Osteosarcoma/Ewing Sarcoma

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 (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.