Conventional High-grade Osteosarcoma Research Articles

Prognostic factors for overall survival of conventional osteosarcoma of the appendicular skeleton.

The aim of this study is to determine the predictors of overall survival (OS) and predictive factors of poor prognosis of conventional high-grade osteosarcoma of the limbs in a single-centre in South Africa. We performed a retrospective cross-sectional analysis to identify the prognostic factors that predict the OS of patients with histologically confirmed high-grade conventional osteosarcoma of the limbs over ten years. We employed the Cox proportional regression model and the Kaplan-Meier method for statistical analysis. This study comprised 77 patients at a three-year minimum follow-up. The predictors of poor OS were: the median age of ≤ 19 years (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.92 to 0.99; p = 0.021); median duration of symptoms ≥ five months (HR 0.91; 95% CI 0.83 to 0.99; p < 0.037); metastasis at diagnosis (i.e. Enneking stage III) (HR 3.33; 95% CI 1.81 to 6.00; p < 0.001); increased alkaline phosphatase (HR 3.28; 95% CI 1.33 to 8.11; p < 0.010); palliative treatment (HR 7.27; 95% CI 2.69 to 19.70); p < 0.001); and amputation (HR 3.71; 95% CI 1.12 to 12.25; p < 0.032). In contrast, definitive surgery (HR 0.11; 95% CI 0.03 to 0.38; p < 0.001) and curative treatment (HR 0.18; 95% CI 0.10 to 0.33; p < 0.001) were a protective factor. The Kaplan-Meier median survival time was 24 months, with OS of 57.1% at the three years. The projected five-year event-free survival was 10.3% and OS of 29.8% (HR 0.76; 95% CI 0.52 to 1.12; p = 0.128). In this series of high-grade conventional osteosarcoma of the appendicular skeleton from South Africa, 58.4% (n = 45) had detectable metastases at presentation; hence, an impoverished OS of five years was 29.8%. Large-scale future research is needed to validate our results.

Small cell osteosarcoma versus fusion-driven round cell sarcomas of bone: retrospective clinical, radiological, pathological, and (epi)genetic comparison with clinical implications.

Small cell osteosarcoma (SCOS), a variant of conventional high-grade osteosarcoma (COS), may mimic fusion-driven round cell sarcomas (FDRCS) by overlapping clinico-radiological and histomorphological/immunohistochemical characteristics, hampering accurate diagnosis and consequently proper therapy. We retrospectively analyzed decalcified formalin-fixed paraffin-embedded (FFPE) samples of 18 bone tumors primarily diagnosed as SCOS by methylation profiling, fusion gene analysis, and immunohistochemistry.In eight cases, the diagnosis of SCOS was maintained, and in 10 cases it was changed into FDRCS, including three Ewing sarcomas (EWSR1::FLI1 in two cases and no identified fusion gene in the third case), two sarcomas with BCOR alterations (KMT2D::BCOR, CCNB3::BCOR, respectively), three mesenchymal chondrosarcomas (HEY1::NCOA2 in two cases and one case with insufficient RNA quality), and two sclerosing epithelioid fibrosarcomas (FUS::CREBL3 and EWSR1 rearrangement, respectively).Histologically, SCOS usually possessed more pleomorphic cells in contrast to the FDRCS showing mainly monomorphic cellular features. However, osteoid was seen in the latter tumors as well, often associated with slight pleomorphism. Also, the immunohistochemical profile (CD99, SATB2, and BCOR) overlapped.Clinically and radiologically, similarities between SCOS and FDRCS were observed, with by imaging only minimal presence or lack of (mineralized) osteoid in most of the SCOSs.In conclusion, discrimination of SCOS, epigenetically related to COS, versus FDRCS of bone can be challenging but is important due to different biology and therefore therapeutic strategies. Methylation profiling is a reliable and robust diagnostic test especially on decalcified FFPE material. Subsequent fusion gene analysis and/or use of specific immunohistochemical surrogate markers can be used to substantiate the diagnosis.

Identification of New Potential Prognostic and Predictive Markers in High-Grade Osteosarcoma Using Whole Exome Sequencing.

Conventional high-grade osteosarcoma (OS) is the most common primary cancer of bone and it typically affects the extremities of adolescents. OS has a complex karyotype, and molecular mechanisms related to carcinogenesis, progression and resistance to therapy are still largely unknown. For this reason, the current standard of care is associated with considerable adverse effects. In this study, our aim was to identify gene alterations in OS patients using whole exome sequencing (WES) to find new potential prognostic biomarkers and therapeutic targets. We performed WES on formalin-fixed paraffin-embedded (FFPE) biopsy materials collected from 19 patients affected by conventional high-grade OS. The clinical and genetic data were analyzed according to response to therapy, presence of metastasis and disease status. By comparing good and poor responders to neoadjuvant therapy, we detected a clear prevalence of mutations in the ARID1A, CREBBP, BRCA2 and RAD50 genes in poor responders that negatively influence the progression-free survival time. Moreover, higher tumor mutational burden values correlated with worse prognosis. The identification of mutations in ARID1A, CREBBP, BRCA2 and RAD50 may support the use of a more specific therapy for tumors harboring these alterations. In particular, BRCA2 and RAD50 are involved in homologous recombination repair, and could thus be used as specific therapy targets of inhibitors of the enzyme Poly ADP Ribose Polymerase (PARP). Finally, tumor mutational burden is found to be a potential prognostic marker for OS.

NKX3.1 immunohistochemistry and methylome profiling in mesenchymal chondrosarcoma: additional diagnostic value for a well-defined disease?

Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript involving HEY1 and NCOA2. Histologically, the tumours show a biphasic appearance consisting of an undifferentiated blue and round cell component as well as islands of highly differentiated cartilage. Particularly in core needle biopsies, the chondromatous component can be missed and the non-specific morphology and immunophenotype of the round cell component can cause diagnostic challenges. We applied NKX3.1 immunohistochemistry which was recently reported as a highly specific marker as well as methylome and copy number profiling to a set of 45 well characterised MCS cases to evaluate their potential diagnostic value. Methylome profiling revealed a highly distinct cluster for MCS. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. NKX3.1 immunohistochemistry showed positivity in 36% of tumours, the majority of which was rather focal and weak. Taken together, NKX3.1 expression showed a low sensitivity but a high specificity in our analysis. Methylome profiling on the other hand represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. Furthermore, it can aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.

Metastatic sarcomas to pleural effusion: a 10-year large tertiary care center experience with emphasis on clinical features and cytomorphologic characteristics.

Metastatic sarcomas to pleural effusion are extremely rare, accounting for <1% of all malignant pleural effusions. We aim to present our experience with pleural effusion specimens containing metastatic sarcomas over a 10-year period. We performed a 10-year retrospective search of cytopathology archives to identify all pleural effusions that were involved by metastatic sarcoma. All available cytopathology and surgical pathology specimens were retrieved and reviewed. Twenty-eight pleural fluids from 22 patients with metastatic sarcoma were identified in our search. The patients' ages ranged from 12 to 73 years. The pleural fluid volumes ranged from 10 to 1500 ml. Rhabdomyosarcoma was the most commonly encountered metastatic sarcoma to pleural effusion (n = 7). Other metastatic sarcomas were as follows: epithelioid angiosarcoma (n = 4), Ewing sarcoma (n = 3), clear cell sarcoma (n = 2), high grade conventional osteosarcoma (n = 2), undifferentiated pleomorphic sarcoma (n = 1), epithelioid sarcoma, proximal type (n = 1), dedifferentiated liposarcoma (n = 1), and conventional chondrosarcoma (n = 1). The time between initial diagnosis and effusion varied from 3 months to 25 years. Two patients are alive with disease at 6 and 21 months of follow-up. All other patients were dead of disease and the survival after a malignant pleural effusion ranged from <1 month to 18 months. Metastatic bone and soft tissue sarcomas to pleural effusions are rare and their cytologic features can be mistaken for carcinoma, melanoma, or mesothelioma. Careful review of the patient's medical history, comparison of the previous pathology and the use of ancillary studies are crucial for the evaluation of pleural effusions involved by metastatic sarcomas.

Dedifferentiated Low-Grade Osteosarcoma, Outcome with or Without Chemotherapy: A Systematic Review.

The treatment of low-grade osteosarcomas is surgical resection with wide margins. In instances of dedifferentiation, a therapeutic paradigm similar to that of conventional high-grade osteosarcoma has not been adequately evaluated in these neoplasms. The main objective of this review was to define whether the addition of chemotherapy to surgical treatment has an impact on the survival of patients with dedifferentiated low-grade osteosarcomas. Secondary objectives were to observe the degree of histological response to neoadjuvant chemotherapy and to describe the percentage of de novo dedifferentiation. A systematic search of articles including dedifferentiated low-grade osteosarcomas, published between 1980 and 2022 was carried out in the PubMed, Cochrane and Scielo databases. A qualitative synthesis of the results was performed. Twenty-three articles comprising 117 patients were included. The survival of patients treated with surgery alone and surgery with chemotherapy was not statistically significant between the two groups. A good histological response was seen in 20% of specimens treated with neoadjuvant chemotherapy. De novo dedifferentiation was seen in approximately a fifth of low-grade osteosarcomas. The evidence available suggests that the addition of chemotherapy does not have an impact on the survival of patients with low-grade dedifferentiated osteosarcomas.

Differences in p53 Expression in High-Grade Conventional Osteosarcoma and Giant Cell Tumor of Bone

Background: Osteosarcoma is the most common primary tumor of bone. Generally, patients with osteosarcoma have a poor prognosis. So it is very important to be able to diagnose as early as possible. Histopathologically, osteosarcoma has a variety of types similar to non-malignant lesions, such as giant cell tumor of bone. Therefore, caution is needed in diagnosing because if it is misdiagnosed, it will result in different management. This study aims to look at differences in p53 protein expression in high-grade conventional osteosarcoma and giant cell tumor of bone.&#x0D; Methods: This observational analytic study used 30 samples from tissue biopsies/surgeries diagnosed with conventional high-grade osteosarcoma and 30 samples of giant cell tumor of bone at the Anatomical Pathology Installation of Dr. Saiful Anwar General Hospital Malang, Indonesia, between 2018-2022. p53 expression was examined using the immunohistochemical staining method. Positive if stained with brown on the nucleus of the cell, the percentage of 500 malignant cells was calculated in the large field of view of the objective lens (x40) randomly. Univariate and bivariate data analysis was performed using SPSS.&#x0D; Results: The average p53 protein expression in conventional high-grade osteosarcoma was 80.0% ± 26.2, with the lowest value being 19% and the highest value being 100%. Whereas in giant cell tumor of bone, the average p53 expression was 1.7% ± 4.3, with the lowest value being 0% and the highest value being 17.6%. Statistical analysis using the Mann-Whitney test showed that p53 expression in conventional high-grade osteosarcoma and giant cell tumor of bone showed a significant difference (p=0.000). &#x0D; Conclusion: There is a significant difference between p53 expression in high-grade conventional osteosarcoma and giant cell tumor of bone.

Role of MDM2, CDK4, BCL2, Parafibromin and Galectin 1 in Differentiating Osteosarcoma from its Benign Fibro-osseous Lesions.

Benign fibro-osseous lesions (BFOLs) are a diverse group of lesions showing considerable degree of overlap with low grade osteosarcoma (LGOS). Further, de-differentiated osteosarcoma (DOS) is usually indistinguishable from conventional high-grade OS (COS) if LGOS foci are not identified. Thus, there is a need for adjunctive immunohistochemical markers to differentiate OS from benign FOLs as well as DOS from COS. This study evaluated the role of immunohistochemical expression of MDM2, CDK4, parafibromin, BCL-2 and Galectin-1 (Gal-1) in accurate characterization of benign FOLs and in differentiating them from OS. From our archives, we retrieved 101 tissue samples which were diagnosed as osteosarcoma (OS) /ossifying fibroma (OF) / fibrous dysplasia (FD) or fibrous hyperplasia (FH) and examined their immunohistochemical staining pattern with the aforementioned antibodies. MDM2 showed 100% specificity for diagnosing OS. CDK4 and Gal-1 showed linear increase in immunoexpression from benign BFOLs to OS. BCL-2 showed equivocal immunopositivity in OF and OS, but the positivity was higher than that observed in FD. The highest immunoexpression for parafibromin was seen in FD followed by OF and OS cases. Thus, MDM2 is most specific, and Gal-1 is most sensitive of all the markers studied in differentiating OS from benign mimics. Combination of these two markers can be used as an adjunct to conventional imaging and microscopy in accurate characterization of these lesions. Further MDM2 overexpression can differentiate DOS and COS.

Impact of psychosocial factors on the receipt of guideline concordant care in adolescent and young adults with localized Ewing sarcoma and osteosarcoma.

e18658 Background: Adolescent and young adults (AYAs) experience poorer outcomes, including lower survival improvements, compared to younger and older patients. As higher compliance with National Comprehensive Cancer Network (NCCN) guidelines has been associated with improved outcomes, we sought to understand the influence of psychosocial factors on receipt of care concordant with NCCN guidelines in AYAs with bone sarcomas. Methods: Retrospective chart review was performed on adult AYA patients (18-39 years) with localized Ewing sarcoma (ES) or high-grade conventional osteosarcoma (OS) seen at least once between 2015-2019 at the University of Wisconsin (UW). These tumor types were selected given uniform guideline-based care recommendations. Chart review identified receipt of standard care as per NCCN Bone Cancer guidelines, defined as neoadjuvant chemotherapy, local therapy (surgery/radiation), and adjuvant chemotherapy with receipt of at least 75% of recommended chemotherapy cycles, and compared to interpersonal relationships (marital status and presence of children at cancer diagnosis), changes in school or work following cancer diagnosis, substance use, and residential location. Results: We identified 21 AYA patients with localized ES (10/21, 48%) or OS (11/21, 52%), with 67% (14/21) receiving NCCN guideline concordant care. Receipt of guideline concordant care was associated with interpersonal relationships, with only 33% (1/3) of patients with children versus 72% (13/18) of patients without children receiving guideline concordant care. Additionally, the one patient noted to divorce following cancer diagnosis did not receive guideline concordant care (0/1, 0%) as compared with 67% (10/15) of single patients and 80% (4/5) of married patients. Vocational changes also affected care, with only 56% (5/9) of patients with work change following cancer diagnosis receiving guideline concordant care versus 75% (9/12) without work changes. Guideline concordant care was less common in patients with alcohol use (5/10, 50%) as compared with patients without alcohol use (9/11, 82%). Residential distance to UW was also associated with receipt of guideline concordant care, which was more common in patients living 0-20 miles from UW (86%, 6/7) as compared with those 21-100 miles from UW (60%, 6/10) or &gt; 100 miles from UW (50%, 2/4). Conclusions: Given the occurrence of cancer during a complex developmental time, AYAs have a relatively high occurrence of psychosocial changes and needs, which we found to be associated with receipt of NCCN guideline concordant care in patients with localized ES and OS. While a limited sample size, as the first study to define specific psychosocial factors that affect receipt of guideline concordant care, these finding suggest the need to improve identification and support of these discrete patient factors.

Pediatric Osteosarcoma: Pearls and Pitfalls

Osteosarcoma is a malignant bone tumor most commonly presenting in children. It has a bimodal distribution with a peak incidence occurring during the ages of 10-14 years old and in adults greater than age 65. The first peak of osteosarcoma correlates with the increased proliferation of bone during the pubertal growth period. Osteosarcoma most frequently presents with localized bone pain, swelling, and an antalgic gait. The patient may attribute symptoms to trauma or strenuous exercise, causing the patient to be managed conservatively. In these cases, the pain persists and eventually leads to further evaluation. The most common type of osteosarcoma is the conventional high-grade osteosarcoma. For conventional osteosarcoma, the diagnosis is typically made or strongly suggested based upon the initial radiographic appearance. Other types of osteosarcomas include low grade central, telangiectatic, small-cell, surface and intracortical. Consequently, it is important for radiologists to be aware of these subtypes and the imaging features that differentiate them from other etiologies to prevent a delay in treatment.

Temporal hemiarthroplasty for distal femoral osteosarcoma in early childhood: a case report

BackgroundProsthetic reconstruction for distal femoral osteosarcoma is challenging for younger children. We herein report a successful case of limb-sparing surgery for a younger patient with distal femoral osteosarcoma requiring osteo-articular resection.Case presentationA 5-year-old girl with high-grade conventional osteosarcoma in the left distal femur underwent a series of surgeries. After three cycles of neoadjuvant chemotherapy, limb-salvage surgery was planned because femoral rotationplasty had been refused. At 6 years and 2 months old, distal femoral resection and temporary spacer insertion using a 7-mm-diameter intramedullary nail and molded polymethylmethacrylate was performed. At 7 years and 8 months old, secondary surgery was performed because the first spacer had been dislocated and the residual femur became atrophic. The distal end of the residual femur was removed by 1 cm, but the periosteum and induced membrane around polymethylmethacrylate was preserved. In order to stabilize the spacer against the tibia, a custom-made ceramic spacer with a smooth straight 8-mm-diameter stem was utilized. The bone-spacer junction was fixed with polymethylmethacrylate and then covered with the preserved periosteum and induced membrane. After surgery, the bone atrophy improved. At 9 years and 7 months old, the second spacer was removed because it had loosened, and the knee joint was reconstructed using a custom-made growing femoral prosthesis with a curved porous 8.5-mm-diameter stem. Cancellous bone tips from the proximal tibia were grafted around the bone-prosthesis junction underneath the induced membrane. At 10 years and 5 months old, the patient was able to walk unsupported and a radiograph showed further thickening of the cortex of the residual femur without any stress shielding. Although having 5 cm of limb length discrepancy, the patient and her mother were satisfied with the function. The MSTS score was 24 out of 30 points. Repeated limb length extensions are planned.ConclusionsThis case report provides an example of limb-salvage surgery after distal femoral resection in a small child. The use of a temporary spacer utilizing partial cementation and preservation of the periosteum and induced membrane appears to afford a viable limb-salvage option after distal femoral resection for younger children.

Antiproliferative effect of bupivacaine on patient-derived sarcoma cells.

Sarcomas are rare tumors with limited treatment options. Although chemotherapy is standard for certain subtypes, overall survival has not improved in several decades. Bupivacaine has been shown to induce apoptosis and prevent cell growth in multiple different types of malignancies but has not been studied in sarcoma. The current study evaluated the effects of bupivacaine on multiple patient-derived sarcoma cells and a commercial sarcoma cell line. Multiple patient-derived sarcoma cell subtypes and a commercial synovial cell sarcoma cell line were exposed to bupivacaine for different durations and at different concentrations. The patient-derived cells included a high-grade conventional osteosarcoma, a high-grade undifferentiated pleomorphic sarcoma of bone, and a high-grade synovial sarcoma. Flow cytometry and an MTT assay were used to evaluate whether a treatment effect was observed. Treatment of all the subtypes of sarcomas in this study with bupivacaine demonstrated a time- and dose-dependent increase in apoptosis and decrease in cell viability. A cell viability assay demonstrated that the IC50 was between 0.04 and 0.05% and that the treatment effect occurred at clinically relevant doses in vitro. Bupivacaine was toxic to both the patient-derived cells and the commercial cell line at doses commonly used in the clinical setting. These findings provide a foundation for further in vivo studies to evaluate whether these effects will translate to the clinical setting. Although further research is necessary, bupivacaine shows promise as not only an adjunct for pain management but as a treatment modality for sarcoma.

Tumour volume as a predictor of metastases in patients presenting with high-grade conventional osteosarcoma of the extremities

ABSTRACT BACKGROUND: The aim of this study was to compare the initial tumour volume in patients with and without pulmonary and/or skeletal metastases at time of presentation. The secondary aim was to compare the value of tumour volume in the prediction of metastases at time of presentation with known predictive factors, namely serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). MATERIALS AND METHODS: A retrospective cross-sectional analysis was performed comparing the primary tumour volume in patients with and without metastases. All patients with histologically confirmed high-grade conventional osteosarcoma over a five-year period were included. RESULTS: The study comprised 61 patients. The mean age was 21 years (SD: 11.9, range 5-56) with an equal distribution of males and females (51% vs 49%). There was no correlation between tumour volume and age at presentation (p=0.31). There was no evidence of metastases in only 20% (n=12) of patients. Skeletal metastases were present in 28% (n=16) of the patients and pulmonary metastases were present in 44 cases (72%). There was no significant difference in the tumour volume at presentation between patients with and without pulmonary metastases (p=0.11). However, tumour volume did appear to predict the presence of skeletal metastases (p=0.02). A tumour volume of 1 383 cm3 had a negative predictive value (NPV) of 92% and positive predictive value (PPV) of 55% for the presence of skeletal metastases (area under curve [AUC]=0.76; sensitivity 66%; specificity 87%). A tumour volume of 480 cm3 had a 100% NPV for the presence of skeletal metastases (AUC=0.74). A tumour volume &gt; 1 380 cm3 had an odds ratio (OR) of 13.6 (p&lt;0.01; 95% CI 2.6-72.5) as an independent variable in relation to skeletal metastases. Multivariate analysis (with ALP and LDH) of tumour volume &gt;1 380 cm3 yielded an OR of 8.6 (p=0.04; 95% CI 1.1-67) for presence of skeletal metastases. CONCLUSION: In this series of conventional high-grade osteosarcoma of the extremities, we found a very high rate of metastases at time of diagnosis. While there was no association with pulmonary metastases, increased tumour volume was associated with an increased risk for the presence of skeletal metastases. More studies in the developing world clinical setting are required to investigate this further; the high rate of metastases seen at time of diagnosis also requires further investigation Level of evidence: Level 4. Keywords: osteosarcoma, metastases, tumour volume, prognosis, staging

Jaw osteosarcoma models in mice: first description

BackgroundOsteosarcoma (OS) is the most common cancer of bone. Jaw osteosarcoma (JOS) is rare and it differs from other OS in terms of the time of occurrence (two decades later) and better survival. The aim of our work was to develop and characterize specific mouse models of JOS.MethodsSyngenic and xenogenic models of JOS were developed in mice using mouse (MOS-J) and human (HOS1544) osteosarcoma cell lines, respectively. An orthotopic patient-derived xenograft model (PDX) was also developed from a mandibular biopsy. These models were characterized at the histological and micro-CT imaging levels, as well as in terms of tumor growth and metastatic spread.ResultsHomogeneous tumor growth was observed in both the HOS1544 and the MOS-J JOS models by injection of 0.25 × 106 and 0.50 × 106 tumor cells, respectively, at perimandibular sites. Histological characterization of the tumors revealed features consistent with high grade conventional osteosarcoma, and the micro-CT analysis revealed both osteogenic and osteolytic lesions. Early metastasis was encountered at day 14 in the xenogenic model, while there were no metastatic lesions in the syngenic model and in the PDX models.ConclusionWe describe the first animal model of JOS and its potential use for therapeutic applications. This model needs to be compared with the usual long-bone osteosarcoma models to investigate potential differences in the bone microenvironment.

Life and limb after limb salvage surgery for osteosarcoma in an Indian tertiary cancer center

Background: Limb salvage surgery (LSS) is the current surgical standard for malignant bone tumors. The advancements in imaging, surgical techniques, chemotherapy, and biomedical engineering have made LSS oncologically safe and with improved functional outcome. In this retrospective study, we report our experience with LSS and perioperative chemotherapy for osteosarcoma in a tertiary cancer center in India. Materials and Methods: A total of 41 LSS were performed from January 2009 to January 2015. Perioperative chemotherapy was administered to all patients after histopathological confirmation of osteosarcoma. The functional outcome of the patients was evaluated using the musculoskeletal tumor society (MSTS) scoring system at regular intervals. Statistical analysis involved the use of descriptive and inferential statistics for data analysis. Kaplan–Meier method was used for calculating the recurrence free and overall survival (OS) and log-rank test for comparing survival functions. Spearman and Karl Pearson's methods were used for correlation analysis. Results: The mean age was 19.3 years (range, 8–49 years). Twenty-five (61%) patients were males. Thirty-six (88%) patients had conventional high-grade osteosarcoma. Five-year relapse-free survival and OS were 56.1% ± 7.8% (95% confidence interval [CI], 53.7–58.5) and 58.5% ± 7.7% (95% CI, 56.1–60.9), respectively. The mean MSTS scores at 1 year for tumors of the upper tibia and distal femur were 64 and 75.9, respectively. Patients with high rate of chemotherapy-induced tumor necrosis (>99%) had significantly better median OS (85.70 ± 8.22 months) compared to those with less ( Conclusion: The oncological and functional outcomes in osteosarcoma patients in the present study are comparable to those from the world literature. Chemotherapy-induced tumor necrosis is a favorable prognostic factor for patients treated for osteosarcoma with curative intent.

Socioeconomic measures influence survival in osteosarcoma: an analysis of the National Cancer Data Base

BackgroundWhile previous studies have identified low socioeconomic status as a risk factor for metastatic disease in patients with high-grade osteosarcoma, the influence of socioeconomic status on overall survival remains unclear. The present study aims to investigate the relationship between survival and socioeconomic status in patients with high-grade conventional osteosarcoma. MethodsThe National Cancer Data Base (NCDB) was queried from 1998-2012 to identify all patients <40years of age with a diagnosis of high-grade conventional osteosarcoma. A total of 3,503 patients were identified that met inclusion and exclusion criteria. Univariate relationships were investigated using Kaplan-Meier survival analysis and associated log-rank tests in order to determine patient, socioeconomic, tumor, and treatment variables associated with overall survival. Multivariate analysis was performed to determine independent predictors of survival. ResultsIn order of decreasing magnitude, metastatic disease (Hazard Ratio [HR] 3.28, 95% Confidence Interval [CI] 2.82-3.82), primary site in the pelvis or spine (HR 2.15, 95% CI 1.79-2.59), positive surgical margins (HR 1.82, 95% CI 1.46-2.27), tumor size >8cm (HR 1.47, 95% CI 1.24-1.74), age ≥18 years (HR 1.30, 95% CI 1.14-1.48), lowest quartile of composite socioeconomic status (HR 1.23, 95% CI 1.02-1.51), and Medicaid insurance (HR 1.18, 95% CI 1.02-1.38) were predictors of decreased survival at 5 years. ConclusionTreating providers should be aware that some of their patients may have challenges unrelated to their diagnosis that make timely presentation, adherence to treatment, and continued close surveillance difficult. This investigation suggests that socioeconomic variables influence overall survival for osteosarcoma in the United States, although not as dramatically as established tumor- and treatment-related risk factors.

Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases

BackgroundHistone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown.MethodsIn this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes H3F3A and H3F3B. H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and H3F3A G34W/L mutant GCTBs.ResultsSix osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005).ConclusionsH3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB.

Dendritic and mast cell involvement in the inflammatory response to primary malignant bone tumours.

BackgroundA chronic inflammatory cell infiltrate is commonly seen in response to primary malignant tumours of bone. This is known to contain tumour-associated macrophages (TAMs) and lymphocytes; dendritic cells (DCs) and mast cells (MCs) have also been identified but whether these and other inflammatory cells are seen commonly in specific types of bone sarcoma is uncertain.MethodsIn this study we determined the nature of the inflammatory cell infiltrate in 56 primary bone sarcomas. Immunohistochemistry using monoclonal antibodies was employed to assess semiquantitatively CD45+ leukocyte infiltration and the extent of the DC, MC, TAM and T and B lymphocyte infiltrate.ResultsThe extent of the inflammatory infiltrate in individual sarcomas was very variable. A moderate or heavy leukocyte infiltrate was more commonly seen in conventional high-grade osteosarcoma, undifferentiated pleomorphic sarcoma and giant cell tumour of bone (GCTB) than in Ewing sarcoma, chordoma and chondrosarcoma. CD14+/CD68+ TAMs and CD3+ T lymphocytes were the major components of the inflammatory cell response but (DC-SIGN/CD11c+) DCs were also commonly noted when there was a significant TAM and T lymphocyte infiltrate. MCs were identified mainly at the periphery of sarcomas, including the osteolytic tumour-bone interface.DiscussionOur findings indicate that, although variable, some malignant bone tumours (e.g. osteosarcoma, GCTB) are more commonly associated with a pronounced inflammatory cell infiltrate than others (e.g. chondrosarcoma. Ewing sarcoma); the infiltrate is composed mainly of TAMs but includes a significant DC, T lymphocyte and MC infiltrate.ConclusionTumours that contain a heavy inflammatory cell response, which includes DCs, TAMs and T lymphocytes, may be more amenable to immunomodulatory therapy. MCs are present mainly at the tumour edge and are likely to contribute to osteolysis and tumour invasion.

Proximal location in extremity long bones is a poor prognostic factor for osteosarcoma: A retrospective cohort study of 153 patients

Background: Osteosarcomas arising in the proximal femur, humerus, and tibia appear to have poorer outcomes than those arising in distal long bones. However, the strength of this association is uncertain, particularly in light of other prognostic factors. Therefore, this retrospective cohort study was performed to compare patient outcomes between proximal and distal tumor location within extremity long bones. Material and methods: A total of 153 patients with conventional high-grade osteosarcoma of the extremity long bones, pelvis, or axial skeleton who had undergone neoadjuvant chemotherapy and surgical resection between 1985 and 2010 were identified in the Surgical Pathology files at Vanderbilt Medical Center. Effect of anatomic location within a proximal long bone was assessed using multivariable Cox proportional hazard regression. Results: Proximal tumor location was a strong predictor of poor prognosis in univariate survival analysis. Multivariate regression analysis showed that after controlling for American Joint Committee on Cancer (AJCC) stage, histologic response to chemotherapy, surgical resection margin status, and histologic type, location in the proximal femur, tibia, and humerus were independent risk factors for death due to osteosarcoma, but not event-free survival. Conclusion: Osteosarcomas of the proximal extremity long bones are associated with decreased disease-specific survival compared to tumors of the distal long bones, even after accounting for other key prognostic covariates.

Giant cell rich osteosarcoma revisited-diagnostic criteria and histopathologic patterns, Ki67, CDK4, and MDM2 expression, changes in response to bisphosphonate and denosumab treatment.

Defining giant cell-rich osteosarcoma (GCRO) as "an osteosarcoma in which more than 50% of the tumor consists of numerous uniformly distributed osteoclastic giant cells amidst oval or spindle mononuclear cells embedded in a fibrovascular stroma," eight such cases identified among 265 cases of osteosarcoma were analysed. Their age ranges from 11 to 33years, with peak incidence in the second decade and equal sex distribution. Seventy-five percent presented with pain, commonest in the knee, affecting the metaphysis. Most appeared radiologically as well-circumscribed expansile multiloculated osteolytic lesions, and many are displayed periosteal reaction. They showed several distinct histologic patterns: the stromal and giant cell, fibrohistiocytic, aneurysmal-cystic, osteoblastoma-like, and parosteal and fibrous dysplasia-like patterns. Focal subtle lacelike osteoid deposition, permeative infiltration into adjacent native bony trabeculae and over 30% Ki67 proliferative index were characteristic. There was no CDK4 and MDM2 amplification. In those having bisphosphonate and denosumab treatment, there was limited focal necrosis with reduction in the number of giant cells and broad trabecular woven bone formation but no giant osteoclast was seen. Two patients with initial diagnosis of giant cell tumor treated by curettage and local resection pursued aggressive clinical courses, died after 14 and 21months. The others survived 12 to 110months. GCRO accounts for about 3% of all osteosarcomas and apart from its more frequent diaphyseal location and associated normal bone-specific alkaline phosphate levels; it shares with conventional high-grade osteosarcoma the same patient demographics, sites of occurrence, absence of CDK4 and MDM2 amplification, and probably clinical course.