A novel patient-derived immortalised cell line of myxofibrosarcoma: a tool for preclinical drugs testing and the generation of near-patient models.

BACKGROUND: Myxofibrosarcoma is a rare malignant soft tissue sarcoma characterised by multiple local recurrence and can become of higher grade with each recurrence. Consequently, myxofibrosarcoma represents a burden for patients, a challenge for clinicians, and an interesting disease to study tumour progression. Currently, few myxofibrosarcoma preclinical models are available. METHODS: In this paper, we present a spontaneously immortalised myxofibrosarcoma patient-derived cell line (MF-R 3). We performed phenotypic characterization through multiple biological assays and analyses: proliferation, clonogenic potential, anchorage-independent growth and colony formation, migration, invasion, AgNOR staining, and ultrastructural evaluation. RESULTS: MF-R 3 cells match morphologic and phenotypic characteristics of the original tumour as 2D cultures, 3D aggregates, and on the chorioallantoic membrane of chick embryos. Overall results show a clear neoplastic potential of this cell line. Finally, we tested MF-R 3 sensitivity to anthracyclines in 2D and 3D conditions finding a good response to these drugs. CONCLUSIONS: In conclusion, we established a novel patient-derived myxofibrosarcoma cell line that, together with the few others available, could serve as an important model for studying the molecular pathogenesis of myxofibrosarcoma and for testing new drugs and therapeutic strategies in diverse experimental settings.

Modeling Myxofibrosarcoma: Where Do We Stand and What Is Missing?

Myxofibrosarcoma (MFS) is a malignant soft tissue sarcoma (STS) that originates in the body's connective tissues. It is characterized by the presence of myxoid (gel-like) and fibrous components and typically affects patients after the fifth decade of life. Considering the ongoing trend of increasing lifespans across many nations, MFS is likely to become the most common musculoskeletal sarcoma in the future. Although MFS patients have a lower risk of developing distant metastases compared with other STS cases, MFS is characterized by a high frequency of local recurrence. Notably, in 40-60% of the patients where the tumor recurs, it does so multiple times. Consequently, patients may undergo multiple local surgeries, removing the risk of potential amputation. Furthermore, because the tumor relapses generally have a higher grade, they exhibit a decreased response to radio and chemotherapy and an increased tendency to form metastases. Thus, a better understanding of MFS is required, and improved therapeutic options must be developed. Historically, preclinical models for other types of tumors have been instrumental in obtaining a better understanding of tumor development and in testing new therapeutic approaches. However, few MFS models are currently available. In this review, we will describe the MFS models available and will provide insights into the advantages and constraints of each model.

NTRK rearranged sarcoma of the bone. Role for larotrectinib in the neoadjuvant setting of an ultra-rare tumor: a case report.

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene-fusion targeted molecules revolutionized the paradigm of treatment of a limited subgroup of cancers of various histologies. Entrectinib and larotrectinib obtained unprecedented response rates in patients with cancer harboring NTRK rearrangements. This evidence recently led to the agnostic approval of these drugs, and evidence (confirmation) of their activity in a broader disease setting is emerging. Here, we report the case of a patient affected by EML4-NTRK3 rearranged undifferentiated spindle cell bone sarcoma treated with larotrectinib, and we argue (discuss about) the incidence and clinical presentation of NTRK gene-fusion positive bone sarcomas, the potential use of upfront treatment with NTRK inhibitors in neoadjuvant setting, and the role of a multidisciplinary tumor board. Despite the rarity of these rearrangements in patients with primitive bone sarcomas, the therapy with NTRK inhibitors represents a highly effective strategy to be pursued in selected cases even in neoadjuvant settings. The management of these very rare cancers should always be discussed in a multidisciplinary board of reference centers.

Osteogenic sarcomas of the hands: A case series with emphasis in its peculiarities and literature review.

AIM: To present our experience on osteosarcomas of the hands and review the existing literature pertaining osteosarcomas in this extremely rare location. METHODS: and results: Seven cases of osteosarcomas of the hands were reviewed, and a literature search of all primary osteosarcomas of the hands was performed. All tumors occurred in adults (mean age, 41 years) and were located mainly around the metacarpophalangeal joints. All patients presented with localized long-lasting pain as main symptom. The mean size at diagnosis was 33 mm. Three tumors were low-grade central osteosarcomas, 1 low-grade central chondroblastoma-like osteosarcoma and 3 high-grade osteosarcomas. All tumors were positive for mouse double-minute 2 homolog (MDM2) immunohistochemistry. Three cases yielded results with fluorescence in-situ amplification for MDM2 (12q15)/CEP12. At last follow-up, one patient with a high-grade osteosarcoma was dead of disease. The literature review revealed similar demographic and site distribution of osteosarcomas within the hands than our series and an unusually high proportion of low-grade central and parosteal osteosarcomas when compared to the proportion of these infrequent neoplasms in the whole skeleton. CONCLUSIONS: osteosarcomas of hands present in older individuals compared to the population affected by conventional osteosarcomas of all sites. Importantly from a diagnostic, therapeutic and prognostic points of view, around 40% of osteosarcomas of the hands are low-grade osteosarcomas of the central or parosteal types.

The role of conventional radiography to assess the outcome of oncologic skeletal reconstructions of lower limbs aided by vascularized fibular autograft.

INTRODUCTION: Vascularized fibular autografts (VFA) are used in the oncologic skeletal reconstructions of long bones, alone or combined with massive bone allografts (MBA). Data regarding the role of imaging in assessing these complex skeletal reconstructions are lacking, and have mainly focused on Computed Tomography (CT). Our aim was to evaluate if early conventional radiography (CR) findings are correlated with the outcome of these skeletal reconstructions. MATERIALS AND METHODS: All consecutive patients who underwent oncologic resection of lower limbs long bones followed by VFA reconstruction were included in this single-center retrospective study. We compared the CR obtained immediately after surgery with the CR at the 6-month control, as well as the CR at 6 months with the CT at 6 months when available. The following scores were assigned to the VFA: 0 (unchanged), 1 (osteopenia-cortical bone thinning), 2 (increase in bone density-cortical thickening). We then investigated whether this score correlated with the implant outcome within 12 months (optimal integration, suboptimal integration, integration requiring further surgery or lack of integration) using Kaplan-Meier and Cox regression analyses, considering the occurrence of integration and the duration time before the surgical removal of the whole bone reconstruction. RESULTS: Forty-five patients were included (32 men [71.1%], mean age 14.6 years), 26 affected by osteosarcoma, 14 by Ewing sarcoma, 3 by adamantinoma and 2 operated for the failure of previous reconstructions for bone sarcoma. VFA changes on 6-month CR were significantly associated with optimal integration of the implants (log-rank P = 0.0137, multivariate Hazard ratio = 7.62, 95% confidence interval = 1.13-51.25). None of the other clinical and surgical features were associated with the implant outcome. The findings on 6-month CR and CT follow-up were not significantly different. CT at 6 months was available in 36 patients (80.0%). CONCLUSION: The assessment of VFA morphological changes on CR performed at 6 months can predict the outcome of the skeletal implant. This data should be considered for clinical decision-making, selecting patients requiring additional images (CT), and possible subsequent revision surgical procedures.

Periacetabular Tumour Resection under Anterosuperior Iliac Spine Allows Better Alloprosthetic Reconstruction than Above: Bone Contact Matters.

BACKGROUND: Periacetabular resections are more affected by late complications than other pelvic resections. Reconstruction using bone allograft is considered a suitable solution. However, it is still not clear how the bone-allograft contact surface impacts on mechanical and functional outcome. MATERIALS AND METHODS: This paper presents the results of a retrospective analysis of 33 patients with resection of the entire acetabulum and reconstruction with an allograft-prosthetic composite for the period 1999 to 2010. Patients were divided in two groups, based on type of resection. In Group 1. patients had resections under anterosuperior iliac spine allowing the highest bone-allograft surface contact in reconstruction, while in Group 2 patients had resections over it. RESULTS: Mechanical survival of the implant and Musculoskeletal Tumor Society functional score were calculated. Impact of age and artificial ligament were investigated as well. Patients in Group 1 had 38% mechanical failure rate of the implant while patients in Group 2 had 88%. Average functional score was higher in Group 1 compared with patients in Group 2. An artificial ligament was shown to have non-significant impact on survival of the reconstruction in Group 1, while significantly improving survival of reconstruction in Group 2. CONCLUSION: Bone-allograft contact matters: resection under anterosuperior iliac spine allows better mechanical survival and offers better reconstruction functional scores.

Long-term functional recovery in patients with custom-made 3D-printed anatomical pelvic prostheses following bone tumor excision.

BACKGROUND: Anatomical custom-made prostheses make it possible to reconstruct complicated bone defects following excision of bone tumors, thanks to 3D-printed technology. To date, clinical measures have been used to report clinical-functional outcome and provide evidence for the effectiveness of this new surgical approach. However, there are no studies that quantified the achievable recovery during common activities by using instrumental clinical-functional evaluation in these patients. RESEARCH QUESTION: What is the motor performance, functional outcome and quality of life in patients with custom-made 3D-printed pelvic prostheses following bone tumor? METHODS: To analyze motor performance, six patients performed motion analysis during five motor activities at follow-up of 32 ± 18 months. Joint angles, ground reaction forces and joint moments of the operated and contralateral limbs were compared. On-off activity of lower-limb muscles were calculated from electromyography and compared to a healthy matched population. To analyze functional outcome and quality of life, differences in measured hip abductor strength between limbs were evaluated, as well as clinical-functional scores (Harris Hip Score, Barthel Index, Musculoskeletal Tumor Society score), and quality of life (SF-36 health survey). RESULTS: We found only slight differences in joint kinematics when comparing operated and contralateral limb. The activity of gluteal muscles was normal, while hamstrings showed out-of-phase activities. Ground reaction forces and hip moments showed asymmetries between limbs, particularly in more demanding motor activities. We found a mean difference in hip abductor strength of 48 ± 82 N between limbs, good clinical-functional scores, and quality of life scores within normative. SIGNIFICANCE: Our study showed optimal long-term results in functional recovery, mainly achieved through recovery of the gluteal function, although minor impairments were found, which may be considered for future improvement of this innovative surgery. The effect of a more loaded contralateral limb on internal loads and long-term performance of the implant remains unknown and deserves further investigation.

Periosteal chondrosarcoma: A case series in a referral center with survivorship analysis.

BACKGROUND: Periosteal chondrosarcomas are among the rarest types of chondrosarcomas dealt with in few small series of cases. In this study, we aimed to present our experience with this chondrosarcoma, seek for prognostic factors for OS and DFS and survey the status of IDH1 and IDH2. RESULTS: 55 periosteal chondrosarcomas were retrospectively identified. Median age was 37 years, there was a male predominance (62%). The great majority of cases involved the metaphysis of long bones of the extremities. The median size of the tumors was 7.5 cm. Thirty patients underwent to subtotal surgical resection, 22 to tangential resection and the remaining 3 to amputation. The margins, reported in 54 cases, were wide/radical in 38 patients (70.4%), marginal in 9 (16.7%) and intralesional in 7 (12.9%). Histologically, 23 (42%) were grade 1; 27 (49%), grade 2; 3 (5%), grade 3 and 2 (4%) were dedifferentiated. A third of cases in which mutational analysis was feasible harbored heterozygous mutations in codon 132 of IDH1. Fifty-four cases were included for follow-up (median, 137 months). Four patients had local recurrences and six patients developed metastasis to the lungs. All patients that developed metastasis died of disease, two died of unrelated causes and 46 were alive without disease. OS and DFS was not found to be statistically associated with clinical and pathological parameters considered. CONCLUSIONS: periosteal chondrosarcomas exhibit a low-grade behavior that can be adequately treated with marginal excisions. Clinical and morphologic parameters do not seem to predict their outcome.

Primary malignant peripheral nerve sheath tumors of bone: a clinicopathologic reappraisal of 8 cases.

Primary spindle cell and pleomorphic sarcomas of bone represent an exceedingly rare group of mesenchymal malignancies that include soft tissue histotypes, as malignant peripheral nerve sheath tumor. Outside the head and neck region, only 36 cases of primary malignant peripheral nerve sheath tumor of bone have been described. We retrieved from our archives eight cases of primary malignant peripheral nerve sheath tumor of bone arising outside the head and neck region, describing their clinical, radiological, and morphologic features. Our series, in which all but one patient died of diseases after a median of seven months, confirms that primary malignant peripheral nerve sheath tumors of bone are aggressive tumors. Pathologists should be aware of this rare histotype. More aggressive and active adjuvant treatments should be investigated.

Custom-made 3D-Printed Prosthesis in Periacetabular Resections Through a Novel Ileo-adductor Approach.

Resection of sarcomas around the acetabulum presents major challenges. The resulting bone effect can be reconstructed with personalized custom-made prostheses. Patient-specific instruments (PSIs) have been demonstrated to be of added value for bone-cutting accuracy, and they may improve pelvic surgery. The authors describe a novel ileo-adductor approach for pelvic tumor surgery and report the preliminary results of 5 reconstructions using custom 3D-printed prostheses associated with PSI surgical guides. This combined technique allows an optimal restoration of the anatomy with reduced surgical time and reduced postoperative complications such as infections and wound healing problems. [Orthopedics. 2022;45(2):e110-e114.].

CIC rearranged sarcomas: A single institution experience of the potential pitfalls in interpreting CIC FISH results.

AIM: The aim of this study was to establish how reliable FISH CIC analysis using an IVD (in vitro diagnostic) commercial probe is. METHODS AND RESULTS: A series of 19 CIC-DUX4 sarcomas were evaluated. The samples presenting CIC-DUX4 fusion transcript detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Sanger sequencing and/or Next Generation Sequencing were selected for Fluorescent in Situ Hybridization (FISH) CIC analysis with CIC break-apart IVD probe and compared to molecular analysis. CIC FISH analysis showed 26% of false negatives. CONCLUSION: Our results indicate that, in the setting of CIC-DUX4 fusion positive small round cell sarcomas, CIC FISH using IVD commercial probe may lead to false-negative results. This novel study evaluates the diagnostic use of a commercial IVD CIC probe for FISH.

Minimally invasive treatment of long bone non-unions with bone marrow concentrate, demineralized bone matrix and platelet-rich fibrin in 38 patients.

To determine the efficacy of percutaneous injection of autologous bone marrow concentrated (BMC), demineralized bone matrix (DBM), and platelet rich fibrin (PRF) in the treatment of long bone non-unions. From January 2011 to January 2018 patients with non-union of the lower limbs who were on the waiting list for open grafting with established tibial or femoral non-union and minimal deformity were eligible to participate in this study. Patients were treated with a single percutaneous injection of DBM, BMC and PRF. Our study group comprised 38 patients (26 males and 12 females; mean age 39, range 18 to 65). Non-unions were located in the femur (18 cases) and in the tibia (20 cases). Clinical and imaging follow-up ranged from 4 to 60 months (mean 20 months). Bone union occurred in 30 out of 38 patients (79%) in an average of 7 months (range 3 to 12) and all healed patients had full weight bearing after 9 months on average (range 6 to 12) from injection. In 19 cases the osteosynthesis was removed 12 months on average (range 3 to 36) from surgery. One patient developed infection at the non-union site after treatment. Percutaneous injection of DBM, BMC, and PRF is an effective treatment for long-bone non-unions. This technique allows the bone to heal with a minimally invasive approach and with a hospitalization of 2 days. Key elements of bone regeneration consist of a combination of biological and biomechanical therapeutic approach.

Giant Cell Tumor of Bone in Patients under 16 Years Old: A Single-Institution Case Series.

BACKGROUND: Giant cell tumor of bone is a locally aggressive, rarely metastasizing tumor that accounts for about 5% of bone tumors and generally occurs in patients between 20 and 45 years old. A driver mutation in the histone 3.3 (H3.3) gene H3F3A has been identified in as many as 96% of giant cell tumors of bone. The immunohistochemical expression of H3F3A H3.3 G34 expression was found in 97.8% of cases. In the present study, we describe our series of cases of giant cell tumor of bone in pediatric patients <16 years old. METHODS: All cases of giant cell tumor of bone in pediatric patients <16 years old treated in our institute between 1982 and 2018 were reviewed. Immunohistochemistry and/or molecular analysis for H3F3A gene mutations was performed to confirm the diagnosis. A group of aneurysmal bone cysts in patients <16 years old was used as a control group. RESULTS: Fifteen cases were retrieved. A pronounced female predominance (93%) was observed. A pure metaphyseal central location occurs in 2 skeletally immature patients. CONCLUSIONS: Giant cell tumor of bone should be distinguished from its mimickers due to differences in prognosis and treatment. Immunohistochemical and molecular detection of H3F3A gene mutation represents a reliable diagnostic tool.

Primary sclerosing epithelioid fibrosarcoma of the spine: a single-institution experience.

AIMS: To present our experience on spinal sclerosing epithelioid fibrosarcoma (SEF) and review the existing literature pertaining to SEF of the spine. METHODS AND RESULTS: Six cases of spinal SEF were reviewed, and a literature search of all primary SEFs of the spine was performed. All tumours occurred in adults (median age, 41 years) and were located all along the spine, the lumbar vertebrae being the most commonly involved. All patients presented with pain that they had experienced for months. The mean tumour size at diagnosis was 52 mm. Five tumours showed a spectrum of microscopic features consistent with pure SEF, and one showed a hybrid morphology with areas of low-grade fibromyxoid sarcoma. All were diffusely and strongly positive for mucin 4. Two cases were initially misdiagnosed as epithelioid haemangioendothelioma and aggressive chondroblastoma. Fluorescence in-situ hybridisation showed rearrangements of either FUS or EWSR1 in four cases. Reverse transcription polymerase chain reaction showed the presence of FUS-CREB3L1 and EWSR1-CREB3L1 fusion transcripts in two cases and one case, respectively. Of five patients with follow-up data available, two developed one or more local recurrences and three patients had metastatic disease. Distant metastases were mainly to other osseous locations, followed by lungs and lymph nodes. At last follow-up, three patients had died of disease and one was alive with multiple metastases. CONCLUSIONS: SEF is an aggressive sarcoma that can involve the spine. It is important to recognise the spine as the primary location of SEF, in order to avoid misdiagnosis as more common primary spinal neoplasms, which can impact on therapeutic approaches.

Usefulness of ß-catenin expression in the differential diagnosis of osteosarcoma, osteoblastoma, and chondroblastoma.

The aim of this study is to assess the usefulness of beta-catenin immunohistochemical expression in the differential diagnosis of osteoid-producing primary tumors of bone. Seventy cases of osteoid-producing tumors of bone (24 conventional osteosarcomas, 18 osteoblastomas, 13 osteoblastoma-like osteosarcomas, 10 chondroblastomas, and 5 chondroblastoma-like osteosarcomas) diagnosed at Istituto Ortopedico Rizzoli were reviewed and evaluated for the intensity, extension, and subcellular distribution of immunohistochemical expression of beta-catenin. A majority of cases (73%, 51 cases) exhibited cytoplasmic and/or membranous positivity in varied degrees of intensity and proportion of positive cells, in the absence of nuclear staining. Fifteen cases (21%) were completely negative, including two osteoblastomas, five chondroblastomas, three conventional osteosarcomas, four osteoblastoma-like osteosarcomas, and one chondroblastoma-like osteosarcoma. A minority of cases (6%) including three osteoblastoma-like osteosarcomas and one osteoblastoma showed focal nuclear beta-catenin positivity with or without concomitant cytoplasmic staining. In the current series, beta-catenin showed not to be useful in the differential diagnosis of osteoid-producing primary bone tumors.

Computer Navigation and 3D Printing in the Surgical Management of Bone Sarcoma.

The long-term outcomes of osteosarcoma have improved; however, patients with metastases, recurrence or axial disease continue to have a poor prognosis. Computer navigation in surgery is becoming ever more commonplace, and the proposed advantages, including precision during surgery, is particularly applicable to the field of orthopaedic oncology and challenging areas such as the axial skeleton. Within this article, we provide an overview of the field of computer navigation and computer-assisted tumour surgery (CATS), in particular its relevance to the surgical management of osteosarcoma.

Mesenchymal stromal cells mediated delivery of photoactive nanoparticles inhibits osteosarcoma growth in vitro and in a murine in vivo ectopic model.

BACKGROUND: Osteosarcoma (OS) is an aggressive malignant neoplasm that still suffers from poor prognosis in the case of distal metastases or occurrence of multi-drug resistance. It is therefore crucial to find novel therapeutic options able to go beyond these limitations and improve patients' survival. The objective of this study is to exploit the intrinsic properties of mesenchymal stromal cells (MSCs) to migrate and infiltrate the tumor stroma to specifically deliver therapeutic agents directly to cancer cells. In particular, we aimed to test the efficacy of the photoactivation of MSCs loaded with nanoparticles in vitro and in a murine in vivo ectopic osteosarcoma model. METHODS: AlPcS4@FNPs were produced by adding tetra-sulfonated aluminum phthalocyanine (AlPcS4) to an aqueous solution of positively charged poly-methyl methacrylate core-shell fluorescent nanoparticles (FNPs). The photodynamic therapy (PDT) effect is achieved by activation of the photosensitizer AlPcS4 in the near-infrared light with an LED source. Human MSCs were isolated from the bone marrow of five donors to account for inter-patients variability and used in this study after being evaluated for their clonogenicity, multipotency and immunophenotypic profile. MSC lines were then tested for the ability to internalize and retain the nanoparticles, along with their migratory properties in vitro. Photoactivation effect was evaluated both in a monolayer (2D) co-culture of AlPcS4@FNPs loaded MSCs with human OS cells (SaOS-2) and in tridimensional (3D) multicellular spheroids (AlPcS4@FNPs loaded MSCs with human OS cells, MG-63). Cell death was assessed by AnnexinV/PI and Live&Dead CalceinAM/EthD staining in 2D, while in the 3D co-culture, the cell killing effect was measured through ATP content, CalceinAM/EthD staining and TEM imaging. We also evaluated the effectiveness of AlPcS4@FNPs loaded MSCs as delivery systems and the ability of the photodynamic treatment to kill cancer cells in a subcutaneous mouse model of OS by bioluminescence imaging (BLI) and histology. RESULTS: MSCs internalized AlPcS4@FNPs without losing or altering their motility and viability in vitro. Photoactivation of AlPcS4@FNPs loaded MSCs induced high level of OS cells death in the 2D co-culture. Similarly, in the 3D co-culture (MSCs:OS ratios 1:1 or 1:3), a substantial decrease of both MSCs and OS cells viability was observed. Notably, when increasing the MSCs:OS ratio to 1:7, photoactivation still caused more than 40% cells death. When tested in an in vivo ectopic OS model, AlPcS4@FNPs loaded MSCs were able to decrease OS growth by 68% after two cycles of photoactivation. CONCLUSIONS: Our findings demonstrate that MSCs can deliver functional photosensitizer-decorated nanoparticles in vitro and in vivo and inhibit OS tumor growth. MSCs may be an effective platform for the targeted delivery of therapeutic nanodrugs in a clinical scenario, alone or in combination with other osteosarcoma treatment modalities.

Identification of a novel fusion transcript EWSR1-VEZF1 by anchored multiplex PCR in malignant peripheral nerve sheath tumor.

The aim of the study is to describe a novel genetic finding examining the molecular and pathological features of a case of malignant peripheral nerve sheath tumor occurring in the thigh of a 17-year-old male. Fusion gene detection using a next-generation sequencing-based anchored multiplex PCR technique (Archer FusionPlex Sarcoma Panel) was used to identify the novel fusion of EWSR1-VEZF1 from the frozen tumor sample. EWSR1-VEZF1 fusion is a novel molecular gene rearrangement involving exon 8 of the EWSR1 gene and exon 2 of the VEZF1 gene. Data were validated with gene sequencing and fluorescent in situ hybridization (FISH) analysis. This case report describes a novel rearrangement involving EWSR1 on chromosome 22 and VEZF1 on chromosome 17. The result obtained demonstrates the value of the next-generation sequencing-based anchored multiplex PCR technique (Archer FusionPlex Sarcoma Panel) both in diagnosis and patient care and might become a helpful diagnostic tool for this tumor type.

Parosteal osteosarcoma: a monocentric retrospective analysis of 195 patients.

Parosteal osteosarcoma is a low-grade malignant bone tumor that can undergo dedifferentiation. The aim of this study was to analyze clinicopathologic features associated with clinical outcome in a large cohort of patients. Patients consecutively treated for parosteal osteosarcoma at Rizzoli Orthopedic Institute from 1900 to 2018 were reviewed and analyzed. Clincopathologic data of 195 patients with parosteal osteosarcoma were analyzed. Age at diagnosis ranged from 9 to 75 years (median 31). Median follow-up time was 150 months (range, 3-720). The most common tumor locations were femur (61.5%), humerus (15.9%) and tibia (12.8%). Wide surgical margins were achieved in 125 (64.1%) patients. Medullary involvement was present in 69 (35.4%) cases. Dedifferentiation occurred in 48 (24.6%) patients. Forty-five patients developed recurrence (23.1%; median time to recurrence of 36 months). At last follow-up, 155 (79.5%) patients were alive and without evidence of disease, 8 (4.1%) were alive with active disease, 23 (11.8%) died from disease, and 9 (4.6%) from unrelated causes. Patients with dedifferentiated parosteal osteosarcoma had worse 5-year (65% versus 96%) and 10-year survival (60% versus 96%) when compared to conventional tumors (P < .001). Wide surgical margins had positive impact on both disease-free (P < .001) and overall survival (P = .036). Medullary involvement, age at presentation and tumor size had no impact on survival. Dedifferentiation is the most important factor that negatively impacts clinical outcome. Surgical aim is to ensure radical removal with wide surgical margins to improve disease-free survival.