Successful management of Ewing Sarcoma in a pediatric patient: a case report on epiphyseal preservation and biological reconstruction

Introduction: Total hip arthroplasty (THA) in the setting of developmental dysplasia of the hip (DDH) presents more inherent complexities than routine primary THA for osteoarthritis. These include acetabular bone deficiency, limb length discrepancy (LLD), and abnormal femoral anteversion. Three-dimensional planning and robot-assisted (RA) bone preparation may simplify these complex procedures and make them more reproducible. The purpose of this study was to evaluate radiographic and clinical outcomes in a cohort of patients who had DDH and underwent an RA THA. Materials and Methods: We retrospectively analyzed 26 DDH patients who underwent RA THA by a single surgeon between 2013 and 2019. Their mean age was 54 years (range, 29 to 72 years) and mean follow up was approximately two years. Medical records were reviewed for demographics, clinical scores, Crowe classifications, and complications. There were thirteen Crowe I and seven Crowe II DDH hips, who were routinely managed with primary cementless implants. Two patients who had Crowe III and four patients who had Crowe IV DDH were also identified. All hips were reconstructed with cementless hemispherical acetabular components with or without the use of screws, but no acetabular augments or bulk allografts. Implants allowing control of femoral anteversion were selected in 23.1% of cases, including all six cases with Crowe III or IV dysplasia, and the need for these implants was uniformly identified using preoperative information about femoral version provided by the three-dimensional planning software. No patient was managed with a shortening femoral osteotomy. Postoperative radiographs were examined for LLD, center of rotation (COR), cup position (inclination and anteversion), and component osseous-integration. Results: Mean radiographic LLD was 1.7mm (range, -9 to +14) in patients who had Crowe I DDH, and there was no clinical LLDs greater than 5mm observed. Although patients who had Crowe II and greater DDH had a mean radiographic LLD of -11.6mm (range, -26 to +2.2), again no clinical LLD greater than 5mm was observed other than one patient who had bilateral Crowe II DDH in whom 10mm of clinical lengthening was accepted at the index arthroplasty with the plan to match lengths when her contralateral THA was performed. There were no cases of dislocation or acetabular fixation failure. One patient who had a femoral deformity and an intra-osseous blade plate from a prior femoral osteotomy suffered a failure of femoral osseous-integration, resulting in revision. A 32-point increase in mean modified Harris Hip Score (mHHS) was found (p=0.002), from 48 points preoperatively to 80 points postoperatively. Discussion: RA THA provides an excellent option for the arthroplasty surgeon to both preoperatively localize and characterize the acetabular deficiency, while providing a targeted, optimal, and secure placement of the components intraoperatively. Our results suggest favorable outcomes when compared to previous research on manual THA in DDH. Further studies, including comparative analyses, could discern possible advantages over traditional THA without robotic assistance in DDH. Conclusion: Total hip arthroplasty (THA) in the setting of developmental dysplasia presents more inherent complexities than routine primary THA. Robotic-assisted THA may simplify these complex procedures.

Proximal femur alloprosthesis in a pediatric patient with Ewing sarcoma: Case report

ObjectiveDevelopmental dysplasia of the hip (DDH) refers to a series of deformity of acetabulum and proximal femur and abnormal relationship between them, it represents the most common hip disease in children. Overgrowth and limb length discrepancy (LLD) was common complication in children undergoing femoral shortening osteotomy. Therefore, the purpose of this study was to explore the risk factors of overgrowth after femoral shortening osteotomy in children with DDH.MethodsWe included 52 children with unilateral DDH who underwent pelvic osteotomy combined with femoral shortening osteotomy between January 2016 and April 2018, including seven males (six left and one right hip) and 45 females (33 left and 12 right hips) with an average age of 5.00 ± 2.48 years, and an average follow-up time of 45.85 ± 6.22 months. The amount of overgrowth and limb length discrepancies (LLDs) were calculated. The risk factors of femoral overgrowth ≥1 cm and LLD ≥ 1 cm were analyzed.ResultsThere were statistical differences in age (p < 0.001) and operation duration (p = 0.010) between the two groups with femoral overgrowth <1 cm and ≥1 cm. There was a statistical difference in operation duration (p < 0.001) between the two groups. Age (p < 0.001) was an independent influencing factor of femoral overgrowth in children with unilateral DDH after pelvic osteotomy and femoral shortening osteotomy, and a risk factor (p = 0.008) of LLD in these children.ConclusionThe overgrowth and LLD of children with developmental dislocation of hip after pelvic osteotomy and femoral shortening osteotomy are significantly related to age. There was no significant difference between different pelvic osteotomies for femoral overgrowth in children. Therefore, surgeons should consider the possibility of LLD after femoral shortening osteotomy in children of a young age.

By comparing with the traditional X-ray template measurement method, to explore the accuracy of artificial intelligence preoperative planning system (AI-HIP) to predict the type of prosthesis and guide the placement of prosthesis before total hip arthroplasty (THA) in adult patients with developmental dysplasia of the hip (DDH). Patients with DDH scheduled for initial THA between August 2020 and August 2022 were enrolled as study object, of which 28 cases (28 hips) met the selection criteria were enrolled in the study. Among them, there were 10 males and 18 females, aged from 34 to 77 years, with an average of 59.3 years. There were 12 cases of the left DDH and 16 cases of the right DDH. According to DDH classification, there were 10 cases of Crowe type Ⅰ, 8 cases of type Ⅱ, 5 cases of type Ⅲ, and 5 cases of type Ⅳ. According to Association Research Circulation Osseous (ARCO) staging of osteonecrosis of the femoral head, 13 cases were in stage Ⅲ and 15 cases in stage Ⅳ. The disease duration was 2.5-23.0 years (mean, 8.6 years). The limb length discrepancy (LLD) was 11.0 (8.0, 17.5) mm. Before operation, the prosthesis types of all patients were predicted by AI-HIP system and X-ray template measurement method, respectively. And the preoperative results were compared with the actual prosthesis type during operation in order to estimate the accuracy of the AI-HIP system. Then, the differences in the acetabular abduction angle, acetabular anteversion angle, femoral neck osteotomy position, tip-shoulder distance, and LLD were compared between preoperative planned measurements by AI-HIP system and actual measurement results after operation, in order to investigate the ability of AI-HIP system to evaluate the placement position of prosthesis. The types of acetabular and femoral prostheses predicted based on AI-HIP system before operation were consistent with the actual prostheses in 23 cases (82.1%) and 24 cases (85.7%), respectively. The types of acetabular and femoral prostheses predicted based on X-ray template measurement before operation were consistent with the actual prostheses in 16 cases (57.1%) and 17 cases (60.7%), respectively. There were significant differences between AI-HIP system and X-ray template measurement (P<0.05). There was no significant difference in acetabular abduction angle, acetabular anteversion angle, femoral neck osteotomy position, and tip-shoulder distance between AI-HIP system and actual measurement after operation (P>0.05). LLD after operation was significantly lower than that before operation (P<0.05). There was no significant difference between the LLD predicted based on AI-HIP system and the actual measurement after operation (P>0.05). Compared with the traditional X-ray template measurement method, the preoperative planning of AI-HIP system has better accuracy and repeatability in predicting the prosthesis type. It has a certain reference for the prosthesis placement of adult DDH.

Osteosarcoma and Ewing sarcoma are more common diagnoses in preadolescent and adolescent children compared with the adult population. A greater percentage of patients are treated with limb salvage and reconstruction using modular tumor endoprostheses. Implant-to-bone fixation can be cemented or cementless. Cementless tumor endoprostheses rely on biologic osteointegration for implant stability, and chemotherapy during childhood and adolescence can disturb the bone turnover rate and reduce bone mineral density, which in turn may predispose patients with uncemented endoprostheses to a high rate of revision surgeries. (1) What is the cumulative incidence of revision operations for any cause (wound dehiscence, periprosthetic fracture, hinge breakage, aseptic loosening, infection, local recurrence, implant removal, and amputation) of cementless tumor endoprostheses around the knee? (2) What is the cumulative incidence of aseptic loosening, periprosthetic fracture, hinge breakage, and infection, and what proportion of patients had other complications? (3) What was the mean limb length discrepancy (LLD) at the time of skeletal maturity? (4) What was the median Musculoskeletal Tumor Society (MSTS) score at most recent follow-up or just before implant removal/amputation if implant removal/amputation were performed? Between 2008 and 2019, we treated 328 patients younger than 18 years for a primary bone sarcoma around the knee at our institution. Of those, 138 were treated with resection and reconstruction using two different types of modular tumor endoprostheses. During this period, our general indications for an endoprosthesis were patients who were candidates for an intraarticular resection of the distal femur or proximal tibia and who were at least 10 years of age. Uncemented fixation was always preferred. Cemented fixation was only done when intraoperative press-fitting of a cementless stem was not possible. Among uncemented implants, 26 patients died before completing 2 years of follow-up with intact implants and without further surgery, three were lost to follow-up before 2 years, and four patients received implants as a secondary salvage surgery after a failed primary biologic reconstruction with a vascularized fibular bone graft, leaving 94 patients for evaluation in this retrospective study. The mean age was 15 ± 2 years and the median (interquartile range) follow-up duration was 51 months (39 to 74). We did a competing risks analysis to tally cumulative incidence of all-cause revision procedures and cumulative incidence of aseptic loosening, periprosthetic fracture, hinge breakage, and infection. Other complications, including wound dehiscence, local recurrence, and stem breakage, were characterized descriptively and ascertained by review of electronic records of a longitudinally maintained institutional database by the treating surgeons. LLD was measured by serial clinical assessments and CT scans, starting since primary salvage surgery and until the latest follow-up of every patient. For the analysis of remaining LLD, we included only patients who were skeletally immature at time of primary resection and who had reached skeletal maturity by their latest follow-up (73% [69 of 94]). Functional outcome was assessed using MSTS scores obtained from a review of electronic records of a longitudinally maintained institutional database. The 8-year cumulative incidence of revision surgery for any cause was 32% (95% confidence interval 23% to 42%). The 8-year cumulative incidence of aseptic loosening was 5% (95% CI 2% to 11%), periprosthetic fracture was 9% (95% CI 4% to 15%), hinge breakage was 19% (95% CI 12% to 28%), and infection was 7% (95% CI 3% to 14%). Other complications included wound dehiscence in 2% (2 of 94), stem breakage in 2% (2 of 94), and local recurrence in 2% (2 of 94) of patients. Stress shielding of the cortical bone around implanted stems was observed in 26% (24 of 94). The mean LLD for those who were skeletally immature at the time of primary resection and who reached skeletal maturity was 3.5 ± 2.6 cm. At latest follow-up, the median (IQR) MSTS score for all patients, excluding those who had complete implant removal or amputation, was 26 (24 to 27) of a maximum score of 30. We observed a high rate of early revision and relatively frequent complications associated with the use of cementless fixation, and although this was not a comparative study, the findings were not superior to those reported by others who have studied cemented fixation for this indication. Furthermore, there may be some disadvantages with cementless fixation, such as stress shielding. Comparative studies about fixation methods are needed. The prevalence of bushing breakage in the current study highlights the importance of future modifications in the hinge design of both types of prostheses used in this study. Patients who were skeletally immature at the time of primary surgery had a LLD no more than 5 cm at skeletal maturity; consequently, nonexpandable endoprostheses may be appropriate for some adolescent patients who have limited remaining growth, although which patients are best suited for this approach would require specific study. Level IV, therapeutic study.

Skeletally immature children with a primary malignant tumor in the distal end of the femur are candidates for limb-salvage surgery; however, functional impairment due to subsequent limb-length discrepancy must be considered. Our aim was to evaluate the long-term clinical outcome of limb salvage in patients with a sarcoma of the distal end of the femur who were eleven years old or less, focusing on limb-length discrepancy and complications. The cases of forty children were retrospectively reviewed in a multicenter study based on the responses to a questionnaire. Twenty-eight patients had had endoprosthetic reconstruction, and twelve had had biological reconstruction. Functional evaluation was based on the Musculoskeletal Tumor Society scoring system, with numerical values from 0 to 5 points assigned for each of the following six categories: pain, function, emotional acceptance, use of supports, walking ability, and gait. These values were added, and the functional score was presented as a percentage of the maximum possible score. Limb-length discrepancy was measured with orthoroentgenograms. Complications and their treatment were analyzed. Patient survival and the survival of the reconstructions were analyzed with use of the Kaplan-Meier method. Seven patients died and thirty-three remained alive, for a survival rate of 82% at ten years postoperatively. For the surviving patients, the mean follow-up periods (and standard deviations) were similar for the twenty-two who had endoprosthetic reconstruction (13.2 +/- 3.9 years) and the eleven who had biological reconstruction (10.4 +/- 4.4 years). All patients had reached skeletal maturity. The mean final functional score was 74% +/- 18% in the endoprosthetic reconstruction group and 68% +/- 17% in the biological reconstruction group (p = 0.37). For the nineteen patients who underwent limb-lengthening, the mean functional score increased significantly from 65% +/- 21% before the procedure to 81% +/- 11% after the lengthening (p = 0.0016). There were five early and twenty-eight late complications. In the endoprosthetic reconstruction group, the most frequent complications were deep infection and aseptic loosening. In the biological reconstruction group, the most frequent complications were implant breakage and nonunion. Revision surgeries were required in seventeen patients, including five who had an amputation. The rate of survival of the endoprosthetic reconstructions was 77% at five years and 51% at ten years postoperatively, whereas the rate of survival of the biological reconstructions was 46% at both five and ten years postoperatively. Endoprosthetic or biological reconstructions as limb salvage provided good functional outcome in skeletally immature children with a malignant bone tumor of the distal aspect of the femur despite a high rate of revisions and limb-lengthening procedures.

Limb-length discrepancy (LLD) arising from hip subluxation or dislocation and accompanied by insufficiency of hip abductor in patients with developmental dysplasia of the hip (DDH) can be corrected partially or completely with total hip arthroplasty (THA). However, information about post-THA changes in abductor strength related to preoperative LLD in patients with DDH is lacking. We aimed to explore the post-THA recovery course of abductor muscle strength and its related factors in patients with DDH. A cohort of 45 patients with unilateral DDH was divided into two groups according to their Crowe classification: patients with class I or II DDH formed Group M, and patients in class III and IV DDH formed Group S. The following parameters were measured on standardized antero-posterior hip radiographs taken in the supine position pre- and post-THA: abductor muscle length, abductor lever arm, LLD, and femoral offset (FO). Abductor strength was evaluated quantitatively with the Isomed 2000 isokinetic test system (1 week before the operation and 1, 3, 6, and 12 months after the operation). The contralateral normal hip joint served as a within-patient control. The affected side:healthy side ratios of the parameters above were calculated. Abductor strength ratio evaluated at the five follow-up time points was larger in Group M than that in Group S (p < 0.001). The average abductor strength ratio reached 78.5, 85.4, and 89.2% at the 3, 6, and 12 months postoperative exams, respectively, in Group M, and reached 50.3, 63.2, and 72.9% in Group S. The abductor muscle length ratio, the abductor muscle level arm ratio, and the FO ratio were significantly increased postoperatively, relative to preoperative assessment, in the two groups. LLD was reduced significantly postoperatively, relative to preoperative values, in both groups. Both preoperative LLD (r = -0.791, p < 0.001) and the change in abductor muscle length ratio (r = -0.659, p < 0.001) correlated with abductor strength recovery. Patients showed the greatest improvement in abductor strength within the first 6 months after THA, especially during the first 3 months. Abductor strength was consistently greater in patients with mild dysplasia than in patients with severe dysplasia. The extent of preoperative LLD and the increase in abductor length were related with post-THA abductor strength recovery in patients with DDH.

11531 Background: Treatment of Ewing Sarcoma (EWS) is challenging. While it is known to be sensitive to chemotherapy and radiation, the number of lines of therapy available are limited. This disease affects pediatric patients (PP) more often than adults (AP), and reported outcomes are worse for AP onset EWS in the literature. It is unclear if this is due to difference in the biology of disease in AP compared to PP, or if this is due to differences in treatment approach. Furthermore, optimal treatments and real world impact of treatment is unclear in both the PP and AP populations. This study identifies the features of therapy received by AP and PP with EWS in a large, mutli-institutional cohort, and provides real world evidence for the expected outcomes in both AP and PP with EWS. Methods: A cohort study analysis of the Sarcoma Outcomes Unit database at BC Cancer was conducted to identify patients diagnosed with EWS in British Columbia from January 1, 2000 to December 31, 2018. Data on the frequency, amount, and regimen of chemotherapy were collected. Baseline Charlson comorbidity index, age at diagnosis, progression free survival and overall survival were collected. Results: 108 patients with EWS were identified, 66 AP and 42 PP Median age at diagnosis for adults was 37 (19-86) and median age for diagnosis of pediatric patients was 14 (1-18). Real world median PFS and OS for AP were 23 mos and 79 mos, and for the PP were 32 mos and NE. Five year overall survival was 54% in AP and 77% in PP. Overall, there was no difference in the number of lines of therapy received between PP and AP, but the type of therapy was more dose-dense in the PP than in the AP, (85% vs 28% for dose dense chemo). 5 year overall survival was longer for PP who received dose dense regimens compared to non-dose dense regimens (HR 0.87), but was not different in the AP receiving dose dense regimens (HR 0.95), even when controlling for comorbidities. The most common chemotherapy regimen for AP was Vincristine, Adriamycin, cyclophosphamide alternating with Ifosfamide and Etoposide q3weeks, whereas in the pediatric population the most common chemotherapy regimen was the same but alternating q2weeks. Conclusions: The treatment plans for PP with EWS were more often dose dense compared to the AP. Outcomes for PP were vastly better than for APs, despite overall similarities in the number of lines of therapy and types of agents used. Given the lack of difference between dose dense and non-dose dense regimens for APs, this is not the likely cause of difference in survival between PPs and APs. Extrapolating pediatric protocols to the adult setting may not be appropriate given the differences in outcomes. Further work to identify effective therapies and predictive biomarkers in this disease are needed, and my further identify reasons for discrepant outcomes in pediatric and adult populations.

Objective To investigate the clinical significance of asymmetric skin folds in the diagnosis of developmental dysplasia of the hip (DDH) in infant. Methods The clinical data of 3 266 infants aged up to 6 months who were evaluated because of suspicious findings for DDH, hospitalized at Department of Pediatric Orthopaedics, Shengjing Hospital of China Medical University between January 2012 and April 2019 were reviewed retrospectively, including 1 185 boys and 2 081 girls, with a mean age of 2.8 months (ranging from 1 d to 6 months). The referred reasons included regular screening for DDH without suspicious findings [379 cases(11.6%)], clunk of the hip[59 cases(1.8%)], limb-length discrepancy[188 cases (5.8%)], limitation of hip motion or asymmetrical range of motion[58 cases(1.8%)], asymmetric skin folds[2 107 cases(64.5%)], and combined conditions of musculoskeletal disorder[475 cases(14.5%)]. The Graf′s ultrasound method was used to define the hip conditions.A type Ⅰ or Ⅱa hip was graded as normal, and a type Ⅱb or more serious was graded as DDH.The percentages of DDH for various reasons were compared. Results Among 3 266 patients (6 532 hips), a total of 194 infants(230 hips)were diagnosed as DDH, and the total diagnostic rate was 5.94%, including 31 males and 163 females; there were 109 cases involving in the left, 49 cases in the right, and 36 cases in the bilateral.The DDH diagnosed rate for regular screening was 8.71%(33/379 cases), 6.78%(4/59 cases) for clunk of the hip, 10.34%(6/58 cases) for limitation of hip motion, 14.36%(27/188 cases)for limb-length discrepancy, 4.79%(101/2 107 cases) for asymmetric skin folds, 4.84%(23/475 cases) for combined conditions of musculoskeletal disorder, and the DDH diagnosed rate for asymmetric skin folds was the lowest(χ2=37.14, P<0.05). Conclusions Although asymmetric skin folds is the most common reason for DDH screening in infant up to 6 months, its clinical significance is limited, asymmetric skin folds should not be considered as an independent indication for DDH screening. Key words: Developmental dysplasia of the hip; Asymmetric skin fold; Diagnosis; Ultrasound screening

Osteosarcoma and Ewing sarcoma represent the 2 most common cancers of bone seen in pediatric patients. Given that patients with such tumors can frequently present to nononcologist providers reporting nonspecific symptoms such as musculoskeletal pain or swelling, an understanding of these disease entities by pediatricians is important to ensure appropriate patient referral and care. In addition, because there are a variety of sequelae present in bone sarcoma survivors as a result of disease and treatment, understanding and awareness of such sequelae by nononcologist providers is important for long-term patient care.After completing this article, readers should be able to: Understand the incidence and general epidemiology of osteosarcoma and Ewing sarcoma, including genetic syndromes that increase the risk of developing sarcomas in children.Recognize the clinical presentation of osteosarcoma and Ewing sarcoma.Initiate an evaluation to further characterize a new bone or soft tissue lesion.Describe the prognostic factors associated with osteosarcoma and Ewing sarcoma.Describe the long-term complications associated with the treatment of osteosarcoma and Ewing sarcoma.Osteosarcoma and Ewing sarcoma represent the 2 most common cancers of bone seen in the pediatric population. Bone cancers as a group represent approximately 4% of the approximately 10,000 new pediatric cancer diagnoses made each year in the United States. (1) As with many pediatric tumors, although some cases can be attributed to environmental factors (such as ionizing radiation) or inherited genetic risk, most cases are believed to arise spontaneously. The anatomical location of the tumors shows differences between Ewing sarcoma and osteosarcoma, and Ewing sarcoma can also present as soft tissue masses. Patients commonly present with pain or swelling, leading to the identification of a mass by examination or imaging. Although treatment regimens differ between them, both sarcomas require therapy that includes both systemic chemotherapy and an element of local control, such as surgical resection or radiotherapy. For both sarcomas, survival decreases dramatically when the disease is determined to be metastatic, and the lungs are the most common site of metastases. In both cases, there are a variety of sequelae present in long-term survivors as a result of treatment or because of the location of the primary tumor, requiring special attention in survivorship care.Bone cancers in children rank in incidence behind multiple other types of cancers, including leukemias, lymphomas, and central nervous system tumors. Counting new diagnoses of osteosarcoma and Ewing sarcoma, there are approximately 800 newly diagnosed cases per year in the United States in the pediatric population, with approximately 450 cases in children (ages 0–14 years) and 350 cases in adolescents (ages 15–19 years). Osteosarcoma and Ewing sarcoma are rarely seen in the youngest group of children (ages 0–4 years) and have an incidence that rises with patient age, with the highest rate of diagnoses in adolescents aged 15 to 19 years. A second peak of osteosarcoma is seen in adults older than 65 years, oftentimes associated with Paget disease of bone. Both tumor types show a slight predominance in males: 55% of new diagnoses of osteosarcoma and 58% of diagnoses of Ewing sarcoma. (1)Most cases of bone tumors are sporadic, and few patients have predisposing genetic factors. Compared with Ewing sarcoma, osteosarcoma has a variety of associated syndromes that predispose to its development, including germline mutations in tumor suppressors such as TP53 (Li-Fraumeni syndrome) and RB1 (retinoblastoma). In addition, a variety of relatively rare syndromes that all seem to predispose to tumor development because of their role in genomic and DNA stability have been associated with increased risk of osteosarcoma (Table). (2)(3) However, all of these syndromes are rare in the population. Although not a genetic factor, ionizing radiation is a well-described risk factor for the later development of osteosarcoma, particularly in individuals with an underlying genetic predisposition. In contrast, the development of Ewing sarcoma has no known association with radiation or other named genetic disorders or syndromes. Although Ewing sarcoma does have a characteristic gene fusion present in the tumor cells (see the Diagnosis section), if there are genetic factors that predispose to such a fusion, they are currently unknown.Variations in incidence for both osteosarcoma and Ewing sarcoma have been described for individuals of different ancestry for reasons that remain unclear. Osteosarcoma is diagnosed at a higher rate in children with African and Hispanic ancestry compared with those of European descent, but this difference is reversed in the adult population with osteosarcoma. (4) In contrast, Ewing sarcoma is approximately 9 times more prevalent in individuals of European descent, with comparatively much lower rates in individuals of African descent. (5) This difference seems to be present across patient ages in Ewing sarcoma.Osteosarcoma has a variety of subtypes based on histologic characteristics and appearance. Subtyping based on tumor grading—ranked as low, intermediate, and high grade—has clinical implications for both treatment and outcomes, but further histologic designations within those categories do not. Tumors that have a subtype designation with relevance to management and outcome include the low-grade osteosarcomas, also known as parosteal osteosarcomas, and the intermediate-grade tumors, termed periosteal. (6) Most conventional osteosarcoma tumors are high grade and can be furthered classified into descriptive histologic subgroups such as osteoblastic, telangiectatic, and fibroblastic.For Ewing sarcoma and osteosarcoma, the initial presentation can be subtle, with complaints including nonspecific pain or swelling at the primary site of disease. Pain is present in approximately 70% of patients and is often associated with activity but is also seen at rest or at night. The initial complaint and the onset of symptoms are often associated with trauma, such as a sports-related injury, which can complicate making the diagnosis. (7) Although there is variability in presentation, pain that persists throughout both the day and night, is present for weeks to a month, and/or has no known association with trauma or vigorous activity should increase suspicion for a malignant process.This potential for a relatively subtle initial presentation in patients means that clinicians should hold a high index of suspicion and consider a more thorough evaluation in cases in which the diagnosis for a musculoskeletal complaint is unclear. A history of trauma, the acquisition of radiographs, and the presence of a palpable mass are all associated with shorter time to definitive diagnosis after initial presentation to a provider, but 1 study identified that 10% of patients with osteosarcoma and 28% of patients with Ewing sarcoma had a time to diagnosis that exceeded 6 months between initial presentation of symptoms and definitive diagnosis. (7) However, despite this potential for a delay in diagnosis, survival seems equivalent between patients who experience a delay and those who do not. (8)Sites of disease vary between the sarcomas. Osteosarcoma has a higher likelihood of being found in the appendicular skeleton. Ewing sarcoma is more likely to present in the axial skeleton (Fig 1). (9)(10) Interestingly, the presentation of osteosarcoma in the extremities has a tendency for specific localization within the involved bones; lower extremity lesions are more often localized close to the knee (eg, distal femur and proximal tibia), and lesions in the humerus are more likely to be proximal. The potential for Ewing sarcoma to involve axial structures also means that presentation of such tumors may be even more difficult to detect on history and physical examination given the lower likelihood of an easily detected palpable mass.For both osteosarcoma and Ewing sarcoma, diagnosis follows a similar trajectory: characterization via imaging of the primary site of disease, coupled with investigations to determine whether the disease is localized or metastatic. Biopsy for definitive pathological tissue diagnosis is essential.Initial imaging should be performed with standard radiography. Ewing sarcoma will frequently appear on such imaging with evidence of bony destruction, exhibiting indistinct lesional margins described as a moth-eaten appearance. There is also often evidence of cortical destruction and a soft tissue mass, and periosteal reaction can potentially give rise to such classic imaging findings as a sunburst pattern or onion skinning, (11) Osteosarcoma typically demonstrates a mixed appearance on imaging, with both lytic and radiodense aspects to the lesion. Frequently there is an accompanying soft tissue mass. As with Ewing sarcoma, findings of cortical destruction and a sunburst pattern can be present as a consequence of the tumor’s growth and infiltration, which can also result in a periosteal elevation that is termed the Codman triangle (Fig 2). (12)For bony lesions concerning for a sarcoma on plain films, more detailed magnetic resonance imaging of the affected body region and adjacent joint should be performed. This imaging permits characterization of soft tissue extension, detection of skip lesions that suggest local spread of the tumor in the bone of origin, and possible detection of any extension into adjacent joints or other important structures. Due to the risk of pulmonary metastases for both tumor types, computed tomography of the chest should be performed. In addition to assessing the lungs by computed tomography for any evidence of metastatic disease, fluorodeoxyglucose–positron emission tomography is frequently used to look for other sites of distant metastatic disease.The approach to detection of metastases to bone marrow differs between osteosarcoma and Ewing sarcoma because the likelihood of bone marrow metastases at diagnosis is very low in osteosarcoma compared with Ewing sarcoma. Although bone marrow biopsies are not routinely performed in osteosarcoma, bilateral bone marrow biopsies, typically from the iliac crests, are obtained at diagnosis to characterize the presence or absence of marrow disease in patients with Ewing sarcoma. The rate of metastatic marrow disease is approximately 5% in all patients with Ewing sarcoma, but it rises to nearly 20% in those with other metastatic disease sites. Interestingly, only 1.2% of Ewing sarcoma is metastatic to only the bone marrow. Although the role for positron emission tomography in the detection of metastatic Ewing sarcoma in bone marrow is still evolving, there is emerging data to suggest that it may be a safe alternative to bone marrow biopsy in patients with no other evidence of metastatic disease. (13)Although both osteosarcoma and Ewing sarcoma have certain typical characteristics from imaging, pathological diagnosis is essential to ensure proper treatment. The exact approach depends on the affected anatomical site and adjacent structures but should always be performed by a surgeon or interventional radiologist skilled in the management of sarcomas.Ewing sarcoma appears morphologically as a small round blue cell tumor (Fig 3A). For Ewing sarcoma, the tumors possess a gene fusion between the EWS gene and a member of the ETS gene family. This fusion results in the production of a tumor-specific transcription factor that is a key driver of Ewing sarcoma tumor biology. (14)(15)(16)(17) Given that the fusion is specific to tumor cells, molecular biological techniques such as next-generation sequencing, fluorescent in situ hybridization, or reverse transcription–polymerase chain reaction are used to confirm a presumptive histologic diagnosis. Evidence of osteoid production on a biopsy is pathognomonic for osteosarcoma (Fig 3B). The most critical piece for osteosarcoma is grading of the tumor to determine whether it is low-, intermediate-, or high-grade because that has direct implications for outcome and treatment.Laboratory tests are not helpful in making a definitive diagnosis of either Ewing sarcoma or osteosarcoma. If there is concern for a bone tumor, standard laboratory tests such as a basic metabolic panel, liver function tests, and a complete blood cell count with differential count should be performed, but normal results in no way exclude such a tumor. If they are measured, lactate dehydrogenase and alkaline phosphatase levels will typically be elevated at presentation, given the presence of bony destruction, but these enzyme elevations are relatively nonspecific and, therefore, cannot be used to make a definitive diagnosis.Before the introduction of chemotherapy, the treatment of osteosarcoma was surgical resection alone. Survival was less than 15% secondary to the development of metastatic disease, primarily in the lungs. This underscored the need for systemic therapy. (18) Early therapeutic trials established the efficacy of adjuvant (postoperative) chemotherapy, typically consisting of high-dose methotrexate, doxorubicin, and cisplatin (MAP). (19)(20) Studies from Sloan-Kettering showed an advantage to neoadjuvant (preoperative) chemotherapy. This allowed for limb-sparing surgical procedures and assessment of histologic response to chemotherapy, which has been found to have prognostic significance. Studies have shown that greater than 90% tumor necrosis at the time of resection is associated with improved outcomes. (21) These concepts led to development of the current model of treatment, including neoadjuvant chemotherapy with MAP, surgery to remove the primary tumor and sites of metastatic disease, and adjuvant chemotherapy.In the 1980s, the Multi-Institutional Osteosarcoma Study established the use of MAP as an effective treatment regimen in osteosarcoma. (21) Unfortunately, since that time, there has been little success in increasing overall survival. The most recent international trial, the European and American Osteosarcoma Study (EURAMOS), evaluated whether the addition of adjuvant high-dose ifosfamide and etoposide (IE) to the 3-drug therapy backbone improved outcome for patients with poor tumor necrosis. This trial also evaluated whether there was a role for maintenance therapy with adjuvant pegylated interferon in patients with good histologic response. The study completed in 2011, and neither the addition of IE nor maintenance therapy with pegylated interferon improved outcomes. This leaves neoadjuvant chemotherapy with MAP followed by surgery and adjuvant MAP as the standard of care. The standard chemotherapy management for metastatic osteosarcoma is similar to localized disease, with an emphasis on surgery to remove metastatic tumor where possible. Several recent trials using novel agents have not improved outcomes.Osteosarcoma is relatively radioresistant, and surgery is considered a mainstay of cure. The most important component is wide local excision, where both tumor and a normal tissue margin should be removed. Typically, surgical options include amputation, disarticulation (amputation through a joint), or limb salvage. Historically, more amputations were performed, but as surgical techniques have improved, limb-sparing surgeries have become more common. When either disarticulation or limb salvage is performed, reconstruction is necessary. Reconstruction can include osteoarticular allografts, an endoprosthesis made of different metals, or combinations of the two. More recently, for patients still growing, endoprosthetic devices that expand as the patient grows have been an attractive option. For large tumors of the distal femur or proximal tibia, a van Ness rotationplasty can be performed. In this procedure, the ankle joint becomes a knee joint by rotating the distal part of the lower leg 180° and reattaching to the proximal femur. A custom prosthesis is fitted to the rotated leg, which serves as a below-the-knee prosthesis (Fig 4). This option is attractive for younger patients and those who want to remain active in sports because other prostheses typically limit patients to low-impact activities. (19)(22)Osteosarcoma is thought to be relatively radioresistant, and radiotherapy is not used in the upfront setting. However, in circumstances in which tumors are unresectable or palliative symptom control is necessary, radiotherapy has been shown to be effective. Doses larger than 60 Gy are typically needed.For recurrent disease, treatment remains challenging. Metastatectomy of the lungs or bony sites can be curative in 20% of patients (23)(24) if disease is isolated to the lungs or to a bone amenable to resection. Many agents aimed at targeting some of the pathways known to drive osteosarcoma development have been trialed with mixed success. Agents that have shown some activity in recurrent osteosarcoma and that are often used include ifosfamide, IE, gemcitabine, and docetaxel, as well as tyrosine kinase inhibitors. (24)(25)(26)Patients with localized, completely resected disease have survival rates approaching 70%. Those with unresectable or metastatic disease fare much worse, with survival rates typically less than 25% (Fig 5). Despite many attempts to improve survival rates, these outcomes have remained unchanged for decades, and chemotherapy regimens remain the same.Unlike osteosarcoma, Ewing sarcoma is known to be radiation sensitive. Historically, when radiotherapy was solely used in the treatment of Ewing sarcoma, fewer than 10% survived, underscoring the need for systemic therapy. Most patients are now treated with neoadjuvant chemotherapy followed by local control with surgery or radiotherapy and adjuvant chemotherapy. Survival has increased dramatically with this multidisciplinary approach.In the 1980s, the North American Intergroup Ewing Sarcoma Study Group established the benefit of doxorubicin and higher-dose, intermittent cyclophosphamide in Ewing sarcoma therapy. (27)(28) Because of the dose-limiting cardiac toxic effects of doxorubicin, other alkylating agents were trialed, leading to the INT-0091 study, which established that the addition of IE to a doxorubicin-based backbone increased overall survival in nonmetastatic patients. Through INT-0091 and Children’s Oncology Group trial AEWS0031, the established standard of care is alternating cycles of vincristine, doxorubicin, cyclophosphamide, and IE every 2 weeks. (27)(29)Unfortunately, approximately 25% of newly diagnosed patients with Ewing sarcoma present with metastatic disease, primarily to the lungs, bone, and/or bone marrow. The prognosis for these patients remains poor. Intensified chemotherapy regimens and novel biological therapies have been tried but without major success. (30)(31) High-dose chemotherapy with autologous stem cell rescue is an approach used in certain patient populations in Europe but is not the standard approach in North America. (32)(33) Targeting the EWS fusion would seem attractive; however, to date there has been no clinical success. (34)The standard treatment approach is neoadjuvant chemotherapy followed by local control and adjuvant chemotherapy. The best option for local control is debated because there has never been a randomized controlled trial comparing the effectiveness of surgery versus radiotherapy. Retrospective evidence suggests that there are higher rates of local recurrence with radiotherapy alone, (35)(36) and there are concerns for secondary malignancies related to irradiation. Alternatively, surgery can lead to permanent deficits and morbidity.The most important aspect of surgical resection of the local tumor is the ability to obtain negative margins. This means that the entire tumor is removed along with a small border of normal tissue. Options include amputation and limb salvage with reconstruction. Reconstruction can consist of bone grafts, prosthetic devices, and combinations of the two, similar to surgeries for osteosarcoma. Ewing sarcoma of the pelvis is particularly challenging because the evidence is conflicting on whether surgery, radiotherapy, or a combination produces the best outcomes. (37) This underscores the importance of multidisciplinary discussions with surgeons, oncologists, and radiation oncologists for local treatment of pelvic Ewing sarcoma.Definitive radiotherapy can be used in select patients, including those in whom surgery would carry high morbidity. (35)(36) Definitive radiotherapy doses range from 55 to 60 Gy. In the postoperative setting, radiotherapy is used when there are positive margins after surgery or when there is evidence of tumor spill or rupture. In Europe, postoperative radiotherapy is used in patients with poor histologic response (<90% necrosis), although this is not routinely used in North America. (34)For metastatic disease to the lungs, whole lung radiotherapy is typically recommended during upfront (first-line) therapy. Due to the poor outcomes for patients with metastatic disease, clinical trials are the recommended treatment options. Unfortunately, to date, no trials have significantly improved survival for patients with metastatic disease.Up to 25% of those with initially localized disease will relapse. This number is even higher for those with metastatic disease at diagnosis. (38)(39) Of those who develop recurrent disease, 75% will show evidence of relapse within 2 years of the original diagnosis. Those who have isolated local relapse have a better prognosis. The approach for relapsed disease typically includes local control approaches (surgery or radiotherapy) with systemic therapy. Strategies that have shown efficacy include irinotecan/temodar, topotecan/cyclophosphamide, ifosfamide, tyrosine kinase inhibitors, or clinical trials. (40)(41)The most significant prognostic factor in Ewing sarcoma is the presence of metastatic disease. Patients with metastatic disease isolated to the lung fare better than those with metastatic disease elsewhere (Fig 5). (35)(42) Other factors that lead to a poorer prognosis include older age at diagnosis, tumor volume greater than 200 mL or largest diameter greater than 8 cm, multiple areas of bony involvement, bone marrow involvement, and tumors located in the axial skeleton. (42)Treatment-related late effects include secondary malignancies, cardiac and pulmonary conditions, and chronic conditions related to surgery. Secondary malignancy rates approach a cumulative incidence of 14% at 35 years from diagnosis. Secondary breast cancer and osteosarcoma in the radiation field are the most common solid tumors. (43) Exposure to alkylating agents (cyclophosphamide and ifosfamide) and etoposide increase the risk of secondary leukemia at a rate of 1% to 3%.Cardiac conditions are related to anthracycline (doxorubicin) exposures, particularly in cumulative doses higher than 450 mg/m2. The pathognomonic anthracycline-related cardiac condition is cardiomyopathy leading to progressive cardiac failure. Dexrazoxane is a cytoprotective drug used in conjunction with doxorubicin to try to mitigate cardiomyopathy risks. Lung irradiation is the prime causative agent in chronic lung conditions. Neurologic conditions such as peripheral and sometimes cranial neuropathies are common after surgery and exposure to vincristine. Cisplatin has been associated with ototoxicity in the form of hearing loss and/or tinnitus in survivors. Lifelong follow-up is needed to screen for and manage these conditions.Use of cryotherapy during chemotherapy infusions to reduce mucositis.Implementation of extended high-frequency testing and the ototoxicity grading scale to current ototoxic monitoring protocols in children with solid tumors.Education efforts regarding different local control options to help patients make the best informed decisions.You can find the teaching slides that accompany this article on the Views>Supplementary Data option in the online article toolbar.We thank our pathologist, Amy Treece, MD, Department of Pathology, University of Colorado School of Medicine, Aurora, CO, for her contribution to this article.

What's New in Musculoskeletal Tumor Surgery.

The outcome of limb salvage treatment for femoral osteosarcoma with pathological fractures in children is currently unknown. The aim of the present study was to present two cases of patients who received limb salvage surgery with preservation of the epiphysis at the Department of Orthopedics of The General Hospital of Jinan Military Commanding Region (Shandong, China). Between January, 2007 and January, 2013, two pediatric patients were admitted to our hospital with pathological fractures. One of the patients was a girl, aged 11 years, with confirmed osteosarcoma of the right distal femur; the other patient was a boy, aged 9 years, with osteosarcoma of the left distal femur. After receiving two cycles of neoadjuvant chemotherapy following tumor biopsy, the patients received limb salvage surgery with epiphyseal preservation, with wide resection of the tumor and biological reconstruction by allogeneic bone and fibular autograft, followed by 10 cycles of adjuvant chemotherapy. With a mean follow-up of 64 months, there were no postoperative complications, local recurrence or metastasis. The limb function recovered well, although limb shortening was observed. The female patient underwent a second fixation and limb lengthening after epiphyseal closure. Therefore, with effective neoadjuvant chemotherapy, limb salvage surgery with epiphyseal preservation is not contraindicated for pediatric patients with pathological fractures from femoral osteosarcoma. Biological reconstruction by allogeneic bone and vascularized fibular autograft following wide tumor resection is a viable option for such patients, with a good postoperative functional outcome.

The clinical finding of asymmetric skinfolds (ASF) in infants is used to indicate the possibility of developmental dysplasia of the hip (DDH). The association of ASF and a diagnosis of DDH remains unknown. To determine the association of ASF in the gluteal and femoral regions with a diagnosis of DDH. The correlation of ASF and other physical examination findings with DDH was compared retrospectively. The medical records of infants who underwent DDH screening in the clinic were analyzed. The physical examination findings were reviewed and categorized as ASF, clunk of the hip, limb-length discrepancy, hip abduction limitation, combined conditions of musculoskeletal disorders, and regular screening for DDH. The hip conditions were classified by Graf's ultrasound method. Type IIb and higher classifications were defined as DDH. The diagnosed rate and severity of DDH based on physical examination findings were calculated and compared. Clinical data of 3266 infants aged up to 6 months were reviewed, and 194 infants were diagnosed with DDH by ultrasound examination. ASF was the most common indication for DDH screening (64.5%; 2107/3266). However, this was poorly correlated with a diagnosis of DDH (4.79%; P < .0001). No difference was found between the Graf classification severity and various indications ( P = .079). Clinicians should recognize that, although ASF is the most common reason for DDH screening in infants, ASF does not correlate with a diagnosis of DDH. Additional research should examine the relationship between DDH and ASF in other populations.

The purpose of this study was to investigate the three-dimensional morphological features of the proximal femur of developmental dysplasia of the hip (DDH). From January 2012 to December 2014, 38 patients (47 hips) of DDH were admitted and 30 normal hips were selected as controls. All hips from both groups were examined by CT scan. CT data were imported into Mimics 17.0. Three-dimensional models of the proximal femur were then reconstructed, and the following parameters were measured: neck-shaft angle, neck length, offset, height of the centre of femoral head, level of isthmus, height of the tip of greater trochanter, the medullary canal diameter of isthmus(Di), the medullary canal diameter 10mm above the apex of the lesser trochanter(DT + 10), the medullary canal diameter 20mm below the apex of the lesser trochanter(DT-20), and then DT + 10/Di, DT-20/Di and DT + 10/DT-20 were calculated. There was no significant difference in neck-shaft angle between Crowe I, Crowe II-III DDH and the control group, while the neck-shaft angle was much smaller in Crowe IV DDH. The neck length of Crowe IV DDH was also much smaller than those of Crowe I and Crowe II-III DDH. Height of the tip greater trochanter in Crowe IV was greater than that in Crowe I, Crowe II-III DDH and the control group. The centre of femoral head in Crowe IV DDH was lower than those in Crowe I, Crowe II-III DDH and the control group. The level of isthmus in Crowe IV was much higher than those in Crowe I, Crowe II-III DDH and the control group. DT + 10, DT-20, DT + 10/Di and DT-20/Di were much smaller in Crowe IV DDH than those in Crowe I, Crowe II-III and the control group. Neck-shaft angle in the DDH groups was not larger than that in the control group. Comparing to Crowe I, Crowe II-III DDH and the control group, Crowe IV DDH had a dramatic change in the intramedullary and extramedullary parameters, especially the dramatic narrowing of medullary canal around the level of the lesser trochanter. The on-shelf modular prosthesis may not be an ideal choice for the Chinese patients with Crowe IV hips.

Self-Reported Functional Outcomes and Quality of Life Assessments in Long-Term Survivors of Ewing Sarcoma