Can Survival Scoring Systems for Spinal Metastases be Used to Predict Postoperative Neurologic Recovery? A Retrospective Study on 204 Patients With Thoracolumbar Metastases Treated at a Tertiary Center.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: Scoring systems for metastatic disease of the spine are used to select patients for surgical treatment based on survival estimation, but it is unknown whether they can be used to predict the outcome of surgery. This study aims to investigate the association between two widely used prognostic scores and the neurologic function after surgery. METHODS: Retrospective analysis of 204 patients with thoracolumbar metastases treated with decompressive surgery at Karolinska University Hospital (2001-2020). Modified Bauer and Tokuhashi scores were categorized based on surgical indication, and post-operative neurological function was assessed using the Frankel scale at two different post-surgery intervals. RESULTS: Modified Bauer scores ≥2 yielded higher late follow-up Frankel scores (3.9 ± 1.1) than scores <2 (3.5 ± 1.1), P = .03. Modified Tokuhashi scores ≥9 correlated with higher Frankel scores (4.5 ± .9) than scores <9 (3.5 ± 1.1), P < .0001. Both scoring systems positively predicted neurological outcomes at late follow-up, with odds ratios of 1.6 (P = .03) for Bauer and 9.2 (P < .0001) for Tokuhashi. However, only Tokuhashi predicted ambulatory function at late follow-up (P < .0001), demonstrating its utility in prognosticating post-surgical mobility. CONCLUSION: Higher modified Bauer and Tokuhashi scores were associated with better neurologic function at last follow-up, as well as greater likelihood of being able to walk again. The Tokuhashi score was found to be more accurate than the modified Bauer score in predicting the neurological outcome after surgery.

MDM2 amplification in rod-shaped chromosomes provides clues to early stages of circularized gene amplification in liposarcoma.

Well-differentiated liposarcoma (WDLS) displays amplification of genes on chromosome 12 (Chr12) in supernumerary ring or giant marker chromosomes. These structures have been suggested to develop through chromothripsis, followed by circularization and breakage-fusion-bridge (BFB) cycles. To test this hypothesis, we compared WDLSs with Chr12 amplification in rod-shaped chromosomes with WDLSs with rings. Both types of amplicons share the same spectrum of structural variants (SVs), show higher SV frequencies in Chr12 than in co-amplified segments, have SVs that fuse the telomeric ends of co-amplified chromosomes, and lack interspersed deletions. Combined with the finding of cells with transient rod-shaped structures in tumors with ring chromosomes, this suggests a stepwise process starting with the gain of Chr12 material that, after remodeling which does not fit with classical chromothripsis, forms a dicentric structure with other chromosomes. Depending on if and when telomeres from other chromosomes are captured, circularized or linear gain of 12q sequences will predominate.

Comprehensive Genomic Profiling Alters Clinical Diagnoses in a Significant Fraction of Tumors Suspicious of Sarcoma.

PURPOSE: Tumor classification is a key component in personalized cancer care. For soft-tissue and bone tumors, this classification is currently based primarily on morphology assessment and IHC staining. However, these standard-of-care methods can pose challenges for pathologists. We therefore assessed how whole-genome and whole-transcriptome sequencing (WGTS) impacted tumor classification and clinical management when interpreted together with histomorphology. EXPERIMENTAL DESIGN: We prospectively evaluated WGTS in routine diagnostics of 200 soft-tissue and bone tumors suspicious for malignancy, including DNA and RNA isolation from the tumor, and DNA isolation from a peripheral blood sample or any non-tumor tissue. RESULTS: On the basis of specific genomic alterations or absence of presumed findings, WGTS resulted in reclassification of 7% (13/197) of the histopathologic diagnoses. Four cases were downgraded from low-grade sarcomas to benign lesions, and two cases were reclassified as metastatic malignant melanomas. Fusion genes associated with specific tumor entities were found in 30 samples. For malignant soft-tissue and bone tumors, we identified treatment relevant variants in 15% of cases. Germline pathogenic variants associated with a hereditary cancer syndrome were found in 22 participants (11%). CONCLUSIONS: WGTS provides an important dimension of data that aids in the classification of soft-tissue and bone tumors, correcting a significant fraction of clinical diagnoses, and identifies molecular targets relevant for precision medicine. However, genetic findings need to be evaluated in their morphopathologic context, just as germline findings need to be evaluated in the context of patient phenotype and family history.

Wound healing after surgery for soft tissue sarcomas, and the effect of primary plastic reconstruction - A retrospective cohort study.

BACKGROUND: Immediate vascularized reconstruction after sarcoma resection may reduce wound complications common in primary closure, but previous research is conflicting. The present study analysed wound complication rates and compared wound-related outcomes among immediate vascularized reconstruction with primary closure. MATERIALS AND METHODS: Patient- and tumour characteristics were collected from patients who received primary surgery with curative intent between 2010 and 2020 at the Stockholm Sarcoma Centre. Clinical outcomes were sought in free text in medical records. The primary outcome measures were early (<30 days) wound complications. Secondary outcome measures included late (30-day to 2-year) wound complications, time to wound healing, 30-day postoperative complications according to Clavien Dindo, and health care consumption. RESULTS: A total of 482 patients were included, of whom 69 had immediate vascularized reconstruction. Comparison of early complications for reconstructive surgery with primary closure revealed a significantly higher complication rate for the first group (59.4 % vs 29.8 %, p < 0.01). The groups had comparable health care consumption the first and second postoperative years. In-depth analyses identified BMI >25, smoking and high-grade lesions as factors with adverse effects on wound healing. CONCLUSIONS: Sarcoma patients experience high rates of wound complications and consume considerable health care resources. Reconstructed individuals were more susceptible to such complications than were subjects with primary closure.

Sarcoma care in the era of precision medicine.

Sarcoma subtype classification is currently mainly based upon histopathological morphology. Molecular analyses have emerged as an efficient addition to the diagnostic workup and sarcoma care. Knowledge about the sarcoma genome increases, and genetic events that can either support a histopathological diagnosis or suggest a differential diagnosis are identified, as well as novel therapeutic targets. In this review, we present diagnostic, therapeutic, and prognostic molecular markers that are, or might soon be, used clinically. For sarcoma diagnostics, there are specific fusions highly supportive or pathognomonic for a diagnostic entity-for instance, SYT::SSX in synovial sarcoma. Complex karyotypes also give diagnostic information-for example, supporting dedifferentiation rather than low-grade central osteosarcoma or well-differentiated liposarcoma when detected in combination with MDM2/CDK4 amplification. Molecular treatment predictive sarcoma markers are available for gastrointestinal stromal tumor (GIST) and locally aggressive benign mesenchymal tumors. The molecular prognostic markers for sarcomas in clinical practice are few. For solitary fibrous tumor, the type of NAB2::STAT6 fusion is associated with the outcome, and the KIT/PDGFRA pathogenic variant in GISTs can give prognostic information. With the exploding availability of sequencing technologies, it becomes increasingly important to understand the strengths and limitations of those methods and their context in sarcoma diagnostics. It is reasonable to believe that most sarcoma treatment centers will increase the use of massive-parallel sequencing soon. We conclude that the context in which the genetic findings are interpreted is of importance, and the interpretation of genomic findings requires considering tumor histomorphology.

An intraosseous myoepithelial carcinoma with a EWSR1::PBX3 fusion.

Herein we report a case of an intraosseous myoepithelial carcinoma harboring a EWSR1::PBX3 fusion gene. The patient was a 64-year-old male found to have a 7 cm destructive lesion in the distal ulna with an extraosseous soft tissue component. Microscopic examination of the resected tumor showed a spindle-cell lesion within a sclerotic stroma and intravascular tumor emboli. At higher power the tumor cells showed moderate nuclear atypia with a high mitotic count (20 per mm2 ). Immunohistochemistry revealed diffuse EMA positivity and focal pancytokeratin (AE1/AE3) and S100 expression, consistent with myoepithelial differentiation. NGS using the Oncomine Childhood Cancer Assay (Thermo Fisher Scientific, Inc.) revealed a EWSR1-PBX3 fusion and ABL amplification. The patient subsequently developed local recurrence as well as distant lymph node, lung and vertebral metastases; he is currently awaiting systemic treatment in the context of a clinical trial. In this report, we present a rare case of a skeletal myoepithelial tumor harboring a EWSR1::PBX3 fusion with demonstrated histological and clinical features of malignancy.

Predicting survival of patients with spinal metastatic disease using PathFx 3.0 - A validation study of 668 patients in Sweden.

Introduction: PathFx is a computer-based prediction model for estimating survival of patients with bone metastasis. The model has been validated in several studies, but this is the first validation using exclusively patients with spinal metastases. Research question: Is PathFx 3.0 a tool useful for predicting survival for patients with spinal metastatic disease? Material and methods: 668 patients (67% male, median age 67 years) presenting with spinal metastases at two university hospitals in Sweden 1991-2014 were included. Of those, the majority (82%, n â€‹= â€‹551) underwent surgery. Data on all patients was analyzed with PathFx version 3.0, generating a probability of survival at 1, 3, 6, 12, 18 and 24 months. The predictions were compared to real survival data and the precision in estimation was evaluated with Receiver-Operating Characteristic curve (ROC) analysis where the Area Under Curve (AUC) was calculated. Brier score and decision curve analyses were also assessed. Results: The AUC for 1-, 3-, 6- and 12 months survival predictions were 0.64 (95% CI 0.5-0.71), 0.71 (95% CI 0.67-0.75), 0.70 (95% CI 0.66-0.77) and 0.74 (95% CI 0.70-0.78). For 18- and 24 months survival the AUC were 0.74 (95% CI 0.69-0.78) and 0.76 (95% CI 0.72-0.81). The Brier scores were all 0.23 or lower depending on the estimated survival time. Discussion and conclusion: PathFx 3.0 is a reasonably reliable tool for predicting survival in patients with spinal metastatic disease. As the PathFx computer model can be updated to reflect advancements in oncology, we suggest this type of model, rather than rigid point-based scoring systems, to be used for estimating survival in patients with metastatic spinal disease in the future.

Intralesional margin after excision of a high-grade osteosarcoma: Is it a catastrophe?

BACKGROUND AND OBJECTIVES: Treatment of high-grade osteosarcoma (OS) relies on a combination of systemic chemotherapy and radical surgical excision of the tumor. Little is known on what happens in case of an irrefutably inadequate (intralesional) margin. We aimed to describe the outcome of patients with high-grade OSs of the trunk and the extremities where planned wide resection resulted in an intralesional margin. METHODS: A retrospective study from the Scandinavian Sarcoma Group registry and the Royal Orthopaedic Hospital databases including data from 53 patients surgically treated between the years 1990 and 2017. RESULTS: Local recurrence was observed in 13/53 patients. All patients with local recurrence where the neoadjuvant chemotherapy response could be retrieved (n = 9) were shown to be poor responders. None of the patients with good response to chemotherapy relapsed. Postoperative radiotherapy was not associated with improved local control of the disease. Re-excision surgery was performed in only seven patients, and two of them had tumor relapse. CONCLUSIONS: Good response to chemotherapy salvages the outcome of surgical excision with a poor margin in patients with high-grade OSs and a watchful waiting strategy may be justified in these cases. Poor responders have a higher recurrence risk and their approach should be individualized.

Evaluation of PD-L1 Expression in Undifferentiated Pleomorphic Sarcomas, Liposarcomas and Chondrosarcomas.

Immune checkpoint inhibitors (ICIs) such as PD1/PD-L1 blockers are an established treatment for many solid cancers. There are currently no approved ICIs for sarcomas, but satisfactory results have been seen in some patients with disseminated disease in certain histological types. Most studies on PD-L1 in sarcoma have used small specimens and there are no clear cutoff values for scoring. We investigated PD-L1 immunoreactivity in high-grade chondrosarcomas (CS), abdominal liposarcoma (LS) and undifferentiated pleomorphic sarcomas (UPS). In total, 230 tumors were stained with SP142 and SP263 assays and evaluated by two clinical pathologists. Immunoreactivity in tumor and immune cells was correlated with clinical outcome. Overall, ≥1% PD-L1 immunoreactivity in tumor cells was found in 11 CS, 26 LS and 59 UPS (SP142 assay) and in 10 CS, 26 LS and 77 UPS (SP263 assay). Most tumors exhibited ≤10% PD-L1 immunoreactivity, but a subset across all three subtypes had >50%. Kaplan-Meier survival analysis showed no significant difference in metastasis-free or overall survival in relation to PD-L1 immunoreactivity in tumor or immune cells for any subtype. As there is a lack of clinical data regarding PD-L1/PD-1 status and therapy response, it is not currently possible to establish clear cutoff values. Patients with high (>50%) PD-L1 immunoreactivity in tumor cells (TC) with the SP263 assay would be a logical group to investigate for potentially beneficial PD1/PD-L1-targeted treatment.

Surgical treatment of metastatic bone disease of the distal extremities.

Metastatic bone disease of the distal extremities, also known as acrometastasis, is very rare. Thus, there is very limited information regarding the clinical manifestations and methods of surgical treatment. The current available literature shows that acrometastases are often encountered in the context of advanced disease and are thus associated with poor patient survival. As metastatic bone disease is generally uncurable, the goal of surgical treatment is to provide the patient with good function with as few complications as possible. In this article, we discuss the clinical manifestation of acrometastases, the methods of surgical intervention, and the expected clinical outcome. Non-surgically managed pathological fractures generally remain ununited; therefore, conservative treatment is reserved for patients with poor general condition or dismal prognosis. The current evidence suggests that in lesions of the lower arm and leg, osteosynthesis (plate and screw fixation or intramedullary nail) is the most common method of reconstruction, whereas local excision or amputation are more commonly used in cases of more distal lesions (such as ankle, foot and hand). Following surgery most patients receive adjuvant radiotherapy, even though its role is poorly documented. Close collaboration between orthopedic surgeons and medical oncologists is necessary to improve patient care and treatment outcome. Further studies are needed in order to provide stronger clinical evidence and improve decision-making, in an effort to optimize the patients' quality of life and avoid the need for revision surgery.

Prosthesis or osteosynthesis for the treatment of a pathological hip fracture? A nationwide registry-based cohort study.

AIMS: How endoprosthetic replacement compares to osteosynthesis in the treatment of pathologic hip fractures as far as functional outcome and use of healthcare resources is concerned remains largely unknown. We aimed to investigate this in a nationwide registry. METHODS: We analyzed the functional outcome after surgery for a pathological fracture of the hip in terms of post-operative pain and ambulatory capacity. The preferred surgical method depending on the level of the treating unit was also examined. Furthermore, we documented the length of hospital stay and the patterns of discharge and compared them between these two methods. RESULTS: Patients operated with an endoprosthesis reported significantly lower pain at follow-up. Both methods (endoprosthetic replacement and osteosynthesis) were equally effective in restoring the ambulatory capacity and demanded a similar length of stay in hospital. Orthopaedic surgeons working in hospitals with dedicated sarcoma teams were more likely to use a prosthesis rather than osteosynthesis, when compared to surgeons working at other university hospitals or emergency hospitals. CONCLUSION: Endoprosthetic replacement results in a better functional outcome in terms of post-operative pain without consuming more healthcare resources. Orthopaedic surgeons working in hospitals with sarcoma centers are more likely to use prostheses as compared to surgeons working at hospitals where dedicated musculoskeletal oncology teams are not available.

TERT promoter mutation is an objective clinical marker for disease progression in chondrosarcoma.

Chondrosarcomas are the second most common malignant bone tumor. Activating promoter mutations in telomerase reverse transcriptase (TERT) was recently described by us and others as a frequent mutation in high-grade chondrosarcoma. In this study, we investigate the prognostic significance of TERT promoter mutations in 241 chondrosarcomas from 190 patients collected over 24 years (1994-2017). The TERT promoter was sequenced after microdissection of 135 chondrosarcomas from 106 patients in addition to data from our previous cohort. The TERT promoter mutation at -124 C > T was found in 45% of all patients and was significantly associated (p > 0,001) with higher tumor grade, shorter metastasis-free survival, and disease-specific survival. Additionally, TERT promoter-mutated tumors were associated with a more aggressive metastatic pattern. Shorter survival was observed in patients with wild-type primary tumors who developed a mutated metastasis indicative of tumor progression. Primary tumor genetic heterogeneity and altering mutational status between nonsynchronous metastatic lesions suggests that chondrosarcoma is a multiclonal disease progressing through a branching evolution. Conclusion: TERT promoter mutation seems to be a central event in chondrosarcoma progression with association to metastatic disease and disease-related mortality. As an easily analyzed marker, there is future potential to utilize TERT promoter mutation status as a prognostic marker and investigate telomerase-targeted therapy in chondrosarcomas.

Current Status of Management and Outcome for Patients with Ewing Sarcoma.

Ewing sarcoma is the second most common bone sarcoma in children after osteosarcoma. It is a very aggressive malignancy for which systemic treatment has greatly improved outcome for patients with localized disease, who now see survival rates of over 70%. However, for the quarter of patients presenting with metastatic disease, survival is still dismal with less than 30% of patients surviving past 5 years. Patients with disease relapse, local or distant, face an even poorer prognosis with an event-free 5-year survival rate of only 10%. Unfortunately, Ewing sarcoma patients have not yet seen the benefit of recent years' technical achievements such as next-generation sequencing, which have enabled researchers to study biological systems at a level never seen before. In spite of large multinational studies, treatment of Ewing sarcoma relies entirely on chemotherapeutic agents that have been largely unchanged for decades. As many promising modern therapies, including monoclonal antibodies, small molecules, and immunotherapy, have been disappointing to date, there is no clear candidate as to which drug should be investigated in the next large-scale clinical trial. However, the mechanisms driving tumor development in Ewing sarcoma are slowly unfolding. New entities of Ewing-like tumors, with fusion transcripts that are related to the oncogenic EWSR1-FLI1 fusion seen in the majority of Ewing tumors, are being mapped. These tumors, although sharing much of the same morphologic features as classic Ewing sarcoma, behave differently and may require a different treatment. There are also controversies regarding local treatment of Ewing sarcoma. The radiosensitive nature of the disease and the tendency for Ewing sarcoma to arise in the axial skeleton make local treatment very challenging. Surgical treatment and radiotherapy have their pros and cons, which may give rise to different treatment strategies in different centers around the world. This review article discusses some of these controversies and reproduces the highlights from recent publications with regard to diagnostics, systemic treatment, and surgical treatment of Ewing sarcoma.

CD11c-CD8 Spatial Cross Presentation: A Novel Approach to Link Immune Surveillance and Patient Survival in Soft Tissue Sarcoma.

Checkpoint inhibitors are slowly being introduced in the care of specific sarcoma subtypes such as undifferentiated pleomorphic sarcoma, alveolar soft part sarcoma, and angiosarcoma even though formal indication is lacking. Proper biomarkers to unravel potential immune reactivity in the tumor microenvironment are therefore expected to be highly warranted. In this study, intratumoral spatial cross presentation was investigated as a novel concept where immune cell composition in the tumor microenvironment was suggested to act as a proxy for immune surveillance. Double immunohistochemistry revealed a prognostic role of direct spatial interactions between CD11c+ antigen-presenting cells (APCs) and CD8+ cells in contrast to each marker alone in a soft tissue sarcoma (STS) cohort of 177 patients from the Karolinska University Hospital (MFS p = 0.048, OS p = 0.025). The survival benefit was verified in multivariable analysis (MFS p = 0.012, OS p = 0.004). Transcriptomics performed in the TCGA sarcoma cohort confirmed the prognostic value of combining CD11c with CD8 (259 patients, p = 0.005), irrespective of FOXP3 levels and in a CD274 (PD-LI)-rich tumor microenvironment. Altogether, this study presents a histopathological approach to link immune surveillance and patient survival in STS. Notably, spatial cross presentation as a prognostic marker is distinct from therapy response-predictive biomarkers such as immune checkpoint molecules of the PD-L1/PD1 pathway.

Clear-cell chondrosarcomas: Fine-needle aspiration cytology, radiological findings, and patient demographics of a rare entity.

BACKGROUND: Clear-cell chondrosarcomas (CCCSs) constitute a very rare subtype of chondrosarcoma. CCCS may radiologically mimic chondroblastoma, and given the difference in surgical approach, it is important to distinguish these two entities preoperatively. DESIGN: Using the institutional digital records, we identified histologically verified CCCS between 1996 and 2013, where preoperative fine-needle aspiration (FNA) cytology was available. Clinical characteristics were categorized and described, and FNAs were reviewed by a panel of senior cytopathologists. In addition, corresponding radiological imaging was reviewed by senior radiologists, and a literature review on CCCS and chondroblastoma was conducted. RESULTS: A total of seven CCCS FNAs were identified from six patients. The cytomorphology showed low to intermediate cellular smears of clusters and single round or oval tumor cells. Tumor cells had rounded (sometimes binucleated) nuclei with limited pleomorphism and rich vacuolated cytoplasm. Chondroid background matrix was always found. While CCCS patients had a significantly higher age at diagnosis compared to chondroblastoma, no age cut-off would distinctly separate the two. CONCLUSIONS: CCCS has distinguished cytomorphological features on FNA smears. CCCS should be considered as a possible differential diagnosis in adults (>25 years) with a radiological suspicion of chondroblastoma. Since radiology and patient age cannot conclusively distinguish CCCS from chondroblastoma, FNA may prove an important tool for correct preoperative diagnosis of CCCS.

Validation of PATHFx 2.0: An open-source tool for estimating survival in patients undergoing pathologic fracture fixation.

Treatment decisions in patients with metastatic bone disease rely on accurate survival estimation. We developed the original PATHFx models using expensive, proprietary software and now seek to provide a more cost-effective solution. Using open-source machine learning software to create PATHFx version 2.0, we asked whether PATHFx 2.0 could be created using open-source methods and externally validated in two unique patient populations. The training set of a well-characterized, database records of 189 patients and the bnlearn package within R Version 3.5.1 (R Foundation for Statistical Computing), was used to establish a series of Bayesian belief network models designed to predict survival at 1, 3, 6, 12, 18, and 24 months. Each was externally validated in both a Scandinavian (n = 815 patients) and a Japanese (n = 261 patients) data set. Brier scores and receiver operating characteristic curves to assessed discriminatory ability. Decision curve analysis (DCA) evaluated whether models should be used clinically. DCA showed that the model should be used clinically at all time points in the Scandinavian data set. For the 1-month time point, DCA of the Japanese data set suggested to expect better outcomes assuming all patients will survive greater than 1 month. Brier scores for each curve demonstrate that the models are accurate at each time point. Statement of Clinical Significance: we successfully transitioned to PATHFx 2.0 using open-source software and externally validated it in two unique patient populations, which can be used as a cost-effective option to guide surgical decisions in patients with metastatic bone disease.

Transcriptome profiling of Ewing sarcomas - treatment resistance pathways and IGF-dependency.

Ewing sarcomas (ESs) are aggressive sarcomas driven by EWS fusion genes. We sought to investigate whether whole-transcriptome sequencing (RNA-seq) could be used to detect patterns associated with chemotherapy response or tumor progression after first-line treatment. Transcriptome sequencing (RNA-seq) of 13 ES cases was performed. Among the differentially expressed pathways, we identified IGF2 expression as a potential driver of chemotherapy response and progression. We investigated the effect of IGF2 on proliferation, radioresistance, apoptosis, and the transcriptome pattern in four ES cell lines and the effect of IGF2 expression in a validation series of 14 patients. Transcriptome analysis identified differentially expressed genes (adj. P < 0.005) and pathways associated with chemotherapy response (285 genes), short overall survival (662 genes), and progression after treatment (447 genes). Imprinting independent promoter P3-mediated IGF2 expression was identified in a subset of cases with aggressive clinical course. In ES cell lines, IGF2 induced proliferation, but promoted radioresistance only in CADO cells. High IGF2 expression was also significantly associated with shorter overall survival in patients with ES. Transcriptome analysis of the clinical samples and the cell lines revealed an IGF-dependent signature, potentially related to a stem cell-like phenotype. Transcriptome analysis is a potentially powerful complementary tool to predict the clinical behavior of ES and may be utilized for clinical trial stratification strategies and personalized oncology. Certain gene signatures, for example, IGF-related pathways, are coupled to biological functions that could be of clinical importance. Finally, our results indicate that IGF inhibition may be successful as a first-line therapy in conjunction with conventional radiochemotherapy for a subset of patients.

Subsequent primary neoplasms among bone sarcoma survivors; increased risks remain after 30 years of follow-up and in the latest treatment era, a nationwide population-based study.

BACKGROUND: The long-term risks and time trends of subsequent primary neoplasms (SPNs) among Ewing (ES) and osteosarcoma (OS) survivors are not fully understood. METHODS: We performed a nationwide study of all ES and OS patients identified in the Swedish Cancer Registry from 1958 to 2015 with up to 58 years of follow-up. The risk of SPN was compared with that of the general population using standardised incidence ratios (SIRs) and absolute excess risks (AERs). RESULTS: One hundred and fifteen SPNs were diagnosed among 1779 patients with ES or OS, yielding an overall SIR of 2.3 (95% confidence interval (CI), 1.9-2.7). The risk remained significantly increased in the latest treatment era (SIR2000-2015 2.0; 95% CI, 1.1-3.5). The highest absolute excess risks (AER) was due to breast cancer (AER 15.2/10,000 person-years; 95% CI, 5.0-29.8) followed by female genital malignancies (AER 9.5/10,000 person-years; 95% CI, 2.4-21.5). The excess breast cancer risk among ES survivors was noted also after 30 years of follow-up with 127 extra breast cancers/10,000 person-years (95% CI, 6.6-419). CONCLUSIONS: Breast- and female genital malignancies contribute most to the excess risk of SPN among ES and OS survivors. Importantly, excess risks did not decline over calendar time or long-term follow-up.

The Tumor Microenvironment of Pediatric Sarcoma: Mesenchymal Mechanisms Regulating Cell Migration and Metastasis.

PURPOSE OF REVIEW: This review presents a selection of regulatory molecules of tumor microenvironmental properties and metastasis. Signaling pathways controlling mesenchymal biology in bone and soft-tissue sarcomas found in children and adolescents are prioritized. RECENT FINDINGS: The tumor microenvironment of pediatric tumors is still relatively unexplored. Highlighted findings are mainly on deregulated genes associated with cell adhesion, migration, and tumor cell dissemination. How these processes are involved in a mesenchymal phenotype and metastasis is further discussed in relation to the epithelial to mesenchymal transition (EMT) in epithelial tumors. Cell plasticity is emerging as a concept with impact on tumor behavior. Sarcomas belong to a heterogeneous group of tumors where local recurrence and tumor spread pose major challenges despite intense multimodal treatments. Molecular pathways involved in the metastatic process are currently being characterized, and tumor-regulatory properties of structural components, and infiltrating, non-malignant cell types should be further investigated.

A Low-Grade Myxoid Liposarcoma Arising in a Deep-Seated Conventional Lipoma.

Myxoid liposarcomas (MLS) are known to arise de novo and have not been shown to derive from previous benign lesions (lipomas), whereas lipomas occasionally harbor areas of other benign mesenchymal tissue. Rarely, tumors presenting with MLS or round cell liposarcomas together with conventional liposarcoma have been classified as mixed liposarcomas. However, no case of MLS arising in a conventional lipoma has been described. In this article, we report a case of a young male presenting with a deep-seated soft tissue tumor of the posterior part of the thigh. The tumor was removed en bloc. Grossing revealed a small encapsulated myxoid lesion (2.5 cm) within the larger lipomatous tumor (14 cm). Histological examination and cytogenetic analysis revealed a FUS-CHOP positive low-grade MLS arising in a conventional lipoma without histological atypia, FUS-CHOP fusion, or CDK4/MDM2 amplification. While we cannot conclude whether these were collision tumors or an MLS progression from a lipoma, this case highlights the value of careful grossing in the soft tissue setting.