Primary High-grade Soft Tissue Sarcomas Research Articles

Lung Surveillance Strategy for High-Grade Soft Tissue Sarcomas: Chest X-Ray or CT Scan?

Given the propensity for lung metastases, National Comprehensive Cancer Network guidelines recommend lung surveillance with either chest x-ray (CXR) or CT in high-grade soft tissue sarcoma. Considering survival, diagnostic sensitivity, and cost, the optimal modality is unknown. The US Sarcoma Collaborative database (2000 to 2016) was reviewed for patients who underwent resection of a primary high-grade soft tissue sarcoma. Primary end point was overall survival (OS). Cost analysis was performed. Among 909 patients, 83% had truncal/extremity and 17% had retroperitoneal tumors. Recurrence occurred in 48%, of which 54% were lung metastases. Lung surveillance was performed with CT in 80% and CXR in 20%. Both groups were clinically similar, although CT patients had more retroperitoneal tumors and recurrences. Regardless of modality, 85% to 90% of lung metastases were detected within the first 2 years with a similar re-intervention rate. When considering age, tumor size, location, margin status, and receipt of radiation, lung metastasis was independently associated with worse OS (hazard ratio 4.26; p < 0.01) and imaging modality was not (hazard ratio 1.01; p= 0.97). Chest x-ray patients did not have an inferior 5-year OS rate compared with CT (71% vs 60%; p < 0.01). When analyzing patients in whom no lung metastases were detected, both cohorts had a similar 5-year OS rate (73% vs 74%; p= 0.42), suggesting CXR was not missing clinically relevant lung nodules. When adhering to a guideline-specified protocol for 2018 projected 4,406 cases, surveillance with CXR for 5 years results in savings of $5 million to $8 million/year to the US healthcare system. In this large multicenter study, lung surveillance with CXR did not result in worse overall survival compared with CT. With considerable savings, a CXR-based protocol can optimize resource use for lung surveillance in high-grade soft tissue sarcoma; prospective trials are needed.

Primary high-grade soft-tissue sarcoma of the buttock: a rare but distinct clinical entity.

Sarcoma arising in the region of the buttocks is a rare entity and therefore no consensus regarding management exists in the literature. 16 patients diagnosed with localized, non-metastatic primary soft-tissue sarcoma (STS) in the buttock area, who were consecutively treated between 2005 and 2013, were retrospectively evaluated for the rate of local control, distant metastases and overall survival. Most tumours were classified as high grade (87.5%). The average time between the appearances of symptoms to diagnosis of sarcoma was 4.5 months. At the end of the observation period, 7 (44%) patients were alive without signs of progressive disease, 37.5% patients died as the disease progressed, 13 patients were free of disease and 3 (19%) patients were alive with signs of progressive disease. Seven (44%) patients developed local recurrence. Six (37.5%) patients developed distant metastases. The lung was the most common site of distant failure (four patients); other sites were the liver as well as the adrenal gland and kidney (one patient). Four patients had both distant and local progression, three patients experienced isolated local recurrence and two patients developed isolated distant metastases. 5-year local recurrence-free survival was 58% and 5-year distant metastases-free survival was 63%. It is unclear whether to subsume STS of the buttock under the rubric of pelvic tumours or tumours of the lower extremity. Either way, STS of the buttock seems to be characterized by local control, freedom from distant relapse and survival, which is inferior to accepted standards for either pelvic or lower extremity sarcomas. To improve this poor outcome, oncologists are encouraged to regard sarcoma of the buttock as a distinct clinical entity and to devise innovative therapeutic strategies accordingly. Sarcoma of the buttock area should possibly be regarded as a distinct entity.

Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas

BackgroundHigh-grade soft tissue sarcomas are a heterogeneous, complex group of aggressive malignant tumors showing mesenchymal differentiation. Recently, soft tissue sarcomas have increasingly been classified on the basis of underlying genetic alterations; however, the role of aberrant DNA methylation in these tumors is not well understood and, consequently, the usefulness of methylation-based classification is unclear.ResultsWe used the Infinium HumanMethylation27 platform to profile DNA methylation in 80 primary, untreated high-grade soft tissue sarcomas, representing eight relevant subtypes, two non-neoplastic fat samples and 14 representative sarcoma cell lines. The primary samples were partitioned into seven stable clusters. A classification algorithm identified 216 CpG sites, mapping to 246 genes, showing different degrees of DNA methylation between these seven groups. The differences between the clusters were best represented by a set of eight CpG sites located in the genes SPEG, NNAT, FBLN2, PYROXD2, ZNF217, COL14A1, DMRT2 and CDKN2A. By integrating DNA methylation and mRNA expression data, we identified 27 genes showing negative and three genes showing positive correlation. Compared with non-neoplastic fat, NNAT showed DNA hypomethylation and inverse gene expression in myxoid liposarcomas, and DNA hypermethylation and inverse gene expression in dedifferentiated and pleomorphic liposarcomas. Recovery of NNAT in a hypermethylated myxoid liposarcoma cell line decreased cell migration and viability.ConclusionsOur analysis represents the first comprehensive integration of DNA methylation and transcriptional data in primary high-grade soft tissue sarcomas. We propose novel biomarkers and genes relevant for pathogenesis, including NNAT as a potential tumor suppressor in myxoid liposarcomas.

MicroRNA profiling of primary high‐grade soft tissue sarcomas

High-grade soft tissue sarcomas are a heterogeneous and complex group of tumors. MicroRNAs (miRNAs) are considered as attractive candidates that may improve diagnostic, prognostic, and predictive characterization of this group of malignancies. We performed a comprehensive miRNA expression analysis in a series of 76 untreated, primary high-grade soft tissue sarcomas representing eight subtypes, and in a panel of 15 representative sarcoma cell lines using microarray technology. This screening revealed unique miRNA expression patterns for synovial sarcomas, myxoid liposarcomas, and leiomyosarcomas, and defined unique sets of miRNAs discriminating the different liposarcoma subtypes from non-neoplastic adipose tissue. The over-represented miRNAs included members of the miR-200 family in synovial sarcomas, and the tumor-associated miR-9 and miR-9* in myxoid liposarcomas compared to adipose tissue. Moreover, we found coexpression of 63 miRNAs clustering in a genetically imprinted chromosomal region 14q32.2 separating primary sarcoma samples and sarcoma cell lines into two molecular subgroups. Taken together, our comprehensive miRNA profiling identified a novel set of miRNAs that might contribute to sarcomagenesis and provide a starting point for experimental modulation of relevant targets for new therapeutic strategies in high-grade sarcomas.

18F-FDG-PET/CT Imaging as an Early Survival Predictor in Patients with Primary High-Grade Soft Tissue Sarcomas Undergoing Neoadjuvant Therapy

Neoadjuvant therapy is associated with considerable toxicity and limited survival benefits in patients with soft tissue sarcoma (STS). We prospectively evaluated whether 2[18F]fluoro-2-deoxy-d-glucose ((18)F-FDG)-PET/computed tomographic (CT) imaging after the initial cycle of neoadjuvant therapy could predict overall survival in these patients. Thirty-nine patients underwent (18)F-FDG-PET/CT before and after one cycle of neoadjuvant therapy. Fifty-six patients underwent end-of-treatment PET. Overall survival was, among others, correlated with changes of SUV(peak) and histopathology. One-, two-, and five-year survival rates were 95% ± 3.0%, 86% ± 4.6%, and 68% ± 6.6%, respectively. Median time to death was 30.9 months (mean, 27.7; range, 6.9-50.1). Optimal cutoff values for early and late decreases in SUV(peak) (26% and 57%, respectively) were significant predictors of survival in univariate survival analysis [P = 0.041; HR, 0.27; 95% confidence interval (CI), 0.08-0.95 and P = 0.045; HR, 0.31; 95% CI, 0.10-0.98]. Seven of 15 early PET nonresponders but only four of 24 early PET responders died during follow-up (P = 0.068). The only other significant survival predictor was surgical margin positivity (P = 0.041; HR, 3.31; 95% CI, 1.05-10.42). By multivariable analysis, early metabolic response (P = 0.016) and positivity of surgical margins (P = 0.036) remained significant survival predictors. (18)F-FDG-PET predicted survival after the initial cycle of neoadjuvant chemotherapy in patients with STS and can potentially serve as an intermediate endpoint biomarker in clinical research and patient care.

A new limb salvage surgery in cases of high‐grade soft tissue sarcoma using photodynamic surgery, followed by photo‐ and radiodynamic therapy with acridine orange

To maintain excellent limb function after tumor resection in patients with high-grade malignant sarcomas, we developed and established a new surgical adjuvant therapy using acridine orange (AO) after intra-lesional or marginal resection while sparing normal tissues of major nerves, vessels or bones adjacent to the tumor. Our AO therapy procedure was combined with photodynamic surgery (PDS), photodynamic therapy (PDT) and radiodynamic therapy (RDT). In this study, 26 patients with primary high-grade soft tissue sarcomas were treated with AO therapy. Results showed a low local recurrence rate (7.7%) and good local recurrence-free rate (88%) after AO therapy. Limb function of all patients was maintained at 100% of ISOLS criteria. Based on these results, we concluded that AO therapy is useful for local control after margin-positive tumor resection and for preserving excellent limb function in patients with high-grade soft tissue sarcomas.

Influence of site on the therapeutic ratio of adjuvant radiotherapy in soft-tissue sarcoma of the extremity

The ultimate goal of adjuvant radiotherapy (RT) in soft-tissue sarcoma of the extremity is to improve the therapeutic ratio by increasing local control while minimizing morbidity. Most efforts in trying to improve this ratio have focused on the sequencing of RT and surgery, with little attention to the potential influence of the tumor site. The purpose of this study was to determine the influence of tumor site on local control and complications in a group of patients with primary high-grade soft-tissue sarcoma of the extremity treated at a single institution with postoperative RT. Between July 1982 and December 2000, 369 adult patients with primary high-grade soft-tissue sarcoma of the extremity were treated with limb-sparing surgery and postoperative RT. Patients who underwent surgery or RT outside our institution were excluded. The tumor site was the upper extremity (UE) in 103 (28%) and the lower extremity (LE) in 266 (72%). The tumor was < or = 5 cm in 98 patients (27%), and the microscopic margins were positive in 44 (12%). Of the 369 patients, 104 (28%) underwent postoperative external beam RT (EBRT), 233 (63%) postoperative brachytherapy (BRT), and 32 underwent a combination (9%); 325 (88%) received a "conventional" radiation dose, defined as 60-70 Gy for EBRT, 45 Gy for BRT, and 45-50 Gy plus 15-20 Gy for EBRT plus BRT. Complications were assessed in terms of wound complications requiring repeat surgery, fracture, joint stiffness, edema, and Grade 3 or worse peripheral nerve damage. The UE and LE groups were balanced with regard to age, depth, margin status, and type of RT (EBRT vs. BRT +/- EBRT). However, more patients in the UE group had tumors < or = 5 cm and more received a conventional radiation dose (p = 0.01 and P = 0.03, respectively). With a median follow-up of 50 months, the 5-year actuarial rate of local control, distant relapse-free survival, and overall survival for the whole population was 82% (95% confidence interval [CI], 77-86%), 61% (95% CI, 56-66%), and 71% (95% CI, 66-76%), respectively. The 5-year local control rate in patients with UE STS was 70% (95% CI, 60-80%) compared with 86% (95% CI, 81-91%) for LE STS (p = 0.0004). On multivariate analysis, an UE site (p = 0.001; relative risk [RR], 3; 95% CI, 2-5) and positive resection margins (p = 0.02; RR, 2; 95% CI, 1-4) were significant predictors of poor local control. The RT type or radiation dose, age, tumor depth, and size were not significant predictors of local control. The 5-year wound reoperation rate was 1% (95% CI, 0-3) in the UE compared with 11% (95% CI, 7-15) in the LE (p = 0.002). On multivariate analysis, the UE site retained its significance as a predictor of low wound complications (p = 0.001; RR, 0.08; 95% CI, 0.01-0.7). The site did not significantly influence the incidence of fracture (p = 0.7), joint stiffness (p = 0.2), edema (p = 0.5), or Grade 3 or worse peripheral nerve damage (p = 0.3). The UE site is associated with a greater rate of local recurrence compared with the LE. This difference was independent of other variables and could not be accounted for by an imbalance between the two groups. With a lower wound complication rate associated with an UE site, it would be of interest to determine whether preoperative RT and/or intensity-modulated RT can increase the local control in UE sarcomas, thus improving the therapeutic ratio.

Adjuvant brachytherapy for primary high-grade soft tissue sarcoma of the extremity.

We reviewed single-institution experience using brachytherapy alone for primary high-grade soft tissue sarcoma of the extremity. Between July 1982 and September 1997, 202 adult patients with primary high-grade soft tissue sarcoma of the extremity were treated with limb-sparing surgery and adjuvant brachytherapy. All patients underwent complete gross resection, but the margin of resection was microscopically positive in 18% of patients. The median dose of brachytherapy was 45 Gy delivered over 5 days. Tumors located in the shoulder or groin were defined as central location. Complications were assessed in terms of wound complications, bone fracture, and peripheral nerve damage. With a median follow-up of 61 months, the 5-year local control, distant relapse-free survival, and overall survival rates were 84%, 63%, and 70%, respectively. On multivariate analysis, poor local control correlated with shoulder location, positive microscopic margins of resection, and nonshoulder upper extremity site. The 5-year actuarial rates of wound complications requiring reoperation, bone fracture, and grade > or = 3 nerve damage were 12%, 3%, and 5%, respectively. Adjuvant brachytherapy provides adequate local control and acceptable morbidity that compares favorably with data reported for external beam radiation. Shoulder tumor location was identified as an independent prognostic factor for poor local control, mandating further improvement in the local management of these tumors.

Local Excision Without Radiation for High‐Grade Soft‐Tissue Sarcoma ofthe Extremity and Superficial Trunk

Purpose. Limb-sparing surgery combined with radiation treatment has become the accepted treatment for patients with high-grade soft-tissue sarcoma. Adjuvant radiation was not routinely used at this institution for patients with clear margins after surgery.This retrospective review analyses the outcome of this group of patients. Patients and methods. Patients studied were referred from 1984 to 1995, were over 16 years of age, were diagnosed with primary high-grade soft-tissue sarcoma of the extremity or superficial trunk, had clear margins after excision and did not receive radiation as a part of their initial treatment. A total of 46 patients were identified. Results. At 5 years, the local control rate was 87%, disease-specific survival was 75% and overall survival was 68%. Of the 6 local recurrences, 3 were located in the buttock (from a total of 7 patients with primary tumours of the buttock), 3 had a primary size of ≥ 10 cm (from a total of 8 primary tumours of that size) and all were deep tumours. Discussion. Our data, and those from other reports, suggest that in carefully selected patients appropriate surgery alone results in acceptable local control and survival, and that the morbidity of radiation can be avoided.