Crystal L. Mackall and Jeffrey A. Toretsky
Ewing sarcoma (ES) is the second most common bone tumor in children and adolescents. It was named for James Ewing, a pathologist who first described the tumor in 1921, emphasizing its distinction from osteosarcoma based upon enhanced radiosensitivity and a propensity to involve flat bones of the axial skeleton.1 In the early 1980s, both Ewing sarcoma and peripheral primitive neuroectodermal tumor (PNET) were found to contain identical t(11;22)(q24;q12) translocations.2,3 Based upon the shared translocation, and similar clinical behaviors, Ewing Sarcoma Family of Tumors (ESFT) is now considered one disease entity that includes classical ES, atypical ES, peripheral primitive neuroectodermal tumor, neuroepithelioma, and Askin tumor (an ESFT of the chest wall). It should be emphasized that peripheral PNETs are entirely different from PNETs arising in the central nervous system which do not bear the t(11;22) translocation and are not considered part of the ESFT category.
EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND GENETICS
ESFTs occur in approximately 2 to 3 per million/year in persons less than 20 years4 with a peak in the second decade of life, although they have been reported in infants and occur with a substantial incidence in adults, especially prior to age 40. For unknown reasons, ESFT are extremely rare among individuals of African and Asian heritage.
The cell of origin that gives rise to ESFT is also unknown, with primitive neural cells implicated historically, and recent studies suggesting that mesenchymal stem cells may give rise to the disease.6,7 The classic translocation t(11;22)(q24;q12), or another related translocation, occurs in greater than 95% of ESFT.8 ESFT-associated translocations join the Ewing sarcoma (EWS) gene located on chromosome 22 to an ets-family gene, most commonly FLI1(Friend Leukemia Insertion), located on chromosome 11.9 The 68-kDa protein produced by the EWS-FLI1 fusion transcript functions as an aberrant transcription factor and plays a critical role in initiating and sustaining ESFT. Expression of this molecule can transform mouse fibroblasts,10 and reduction of EWS-FLI1 expression induces death of ESFT cell lines.11-13Such studies have established the EWS-ets translocation as a compelling therapeutic target. However, clinically applicable therapies to successfully prevent expression of EWS-ets or interfere with downstream oncogenic events induced by the fusion transcript have proven elusive thus far.14
CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
ESFTs most often arise in bone and have been reported in virtually every bone, but can also occur in soft tissues without bony involvement. Unlike osteosarcoma, which usually arises in the metaphysis of long bones, ESFT arises more frequently in flat bones (eg, pelvis, vertebrae, ribs, skull), and when it arises in long bones, it commonly involves the midshaft or diaphysis. ESFT patients usually present with pain or a palpable mass, and ESFT should be included in the differential diagnosis of any bone or soft tissue mass in patients from infancy through early adulthood. Unfortunately, many patients ultimately diagnosed with ESFT often describe a history of chronic pain for many months before the correct diagnosis is made. This is especially true for pelvic ESFTs when a palpable mass is not present and the presenting symptoms of neuropathic, radicular pain or vague back discomfort are often attributed to sports-related or other trivial injuries in adolescents and young adults. It is important, therefore, that children and young adults who experience persistent or recurring pelvic, back, or radicular pain undergo appropriate radiographic evaluation to rule out a malignancy involving the spine, pelvis, or extremity. Radionuclide bone scan may be particularly helpful in identifying a neoplastic cause of chronic pelvic, back, or radicular pain. Occasionally, ESFTs present with vertebral involvement, and in such cases, an associated extradural mass can compress the spinal cord and induce paraparesis or paraplegia, with sphincter dysfunction. Tumors adjacent to the spinal canal require immediate magnetic resonance imaging (MRI) scanning because intervention is sometimes needed to prevent neurologic deterioration, which can occur rapidly if spinal cord compression is present.
Classic radiologic findings of ESFT include permeative bone destruction with a moth-eaten appearance, elevation of periosteum with periosteal reaction (Codman triangle) or a lamellar (onion skin) lesion on plain radiographs, which results from cortical destruction followed by reparative cortical bone laid down by reactive osteoblasts (Fig. 454-1). Computerized tomography (CT) scans provide optimal imaging to assess the degree of cortical bone involvement, whereas MRI accurately establishes the extent of soft tissue and marrow involvement (Fig. 454-1). The differential diagnosis of destructive bony lesions should include osteogenic sarcoma, other sarcomas arising in bone (malignant fibrous histiocytoma, chondrosarcoma, fibrosarcoma), giant cell tumors, benign neoplasms, eosinophilic granuloma, lymphoma, or metastases from another primary neoplasm. For patients with a soft tissue mass without bony involvement, the differential diagnosis includes rhabdomyosarcoma, neuroblastoma, other soft-tissue sarcomas, lymphoma, or benign neoplasms. Systemic symptoms of fever and weight loss can occur as part of the presenting symptom complex in patients presenting with ESFT, especially with large primary tumors or metastatic disease.
FIGURE 454-1. Presenting scans from a 16-year-old patient with pain and swelling in the lower leg. Plain radiographs show soft tissue swelling, an “onion skin” periosteal reaction (panel A), and cortical irregularly due to bone destruction (panel B). Magnetic resonance imaging (MRI) of the lower leg (panel C) reveals a large soft tissue mass circumferentially surrounding the fibula. Chest computerized tomography (CT) (panel D) reveals multiple pulmonary metastatic nodules. Histological and molecular studies were diagnostic for a Ewing Sarcoma Family Tumor.
DIAGNOSTIC EVALUATION
Children believed to have a malignant bone or soft-tissue tumor should be referred to a pediatric care center with experience and expertise in the treatment of sarcoma. When ESFT is suspected clinically, consultation with a pediatric oncologist and an orthopedic oncologist should occur prior to biopsy. Selection of the biopsy site and approach should be made in consultation with the orthopedic oncologist, because an inappropriate biopsy can adversely impact future options for resection or radiation therapy. The diagnosis can often be made on routine and immunohistochemical stains; however, there is increasing emphasis on molecular identification of the t(11;22) or a related translocation to confirm the diagnosis. Molecular studies often require specific handling procedures; therefore, the pathologist should be alerted prior to the biopsy to ensure appropriate handling and triaging of the tissue.
Histologically, ESFT is a small round blue cell tumor that can span a spectrum from undifferentiated Ewing sarcoma characterized by sheets of small round blue cells to the more differentiated peripheral primitive neuroectodermal tumor wherein pseudorosettes are seen. Immunohistochemical studies show diffuse membranous staining for CD99 (MIC2)15 in greater than 90% of ESFTs. Although robust CD99 expression can reliably rule out neuroblastoma, nonmembranous CD99 staining is not infrequent in other small round blue cell tumors such as rhabdomyosarcoma and lymphoma; therefore, CD99 expression is not specific or diagnostic as a single finding for ESFT. Muscle and lymphoid markers should routinely be performed to rule out rhabdomyosarcoma and lymphoma, respectively, as well as other immunohistochemical studies deemed necessary by the consulting pathologist. Molecular identification of a ESFT-specific trans-location in a tumor with the appropriate histology is pathognomonic for the diagnosis, and this can be accomplished using standard cytogenetics, FISH or RT-PCR (reverse transcription polymer-ase chain reaction).
Once a histologic diagnosis of ESFT is made, it is important to determine the anatomic extent of the primary tumor using CT and MRI scanning, so that effective delivery of therapies for local control can be rendered. Although such therapies are typically delayed for several weeks following initiation of multiagent chemotherapy, adequate local control must be based upon the initial extent of the primary tumor, rather than on the postchemotherapy tumor extent. The diagnostic evaluation at the time of diagnosis should also distinguish patients with clinically localized ESFT from patients with macrometastatic disease, because this has important effects on prognosis and potentially on the systemic therapy administered. Therefore, all patients with ESFT should also undergo CT scanning of the chest to rule out pulmonary metastases (Fig. 454-1), radionuclide bone scan or positron emission tomography (PET) scan to rule out bony metastases, and bilateral bone marrow aspiration and biopsy to rule out marrow metastases.
TREATMENT
Historical studies demonstrated that aggressive local therapy alone, such as amputation of distal lesions, cured less than 10% of patients with Ewing sarcoma due to metastatic relapse. Because of this, all patients diagnosed with ESFT should be assumed to have disseminated micrometastases, even in the absence of radiographic findings. Cure requires both effective local and systemic therapy. Therefore, all patients with ESFT should receive multimodal therapy, which includes dose-intensive, multiagent chemotherapy with radiation or surgery for local control.
Therapy for ESFT has evolved based upon sequential results from a series of cooperative group studies conducted primarily in North America and Europe. Currently, approximately 70% of patients who present without clinical or radiographic evidence for metastatic disease experience 5-year disease-free survival. Vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide are the most active single agents in ESFT and form the backbone of nearly all initial chemotherapy regimens for this disease.16 In general, dose-intensive regimens have shown improved survival compared to less-intensive regimens, with the most recent Children’s Oncology Group study demonstrating improved survival for patients with nonmetastatic ESFT when chemotherapy is administered on an every-2-weeks schedule.17
In addition to dose-intensive, multiagent, cytotoxic therapy, cure of ESFT requires effective treatment of the primary tumor. This can be accomplished with radiation therapy, surgery, or a combination of both. ESFT is highly radioresponsive, and radiotherapy is considered a standard option for definitive local control. Radiotherapy can be used as an alternative to disfiguring surgery such as amputation. Alternatively, surgery can provide good local control rates if adequate surgical margins are obtained. In general, patients who undergo surgery as therapy for the primary tumor have improved survival. However, because patients with smaller or distal tumors typically undergo surgery, whereas patients with larger or axial tumors typically undergo primarily radiation therapy, the differences observed relate, at least in part, to selection bias. Importantly, however, because radiation therapy for ESFT is associated with a risk for second malignancies within the radiation field, surgery is generally preferred for local control when adequate tumor margins can be accomplished and significant morbidity or functional deficits will not result. Postoperative radiotherapy should be administered when surgical margins are close or positive.
COMPLICATIONS
Toxicity is an important consideration in the therapy of ESFT because the regimens used are dose intensive. For this reason, multidisciplinary (infectious disease, surgical, radiation therapy, nutritional, psychological) care is essential to optimize patient management. Severe neutropenia occurs in most patients, despite G-CSF (granulocyte colony stimulating factor) support, and serious complications related to fever, neutropenia, and mucositis commonly occur. In addition, cumulative irreversible cardiotoxicity from doxorubicin is a potential risk for all patients and requires a careful approach to minimize the extent of this late effect. Finally, the incidence of second malignancies occurring in the radiation field of patients with ESFT is approximately 5%, with a relationship observed between higher radiation doses and an increased rate of second malignant neoplasm.
PROGNOSIS
No widely accepted staging system exists for ESFT. However, the most important prognostic factor is the presence or absence of clinically detectable, metastatic lesions. For patients with localized disease, survival approaches 70%. Among patients without metastasis, those with larger primary tumors and tumors involving the axial skeleton fare worse than those with smaller more distal tumors. However, aggressive multiagent chemotherapy regimens have diminished the importance of tumor site and size on outcome.
FUTURE DIRECTIONS
To improve survival and reduce morbidity, novel combinations of established chemotherapeutic agents and molecular targeted therapies are being tested in ESFT. Because EWS-FLI1 is a specific molecular target, future therapies are likely to focus on inactivating EWS-FLI1 function, although no drugs are currently available.14 The insulinlike growth factor type I receptor is critical for transformation and growth of ESFT.22 New inhibitors of IGF-IR signaling have shown promise in early phase trials, and studies are currently underway to establish true response rates. Future studies will seek to incorporate these therapies along with standard, cytotoxic therapy.