Extraskeletal Ewing sarcoma of the extremities and trunk: a retrospective analysis of a mono-institutional series.

Introduction Extra-skeletal Ewing sarcoma is a rare malignant tumor, and current international recommendations indicate systemic and local treatment like bone Ewing sarcoma; to the best of our knowledge, very few studies tried to explore the clinical and genetic characteristics of this tumor and the most appropriate treatment strategy remains uncertain. Methods We reviewed 35 extra-skeletal Ewing sarcoma (EEwS) cases enrolled at Rizzoli Orthopedic Institute in Bologna, Italy between 1988-2022. We performed RNA sequencing in 18 Ewing sarcoma cases, including 12 bone Ewing sarcomas (BEwS) and 6 EEwS. We analyzed overall survival (OS), local relapse-free survival (LRFS), and metastasis-free survival (MFS) and the risk factors associated to survival. Results Unsupervised Hierarchical clustering showed no differences in the transcriptional profile between EEwS and BEwS. Five-year OS was 67% (95%CI 47-80), 5-year LRFS was 61% (95% CI 43-75), and 5-year MFS was 55% (95% CI 38-70). Recurrent tumors, larger than 8 cm, and elevated LDH serum value resulted to be a negative prognostic factor. Conclusions The founding of a genetic profile indistinguishable between EEwS and BEwS, confirms the view that includes the two subgroups in the same tumor entity and supports the use of a single therapeutic approach for Ewing sarcoma independently from the site of origin. Statistical evaluation showed that size bigger than 8cm, elevated LDH, and recurrent tumors had a worse prognosis, suggesting a risk-stratification method for identifying patients for specific therapy treatment. However, larger, multicentre, prospective trials are called for to validate our findings.

Epithelioid Hemangioma of the Spine: A Case Series and Treatment Flow Chart-Experience from a Single Centre.

Epithelioid hemangioma is recognized by the World Health Organization as a distinct benign neoplasm; however, it is characterized by locally aggressive and rarely metastasizing behavior. Epithelioid vascular tumors are rare bony vascular lesions with varying degrees of malignant potential that remain controversial because of their rarity, unusual morphological features, and unpredictable biological behavior. The application of new molecular tools, such as massive parallel sequencing technologies, have provided new diagnostic markers and an opportunity to further refine the classification of bone vascular neoplasms. Very few cases of EH of the spine have been reported in the literature; therefore, it is difficult to make evidence-based therapeutic decisions for these patients. We report herein our experience with eleven patients suffering from EH of the spine. The study population included three males and eight females treated in our center from 2016 to the present; the average age was 44.8 years (range 14-75 years). The surgical, clinical, and radiographic data were retrospectively analyzed. The mean follow-up was 34.8 months. All patients presented lytic vertebral body lesions, six of them with pathological fracture. The majority of patients (80%) presented myelo-radicular compression. All patients were surgically treated, and preoperative embolization was performed in all cases. In light of the literature review and the clinical experience of our center, we can consider EH a locally aggressive tumor that requires surgical treatment in case of symptoms. Here, we propose a treatment algorithm that could be useful in the management of patients with this rare disease.

Biological Sample Collection to Advance Research and Treatment: A Fight Osteosarcoma Through European Research and Euro Ewing Consortium Statement.

Osteosarcoma and Ewing sarcoma are bone tumors mostly diagnosed in children, adolescents, and young adults. Despite multimodal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been groundbreaking. Better understanding of biological subgroups, the role of the tumor immune microenvironment, factors that promote metastasis, and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic, and clinically linked biological analysis of patient samples, but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage, and analysis of patient samples. Two international panels of scientists, clinicians, and patient and parent advocates have formed the Fight Osteosarcoma Through European Research consortium and the Euro Ewing Consortium. The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, and liquid biopsy tubes), handling, and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonization with practical, legal, and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration, and improve outcomes.

A reduction in tumor volume exceeding 65% predicts a good histological response to neoadjuvant chemotherapy in patients with Ewing sarcoma.

OBJECTIVE: No consensus exists for tumor volume response criteria in patients with Ewing sarcoma. This study aimed to identify an optimal cutoff for predicting a good histological response by analyzing tumor volume changes and tumor necrosis after neoadjuvant chemotherapy. MATERIALS AND METHODS: We performed a retrospective analysis of 184 Ewing sarcoma patients, analyzing tumor volume changes before and after neoadjuvant chemotherapy. Patients were divided into two groups based on histological response: good (tumor necrosis ≥ 95%) and poor (tumor necrosis < 95%) responders. The receiver operating characteristic (ROC) area under the curve (AUC) method was used to determine the optimal thresholds for predicting the histological response. Additionally, the prognostic value of this cutoff for relapse-free survival was assessed. RESULTS: Out of 184 patients, 83 (45%) had tumor necrosis ≥ 95%, while 101 (55%) had tumor necrosis < 95%. ROC analysis identified the optimal cutoff for a good histological response as over 65% tumor volume reduction (AUC = 0.69; p < 0.001). Patients with volume reduction of ≥ 65% had a higher likelihood of a good histological response than those with lesser reductions (p = 0.004; odds ratio = 2.61). Multivariable analysis indicated a correlation between poor histological response and reduced relapse-free survival (hazard ratio = 2.17; p = 0.01), while tumor volume reduction itself did not impact survival. CONCLUSION: We reported that a tumor volume reduction of ≥ 65% was able to predict a good histological response in Ewing sarcoma patients. We recommend preoperative tumor volume assessment to identify patients at greater risk for poor histological response who could benefit from more intensive chemotherapy protocols or additional radiotherapy.

Histological and imaging features of myoepithelial carcinoma of the bone and soft tissue.

OBJECTIVE: To depict histological and imaging features of myoepithelial carcinoma of the bone and soft tissue. MATERIALS AND METHODS: We retrospectively examined histological features in 22 patients with myoepithelial carcinoma of the bone (4 patients) and soft tissue (18 patients) at a single institution. Imaging analysis of 15 patients (bone, 3 patients; soft tissue, 12 patients;) with preoperative images involved classifying lytic bone lesions via the modified Lodwick-Madewell classification; the growth patterns of soft tissue lesions were classified as well-defined, focally invasive, or diffusely invasive. RESULTS: Local recurrence occurred in eight out of 22 patients (36.3%). Four of 22 patients (18.2%) had metastasis at presentation, whereas 11 of 22 patients (50.0%) had distant metastasis during follow-up. Severe cytological pleomorphism was observed in 14 of 22 patients (63.6%), and 10 of 22 tumors (45.5%) showed ≥ 10 mitoses/10 high-power fields. Vascular invasion was observed in 10 of 22 patients (45.5%). Extracapsular/extraskeletal infiltration into the surrounding tissues was assessed in 20 patients, with 14 of them (70%) showing infiltration beyond the tumor border. Regarding imaging of bone lesions, two patients had Ludwick type IIIB, whereas one patient had type II. The growth pattern of soft tissue lesions was well-defined in two patients (16.7%), focally invasive in seven patients (58.3%), and diffusely invasive in three (25.0%) out of 12 patients. CONCLUSION: Myoepithelial carcinoma of the bone and soft tissue presents high risk of local recurrence and distant metastasis. Histological and imaging features might be important to understand the aggressive behavior of the tumor.

Clinical recommendations for treatment of localized angiosarcoma: A consensus paper by the Italian Sarcoma Group.

Angiosarcoma (AS) represents a rare and aggressive vascular sarcoma, posing distinct challenges in clinical management compared to other sarcomas. While the current European Society of Medical Oncology (ESMO) clinical practice guidelines for sarcoma treatment are applicable to AS, its unique aggressiveness and diverse tumor presentations necessitate dedicated and detailed clinical recommendations, which are currently lacking. Notably, considerations regarding surgical extent, radiation therapy (RT), and neoadjuvant/adjuvant chemotherapy vary significantly in localized disease, depending on each different site of onset. Indeed, AS are one of the sarcoma types most sensitive to cytotoxic chemotherapy. Despite this, uncertainties persist regarding optimal management across different clinical presentations, highlighting the need for further investigation through clinical trials. The Italian Sarcoma Group (ISG) organized a consensus meeting on April 1st, 2023, in Castel San Pietro, Italy, bringing together Italian sarcoma experts from several disciplines and patient representatives from "Sofia nel Cuore Onlus" and the ISG patient advocacy working group. The objective was to develop specific clinical recommendations for managing localized AS within the existing framework of sarcoma clinical practice guidelines, accounting for potential practice variations among ISG institutions. The aim was to try to standardize and harmonize clinical practices, or at least highlight the open questions in the local management of the disease, to define the best evidence-based practice for the optimal approach of localized AS and generate the recommendations presented herein.

The utility of FISH analysis in the diagnosis of BCOR-rearranged sarcomas.

BACKGROUND: A BCL6 corepressor (BCOR) gene alteration is a genetic signature of rare subsets of sarcomas. The identification of this alteration has recently contributed to the definition of new entities in the current WHO (2020) classification of soft tissue and bone tumours. We retrospectively examined cases of BCOR-rearranged sarcoma (BRS) to assess the reliability of the BCOR FISH analysis using an IVD (in vitro diagnostic) probe. METHODS: We investigated and compared the molecular diagnostic strategies and features by collecting 17 data from patients with a BCOR gene rearrangement detected using quantitative-Reverse Transcription-Polymerase Chain Reaction (qRTPCR), Next-Generation Sequencing (NGS) and Fluorescence in situ hybridization (FISH). RESULTS: We describe fourteen BCOR::CCNB3 sarcomas, one spindle cell sarcoma with a novel BCOR::MAML1 fusion, one spindle cell sarcoma with a novel BCOR::AHR fusion, and one ossifying fibromyxoid tumour with a BCOR::ZC3H7B fusion. FISH analysis of all, except one, BCOR::CCNB3 sarcoma, showed a FISH break-apart pattern with mild signal separation. The MAML1::BCOR sarcoma showed large-space split signals, while in the two patients with AHR::BCOR and ZC3H7B::BCOR fusions, no BCOR rearrangement was observed using FISH. CONCLUSIONS: Our study indicates that BCOR FISH analysis using an IVD probe, may be useful to detect the presence of a BCOR rearrangement, including both translocations and inversions; however, negative results, in some cases, can occur.

Secondary peripheral chondrosarcoma in multiple osteochondromas: a retrospective single-institution case series.

BACKGROUND: Multiple osteochondromas is genetic disorder characterized by the formation of multiple benign cartilage-capped bone tumors, named osteochondromas, during skeletal development. The most feared complication is the secondary peripheral chondrosarcoma, a malignant cartilaginous neoplasm that arises from the chondroid cap of pre-existent osteochondromas. We conducted a retrospective cohort study on patients diagnosed and followed up from 1960 to 2019 to describe the clinical and pathological features of individuals affected by peripheral chondrosarcoma in multiple osteochondromas, to evaluate follow up information and individual outcome and to compare the results with literature. Data, including age, gender, site, histological grade, cartilage cap thickness, surgical treatments, surgical margins, genotype mutational status as well as treatment details were captured from the hospital electronic health records and from Registry of Multiple Osteochondromas. In addition, a complete histological review of all hematoxylin and eosin (H&E)-stained sections has been performed by expert pathologists. RESULTS: One hundred five of the screened cases were included in the present study. The age at diagnosis of SPC ranges from 13 to 63, with median age at diagnosis of 34 years. The site most frequently affected by malignant degeneration was the pelvis (46 patients, 44%) with higher incidence in male patients (32 males vs.14 females). The second one was lower limbs (including femur, fibula, or tibia), identified in 35 patients. Histological information - available for 103 patients - showed: 59 patients with grade 1; 40 patients had a grade 2 and 4 patients had a grade 3. The most common surgical treatment was the complete resection, followed by debulking, amputation and partial resection. Most of cases did not have recurrence of the disease. Outcome in disease-free survival highlights that a worse course of the disease was associated with histological grade 2 or 3, and partial resection surgery. In most of analyzed cases (94%) a pathogenic variant was identified. CONCLUSIONS: In conclusion, the present study gives an overview of the secondary peripheral chondrosarcomas, confirming that this disease represents an impacting complication for multiple osteochondromas patients and suggests that malignant transformation can occur also in younger patient, in a not irrelevant number of cases.

Diagnostic challenges in low-grade central osteosarcoma.

Aims: Low-grade central osteosarcoma (LGCOS), a rare type of osteosarcoma, often has misleading radiological and pathological features that overlap with those of other bone tumours, thereby complicating diagnosis and treatment. We aimed to analyze the clinical, radiological, and pathological features of patients with LGCOS, with a focus on diagnosis, treatment, and outcomes. Methods: We retrospectively analyzed the medical records of 49 patients with LGCOS (Broder's grade 1 to 2) treated between January 1985 and December 2017 in a single institute. We examined the presence of malignant features on imaging (periosteal reaction, cortical destruction, soft-tissue invasion), the diagnostic accuracy of biopsy, surgical treatment, and oncological outcome. Results: Based on imaging, 35 of 49 patients (71.4%) exhibited malignant features. Overall, 40 of 49 patients (81.6%) had undergone a biopsy before en-bloc resection: 27 of 40 patients (67.5%) were diagnosed on the first biopsy, which was more accurate when carried out by open rather than needle biopsy (91.3% vs 35.3% diagnostic accuracy, respectively; p < 0.001). Of the 40 patients treated by en-bloc resection, surgical margins were wide in 38 (95.0%) and marginal in two (5.0%). Furthermore, nine of 49 patients (18.4%) underwent curettage (intralesional margin) without previous biopsy. All patients with a positive margin developed local recurrence. Distant metastases occurred in five of 49 patients (10.2%). The mean five-year overall survival (OS) and distant relapse-free survival (D-RFS) were 89.3% (SD 5.1%) and 85.7% (SD 5.5%), respectively. Univariate analysis showed that the occurrence of distant metastasis was a poor prognostic factor for OS (hazard ratio 11.54, 95% confidence interval (CI) 1.92 to 69.17; p < 0.001). Local recurrence was a poor prognostic factor for D-RFS (HR 8.72, 95% CI 1.69 to 45.0; p = 0.002). Conclusion: The diagnosis of LGCOS can be challenging because it may present with non-malignant features and has a low diagnostic accuracy on biopsy. If precisely diagnosed, LGCOS can be successfully treated by surgical excision with wide margins.