas' Hospital, and his oncology training at The Royal Marsden. His postgraduate research degree, with Professor Dowsett at the Institute of Cancer Research (ICR), evaluated potential predictive and prognostic factors in breast cancer patients treated with neoadjuvant chemotherapy. In January 2010 he was appointed Associate Professor and Director of the Sarcoma Program at the University of Washington and Fred Hutchinson Cancer Research Center in Seattle. He led a successful, grant funded program and continued his translational and clinical trial-based research. The laboratory work with Dr Seth Pollack evaluated novel immunotherapeutic targets in bone and soft tissue sarcomas, and has led to a number of early-phase immunotherapeutic clinical trials in sarcoma. He returned to The Royal Marsden and Institute of Cancer Research in December 2014, as Sarcoma Clinical Trials Team Leader and Consultant Medical Oncologist. He has experience in conducting Phase I, II and III trials, as well as translational studies in sarcoma. He is continuing a number of trials of investigational agents as well as laboratory-based immunotherapy studies.

The importance of treating by histological subtype in advanced soft tissue sarcoma.

While surgical resection (±radiotherapy) is standard treatment for localized soft tissue sarcomas (STS), chemotherapy is the mainstay for managing locally advanced and metastatic disease. Expanding knowledge of the biologies and sensitivities of STS histotypes, in conjunction with results from a growing collection of retrospective reviews and prospective randomized studies, point to the importance of treating in consideration of histological subtype. Doxorubicin ± ifosfamide continues to be standard first-line therapy for most STS subtypes. Main options for second- or later-line therapy include trabectedin, dacarbazine, gemcitabine combinations, pazopanib and, most recently, eribulin. Using illustrative case studies, treatment options are reviewed for three of the more common STS subtypes - uterine leiomyosarcoma, liposarcoma and synovial sarcoma - with a focus on use of trabectedin.

Application of molecular biology to individualize therapy for patients with liposarcoma.

Liposarcomas are one the most common of over 50 histologic subtypes of soft tissue sarcomas that are mostly resistant to chemotherapy. Histologically, liposarcomas themselves are heterogeneous and fall into four distinct subtypes: well-differentiated/atypical lipomatous tumor, dedifferentiated liposarcoma, myxoid (round cell) liposarcoma, and pleomorphic liposarcoma. Surgical resection with negative margins remains the mainstay for definitive treatment for operable disease. For unresectable disease, retrospective studies have identified myxoid (round cell) and pleomorphic sarcomas to be relatively responsive to chemotherapy. Recent studies have identified distinct genetic aberrations that not only aid in the diagnosis of particular liposarcoma subtypes, but represent actionable targets as they are considered central to disease pathogenesis. Cyclin-dependent kinase 4 (CDK4) and murine double minute 2 (MDM2) are overexpressed in well-differentiated and dedifferentiated liposarcomas and offer tantalizing opportunities that are being pursued in clinical trials. Myxoid (round cell) liposarcomas appear to be sensitive to trabectedin, which is currently under U.S. Food and Drug Administration (FDA) review. Liposarcomas do not represent a uniform disease and understanding the underlying molecular mechanism will help not only in accurate diagnosis but in selecting the appropriate treatment.

Oral contraceptive use, parity, and constitutional characteristics in soft tissue sarcoma: a Swedish population-based case-control study 1988-2009.

PURPOSE: The study was designed to investigate the influence of surrogate factors associated with sex (SH) and growth hormones (GH) on the risk of developing soft tissue sarcomas (STS). BACKGROUND AND METHODS: The etiology of soft tissue sarcoma is largely unknown. We have studied the effect of hormone related factors on STS in the Swedish population between 1988 and 2009 using a population-based matched case-control design. RESULTS: Our study is the largest on this topic to date, including 634 cases in a primary matched analysis and 855 cases in an unmatched sensitivity analysis. We identified protective effects connected to constitutional characteristics, hormonal and reproductive factors. Being shorter than your peers at age 11 was associated with an odds ratio (OR) of 0.51 (0.36-0.74). Having used oral contraceptives (OC), OR 0.75 (0.49-1.15), and high parity, OR 0.16 (0.04-0.63), comparing three or more children to two or less, also appeared to reduce the risk of STS. The risk was further reduced with the duration of OC use (p = 0.01), comparing use for 11 years or more to use for 3 years or less yielded an OR of 0.10 (0.02-0.41). No effect was observed for ever having had perimenopausal hormone therapy OR 1.02 (0.70-1.47). The effect of BMI varied significantly with subtype (p = 0.03) and tumor location (p < 0.001). CONCLUSIONS: We observed surrogates of SH, GH, and insulin-like growth factor 1 to be associated with STS development. These findings are important as they may connect STSs to the group of hormone-dependent tumors, potentially revealing common treatment and prevention targets.

Recurrent retroperitoneal liposarcoma in a patient with neurofibromatosis type I.

INTRODUCTION: Liposarcoma complicating neurofibromatosis is very rare. Only a few cases have been described until now. We present a case of recurrent dedifferentiated retroperitoneal liposarcoma in a patient with neurofibromatosis type I (NF-1). CASE PRESENTATION: A 47-year-old Caucasian woman with NF-1 presented to the hospital initially complaining of left lumbar pain irradiating to the anterior thigh and knee. Physical examination showed atrophy of the lower extremities bilaterally and decreased motor strength on the left lower extremity. Radiological studies demonstrated an enhancing lesion in the left paraspinal region, suggesting malignancy. The patient underwent local resection of tumour with safety margins. Pathological examination was consistent with dedifferentiated liposarcoma (DDLS) with positivity for MDM2 and CDK4 markers. No evidence of metastasis was noted on the radiological studies. The final diagnosis was DDLS, high-grade (G3), pT2bN0M0, stage III. After 6 weeks post-tumour resection, the patient experienced recurrence of malignancy. Chemotherapy with cisplatin and doxorubicin was initiated in the patient. CONCLUSIONS: Liposarcoma in the context of neurofibromatosis is very rare. To the best of our knowledge, only six cases have been reported until now in the literature. We are presenting this case to underline the possibility of recurrence in the case of retroperitoneal DDLSs despite local tumour resection. Also, although the role of chemotherapy is controversial we decided to start treatment with cisplatin and doxorubicin given the success of chemotherapy in similar case presentations.

High fat diet induces formation of spontaneous liposarcoma in mouse adipose tissue with overexpression of interleukin 22.

Interleukin 22 (IL-22) is a T-cell secreted cytokine that modulates inflammatory response in nonhematopoietic tissues such as epithelium and liver. The function of IL-22 in adipose tissue is currently unknown. We generated a transgenic mouse model with overexpression of IL-22 specifically in adipose tissue. The IL-22 transgenic mice had no apparent changes in obesity and insulin resistance after feeding with high fat diet (HFD). Unexpectedly, all the IL-22 transgenic mice fed with HFD for four months developed spontaneous tumors in epididymal adipose tissue. Histological analysis indicated that the tumors were well-differentiated liposarcomas with infiltration of inflammatory cells. IL-22 overexpression promotes production of inflammatory cytokines such as IL-1ß and IL-10 and stimulates ERK phosphorylation in adipose tissue. Furthermore, IL-22 treatment in differentiated 3T3-L1 adipocytes could induce IL-1ß and IL-10 expression, together with stimulation of ERK phosphorylation. Taken together, our study not only established a novel mouse model with spontaneous liposarcoma, but also revealed that IL-22 overexpression may collaborate with diet-induced obesity to impact on tumor development in mouse.

Functional and oncological outcome following marginal excision of well-differentiated forearm liposarcoma with nerve involvement.

PURPOSE: Liposarcoma is one of the most common soft tissue sarcomas in adults. It is often low-grade and can occasionally involve neurovascular structures. We present the functional and oncological outcome resulting from planned marginal excision of a series of forearm low-grade liposarcomas with nerve involvement. METHODS: The Oxford tumor registry was used to identify cases of histologically proven, well-differentiated liposarcoma of the forearm, with nerve involvement, treated surgically between 1997 and 2006. Nerve involvement was identified clinically with symptoms or signs of nerve compression, or by images showing direct contact of the tumor with a nerve on magnetic resonance imaging. This was then further defined at the time of surgery as tumor abutting (capsular involvement) or encasing a peripheral nerve. Demographic and clinical data were collected and oncological outcome was assessed by noting local and distant recurrence during follow-up. Postoperative functional outcome was assessed using the Toronto Extremity Salvage Scores. RESULTS: Eight cases were identified, 6 with preoperative neurological symptoms. The total group comprised 6 men and 2 women with a mean age of 61 (range, 30-71) years. At surgery, all had their tumors successfully excised, with preservation of the involved nerves. In those with preoperative neurological symptoms, complete recovery occurred by 18 months after surgery. The average follow-up was 5 years (range, 3-9 y). There were no cases of either local or distant recurrence of disease, with a mean Toronto Extremity Salvage Score of 99%. CONCLUSIONS: Planned marginal excision of a well-differentiated liposarcoma, arising in the forearm and involving nerve, can result in excellent functional and oncological outcome. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Liposarcoma: exploration of clinical prognostic factors for risk based stratification of therapy.

BACKGROUND: Prognosis and optimal treatment strategies of liposarcoma have not been fully defined. The purpose of this study is to define the distinctive clinical features of liposarcomas by assessing prognostic factors. METHODS: Between January 1995 and May 2008, 94 liposarcoma patients who underwent surgical resection with curative intent were reviewed. RESULTS: Fifty patients (53.2%) presented with well differentiated, 22 (23.4%) myxoid, 15 (16.0%) dedifferentiated, 5 (5.3%) round cell, and 2 (2.1%) pleomorphic histology. With the median 14 cm sized of tumor burden, about half of the cases were located in the retroperitoneum (46.8%). Seventy two (76.6%) patients remained alive with 78.1%, and 67.5% of the 5- and 10-year overall survival (OS) rates, respectively. Low grade liposarcoma (well differentiated and myxoid) had a significantly prolonged OS and disease free survival (DFS) with adjuvant radiotherapy when compared with those without adjuvant radiotherapy (5-year OS, 100% vs 66.3%, P = 0.03; 1-year DFS, 92.9% vs 50.0%, respectively, P = 0.04). Independent prognostic factors for OS were histologic variant (P = 0.001; HR, 5.1; 95% CI, 2.0 - 12.9), and margin status (P = 0.005; HR, 4.1; 95% CI, 1.6-10.5). We identified three different risk groups: group 1 (n = 66), no adverse factors; group 2, one or two adverse factors (n = 28). The 5-year OS rate for group 1, and 2 were 91.9%, 45.5%, respectively. CONCLUSION: The histologic subtype, and margin status were independently associated with OS, and adjuvant radiotherapy seems to confer survival benefit in low grade tumors. Our prognostic model for primary liposarcoma demonstrated distinct three groups of patients with good prognostic discrimination.

Formation of the 12q14-q15 amplicon precedes the development of a well-differentiated liposarcoma arising from a nonchondroid pulmonary hamartoma.

Pulmonary hamartoma is a benign neoplasm that rarely recurs or undergoes malignant transformation. Herein, we report a 48-year-old woman with a history of an incomplete excised nonchondroid pulmonary hamartoma presenting as an indolent tumor recurrence. Excision of the tumor revealed a well-differentiated liposarcoma arising from the hamartomatous component. Fluorescence in situ hybridation analysis for HMGA2 and MDM2 was performed on both hamartomatous and liposarcomatous component. MDM2 and HMGA2 amplification were found in a subset of stromal cells in the hamartomatous component and in most cells of the well-differentiated liposarcoma. No rearrangement HMGA2 was found in the pulmonary hamartoma component. These findings suggest that the formation of the 12q14-q15 chromosome amplicon, the characteristic cytogenetic finding of well-differentiated liposarcomas and the structural genomic component of the supernumerary ring and giant rod chromosomes, occurred before the morphologic changes characteristic of these malignant adipose tissue tumors and likely represents a very early molecular event in their development.

[Local recurrence of spermatic cord liposarcoma: a case report].

A 46-year-old man had undergone radical high orchiectomy because of a tumor of the right spermatic cord. Pathological diagnosis was atypical lipomatous tumor. Six years later, he had asymptomatic swelling in his right groin. Local recurrence was suspected, and surgical resection of the tumor with a sufficient surgical margin was performed. Pathological diagnosis was well-differentiated liposarcoma, sclerosing type. Ten cases of recurrent spermatic cord liposarcoma, including the present case, have been reported in Japan. Because of the possibility of local recurrence, spermatic cord liposarcoma needs strict and long-term follow up.

Late relapse of myelodysplasia after allogeneic transplantation concomitant with new presentation of invasive liposarcoma as a secondary neoplasm.

Second malignancies are uncommon events in the survivors of allogeneic transplant procedures, although they are increased compared to normal control populations. Among these malignancies, sarcomas are exceedingly rare. In addition, relapse of primary myelodysplasia rarely occurs after 5 years from the time of allogeneic transplantation. This report describes an unusual presentation of liposarcoma with concomitant relapse of underlying myelodysplasia developing in a patient 9 years after the first of two allogeneic transplantations.

[Cardiac liposarcoma at the right ventricular outflow tract (RVOT) following lipomatous hypertrophy of the interatrial septum (LHIS); report of a case].

A 23-year-old man, presenting with a 10-year history of a cardiac lipoma (lipomatous hypertrophy of the interatrial septum: LHIS), complained of anterior chest discomfort. Echocardiography and magnetic resonance imaging revealed remarkable hypertrophy of the interatrial septum (IAS) and posterior wall of the right atrium (RA), massive pericardial adipose tissue, and mild aortic valve insufficiency caused by compression of the tumor on the right ventricular outflow tract (RVOT). We performed surgical resection of the tumor stemming from the RVOT following removal of a large amount of the pericardial fat tissue (1,794 g), and then undertook biopsies of the IAS and the posterior wall of the RA. Pathological examination showed the right ventricular (RV) tumor to be liposarcoma and confirmed the benign nature of the biopsy tissues. We herein report a rare case of cardiac liposarcoma following LHIS in a young patient.

Expression of the FUS domain restores liposarcoma development in CHOP transgenic mice.

Fusion proteins created by chromosomal abnormalities are key components of mesenchymal cancer development. The most common chromosomal translocation in liposarcomas, t(12;16)(q13;p11), creates the FUS-CHOP fusion gene. In the past, we generated FUS-CHOP and CHOP transgenic mice and have shown that while FUS-CHOP transgenic develop liposarcomas, mice expressing CHOP, which lacks the FUS domain, display essentially normal white adipose tissue (WAT) development, suggesting that the FUS domain of FUS-CHOP plays a specific and critical role in the pathogenesis of liposarcoma. To test the significance of FUS and CHOP domain interactions within a living mouse, we generated mice expressing the FUS domain and crossed them with CHOP-transgenic mice to generate double-transgenic FUSxCHOP animals. Here we report that expression of the FUS domain restores liposarcoma development in CHOP-transgenic mice. Our results provide genetic evidence that FUS and CHOP domains function in trans for the mutual restoration of liposarcoma. These results identify a new mechanism of tumor-associated fusion genes and might have impact beyond myxoid liposarcoma.

Angiomiolipoma epitelioide hepático / Epithelioid angiomyolipoma of the liver

Describimos en nuestro trabajo un angiomiolipoma (AML) epitelioide hepático en una mujer de 50 años con dolor epigástrico y una masa de 47 mm bien definida en la ecografía. El AML es un tumor mesenquimal benigno poco frecuente, constituido por proporciones variables de células de músculo liso, vasos sanguíneos anormales y tejido adiposo. El diagnóstico preoperatorio es difícil. La inmunorreactividad con el anticuerpo HMB-45 ayuda a diferenciarlo de otros tumores hepáticos tanto benignos como malignos. (AU)