Version May 2024
INTRODUCTION — Ewing sarcoma (ES) is a rare malignancy that most often presents as an undifferentiated primary bone tumor; less commonly, it arises in soft tissue (extraosseous Ewing sarcoma).
The clinical presentation, diagnosis, and staging of ES is presented here. The epidemiology, pathology, molecular genetics, and treatment of ES, diagnosis and biopsy techniques for bone tumors, and CNS embryonal tumors are discussed separately.
●(See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma".)
●(See "Treatment of Ewing sarcoma" and "Radiation therapy for Ewing sarcoma family of tumors".)
●(See "Bone tumors: Diagnosis and biopsy techniques".)
●(See "Uncommon brain tumors", section on 'CNS embryonal tumor NEC/NOS'.)
CLINICAL PRESENTATION
Primary sites — Ewing sarcoma (ES) most often arises in the long bones of the extremities (predominantly the femur, tibia, fibula, and humerus) and the flat bones of the pelvis (such as the ilium). The spine, hands, feet, and skull are affected less often [1-3]. ES can also occur within the spinal canal and not involve bone. In a compilation of data from 975 patients from the European Intergroup Cooperative Ewing Sarcoma Studies (EI-CESS) trials, the distribution of primary sites was as follows (due to rounding of numbers, the percentages do not add up to 100) [2]:
●Axial skeleton – 54 percent (pelvis 25 percent, ribs 12 percent, spine 8 percent, scapula 3.8 percent, skull 3.8 percent, and clavicle 1.2 percent)
●Appendicular skeleton – 42 percent (femur 16.4 percent, fibula 6.7 percent, tibia 7.6 percent, humerus 4.8 percent, foot 2.4 percent, radius 1.9 percent, and hand 1.2 percent)
●Other bones – 0.7 percent
A minority of ES arise in soft tissue. Compared with ES of bone, patients with extraosseous ES (EES) are more frequently older, more likely to be female, and arise more often within the axial, rather than the appendicular, skeleton [1,4-6].
Signs and symptoms — Patients with ES typically present with localized pain or swelling of a few weeks' or months' duration [7-9]. Trauma, often minor, may be the initiating event that calls attention to the lytic lesion and may affect strength. The pain may be mild at first but intensifies fairly rapidly; it may be aggravated by exercise and is often worse at night. A distinct soft tissue mass can sometimes be appreciated. When present, it is moderately to markedly tender to palpation [10,11]. Sometimes this tumor is mistaken for an infection. Swelling of the affected limb with erythema over the mass is not uncommon.
Patients with juxta-articular lesions may present with loss of joint motion, while lesions involving the ribs can be associated with direct pleural extension and large extraosseous masses [12]. When the spine or sacrum is involved, nerve root irritation or compression can result in back pain, radiculopathy, or symptoms of spinal cord compression (eg, weakness or loss of bowel and/or bladder control). (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression".)
Constitutional symptoms or signs, such as fever, fatigue, weight loss, or anemia, are present in approximately 10 to 20 percent of patients at presentation [7]. Fever is related to cytokines produced by the tumor cells and, along with other systemic symptoms, is associated with advanced disease. As a result, infection (osteomyelitis) is included in the differential diagnosis of patients with ES. (See 'Differential diagnosis' below.)
Approximately 80 percent of patients present with clinically localized disease, although as noted previously, subclinical metastatic disease is presumed to be present in nearly all. Overt metastases may become evident within weeks to months in the absence of effective therapy. The significance of this lies in the frequent delay between the onset of symptoms and diagnosis, which in one report averaged over nine months [9,13].
Patients with primary pelvic tumors are significantly more likely to present with metastatic disease compared with other sites (25 versus 16 percent) [2]. These pelvic tumors may grow to larger sizes before they are discovered. Other factors that may be associated with clinically evident metastatic disease at presentation include high level of lactic dehydrogenase (LDH), the presence of fever, an interval between onset of symptoms and diagnosis less than three months, and age older than 12 years [14]. In one series, the rate of metastatic disease at presentation in the subset of patients with none of these risk factors was only 4 percent, with two factors it was 23 percent, while it was almost double (44 percent) if three or four factors were present. Patients with metastatic disease at diagnosis generally do worse than those that develop metastatic disease later.
Sites of metastatic disease at diagnosis are similar to those seen with recurrent disease; lung and bone/bone marrow metastases predominate in roughly equal proportions. The spine is the most frequently involved bone [15,16]. Lung metastases represent the first site of distant spread in 70 to 80 percent of cases and are the leading cause of death for patients with ES. Lymph node, liver, and brain involvement are distinctly uncommon [8,17].
STAGING EVALUATION — The goals of the initial evaluation are to establish the diagnosis, evaluate local disease extent, and determine the presence and sites of metastatic spread. Clinical staging includes all of the data obtained prior to definitive therapy, including the results of imaging, laboratory studies, physical examination, and tissue biopsy.
Radiographic studies — The diagnostic work-up is usually initiated with a plain radiograph of the affected area. Ewing sarcoma (ES) involving bone typically presents as a poorly marginated destructive lesion, most often associated with a soft tissue mass. The tumors tend to be large and, in long bones, are metaphyseal, diaphyseal, or metadiaphyseal in location within the long bone (image 1 and figure 1).
The radiographic appearance has been described as "permeative" or "moth-eaten," indicative of a series of finely destructive lesions that become confluent over time. The cortex at the site of the lesion is often expanded and the periosteum displaced by the underlying tumor, resulting in the clinical sign of Codman's triangle. The characteristic periosteal reaction produces layers of reactive bone, deposited in an "onion peel" appearance (image 2). The soft tissue component of the tumor rarely shows any calcification or ossification. Sclerosis, if present, represents a secondary bone reaction rather than the primary bone formation that characterizes osteosarcoma. A pathologic fracture is present at diagnosis in 10 to 15 percent of cases [7,9].
Compared with plain radiographs, a computed tomography (CT) scan of the primary site better delineates the extent of cortical destruction and soft tissue disease (image 3). A multi-institutional study of 387 patients that included both children and adults concluded that CT and magnetic resonance imaging (MRI) were equally accurate for local staging of bone and soft tissue tumors [18]. However, MRI is preferred in most cases because of its superior definition of tumor size, local intraosseous and extraosseous extent, and the relationship of the tumor to fascial planes, vessels, nerves, and organs (image 4). Imaging of the entire involved bone is necessary to exclude the presence of skip lesions (ie, medullary disease within the same bone but not in direct contiguity with the primary lesion).
Differential diagnosis — For ES presenting as primary bone tumors, the differential diagnosis includes both benign and malignant conditions. The most common nonmalignant possibility is acute or subacute osteomyelitis, which may present similarly (especially the presence of fever and an elevated sedimentation rate), and be associated with intense radiotracer uptake on bone scan and a soft tissue mass on other imaging studies [19]. Aspiration of a tumor may yield purulent-appearing material; however, it will be sterile on culture. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)
"Benign" bone tumors that can present as lytic lesions include eosinophilic granuloma and giant cell tumor of bone. Destructive eosinophilic granulomas usually occur at a younger age and are not associated with a sizable soft tissue mass.
Malignant tumors that should be considered in the differential include other common solid tumors of childhood, including osteosarcoma, primary lymphoma of bone, undifferentiated high-grade pleomorphic sarcoma of bone (previously termed malignant fibrous histiocytoma of bone or spindle cell sarcoma), acute leukemia, and metastasis from a non-bone tumor, particularly neuroblastoma (table 1). A primarily lytic osteosarcoma may be difficult to distinguish from ES on imaging studies. Most often, however, osteosarcoma is located in the metaphysis and usually has a rim of bone formation, which is very uncommon in ES. Primary lymphoma of bone occurs in an older age group and is generally associated with less bone destruction than ES. Chondrosarcoma is uncommon in this age group; furthermore, the soft tissue mass usually contains calcifications. (See "Bone tumors: Diagnosis and biopsy techniques" and "Chondrosarcoma".)
Extraosseous ES (EES) and soft tissue peripheral primitive neuroectodermal tumors (PNETs) must be distinguished from a variety of benign and malignant soft tissue tumors. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Histopathology'.)
Metastatic work-up — Guidelines for imaging studies in patients with ES are available from NCCN and the Children's Oncology Group (COG) Bone Tumor Committee (table 2) [20]:
●The metastatic work-up should include a CT scan of the chest to evaluate the thorax for metastatic disease. Criteria to guide the evaluation of suspected pulmonary metastases are available from the COG that were adopted from the European Ewing Tumor Working Group Initiative of National Groups Ewing Tumour Studies 1999 (EURO-E.W.I.N.G 99) (table 3) [21,22].
●Radionuclide bone scan is recommended to evaluate the entire skeleton for the presence of multiple lesions.
●PET or PET/CT is increasingly used for the initial staging of patients with ES. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend a PET scan and/or bone scan for initial workup [23], and a baseline PET is recommended at presentation by the COG if the primary bone tumor is negative on bone scintigraphy (table 2) [20].
PET imaging may also have greater utility for monitoring the response to chemotherapy and/or radiation therapy (particularly neoadjuvant chemotherapy [24,25]) and in the postoperative evaluation for possible recurrence. (See "Treatment of Ewing sarcoma", section on 'Recurrent disease'.)
Studies have evaluated the utility of positron emission tomography (PET) or integrated PET-CT for initial staging [26-31]. Some observational studies note that PET imaging has better sensitivity for bone scan or other conventional imaging modalities for detection of bone metastases [29,31,32]. However, one potential problem is that integrated PET-CT scanning usually only scans from the neck through the femurs, so the bones are not all visualized as they would be with a bone scan. PET has not yet replaced radionuclide bone scan for initial staging at many institutions. In contrast to the situation with bone metastases, the sensitivity of PET for detection of lung metastases appears to be lower than that of thoracic CT [29,30], although integrated PET/CT is superior to CT alone in this regard [33]. A retrospective study addressing the utility of radionuclide bone scan in patients who had undergone a PET/CT for initial staging concluded that when the primary tumor was lytic, bone scan did not add to staging performed by fluorodeoxyglucose (FDG) PET/CT and that it could be omitted in this setting [34]. In contrast, when the ES is sclerotic in nature, radionuclide bone can detect osseous metastases that were not detected by FDG PET/CT.
Staging system — No commonly used staging systems exist for ES as they do for other solid tumors. Although there are tumor, node, and metastasis (TNM) staging systems for primary tumors of both bone (table 4) [35,36] and soft tissue (table 5 and table 6 and table 7) [37-39] available from the Musculoskeletal Tumor Society and the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC), they are not in widespread use for ES. ES tumors are usually considered "localized" or "metastatic."
Laboratory studies — Initial laboratory studies should include a complete blood count, serum chemistries, and lactate dehydrogenase (LDH), which is a known prognostic factor in patients with ES [2,40,41] (see 'Prognostic factors' below). For cases in which neuroblastoma is in the differential diagnosis, urine catecholamine levels may be useful since they are elevated in neuroblastoma but normal in ES. (See "Epidemiology, pathogenesis, and pathology of neuroblastoma".)
Biopsy
Tumor biopsy — The considerations for appropriate biopsy of a soft tissue or bone mass resemble those for other soft tissue and bone sarcomas. (See "Bone tumors: Diagnosis and biopsy techniques".)
The surgeon should be consulted before any biopsy is carried out, and the procedure should be carefully planned to obtain adequate diagnostic tissue without compromising a later operation, particularly the opportunity for limb salvage.
Adequate amounts of viable tissue are necessary in order to provide sufficient diagnostic material. The extensive pathologic evaluation that is often required to ascertain the correct diagnosis within the group of "small round blue cell tumors" means that tissue is usually needed for special studies, and these samples require special handling. This topic is discussed in detail elsewhere. (See "Bone tumors: Diagnosis and biopsy techniques", section on 'Specimen handling'.)
The diagnosis is most often established by CT- or ultrasound- guided core-needle biopsy (image 3). If only necrotic material is obtained on core biopsy, an open biopsy may be required. A PET-CT scan prior to biopsy may be helpful in identifying the most aggressive and viable portions of the tumors. In either case, specimens should be obtained for microbiology to rule out osteomyelitis (see 'Differential diagnosis' above).
ES and infection are usually distinguished by frozen section and rarely occur together. Fine needle aspiration biopsy is not usually adequate as the only diagnostic material, and should only be used to sample metastatic sites or areas suspicious for recurrence when the histologic diagnosis is known. These issues are discussed in detail separately. (See "Bone tumors: Diagnosis and biopsy techniques", section on 'Biopsy techniques'.)
Bone marrow aspirate and biopsy — Because of the predilection of ES for spread to bone marrow [42], some clinicians advocate bone marrow biopsy (at least unilateral) in all patients to exclude widespread metastatic disease. Neither MRI nor bone scan are entirely sufficient to evaluate the possibility of bone marrow metastases. Although MRI is sensitive to changes in the marrow, they are not specific. Any decrease in the marrow fat content may alter the signal, creating difficulty in differentiating tumor from active hematopoiesis.
Histopathology — The diagnosis of ES is confirmed using histopathologic evaluation and molecular assessment of malignant tissue obtained via tumor biopsy. The histopathology and molecular genetics of Ewing sarcoma is discussed separately. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma".)
PROGNOSTIC FACTORS — Advances in multidisciplinary management of Ewing sarcoma (ES) have improved treatment techniques and survival outcomes for patients presenting with nonmetastatic disease [43-47]. With contemporary multidisciplinary treatment, long-term survival can be achieved in 70 to 80 percent. In data derived from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, five-year survival rates for patients with ES rose in all age groups between 1975 and 2000 [43].
Several clinical and biologic characteristics can assist in defining prognosis and directing the intensity of therapy [48]. These include the presence or absence of metastases, the primary tumor location and size, age, response to therapy, and the presence of certain chromosomal translocations.
Disease extent — The key prognostic factor in Ewing sarcoma is the presence or absence of metastases. Approximate five-year survival rates for patients with localized disease are 70 percent, while they average 33 percent for those who have overt metastases at diagnosis. (See "Treatment of Ewing sarcoma", section on 'Treatment for localized disease' and "Treatment of Ewing sarcoma", section on 'Treatment for metastatic disease'.)
The location of distant disease also impacts outcomes. In the European Intergroup experience, the five-year relapse-free survival rates for patients with localized and metastatic disease at presentation were 55 and 21 percent, respectively [2]. Patients with bone and lung metastases fared significantly worse than those with bone metastases alone, who in turn, fared worse than those with isolated lung metastases. Approximately 30 percent of patients with metastases limited to the lungs will survive five years, as compared with only 10 percent of those with bone or bone marrow involvement.
Patients with limited pulmonary metastases who are candidates for resection may have a reasonable opportunity for cure. (See "Treatment of Ewing sarcoma", section on 'Pulmonary metastases'.)
Tumor site and size — For patients presenting with localized disease, those with axial primary tumors (ie, pelvis, rib, spine, scapula, skull, clavicle, sternum) have a worse treatment outcome than those with extremity lesions [2,49]. In one series, the five-year relapse-free survival rates were 40 versus 61 percent [2]. In addition, patients with small primary tumors (<100 mL) fare better than those with larger tumors [2,50]. Fever, anemia, and elevated serum lactate dehydrogenase (LDH) all correlate with a greater volume of disease and a poorer prognosis [2,14,40,41].
The poorer prognosis of large primary tumors, and those involving the pelvis and spine, is at least partly attributable to the difficulty in achieving wide negative resection margins and to higher rates of local failure after radiation therapy for large lesions. (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management", section on 'Non-extremity lesions' and "Radiation therapy for Ewing sarcoma family of tumors".)
Extraosseous, as compared with osseous, origin does not have an adverse influence on survival [5,51,52]. In fact, tumors that arise in skin or subcutaneous sites have a generally favorable prognosis [52-54].
Response to therapy — Patients with apparently localized disease have only a 10 to 20 percent likelihood of cure if treated with surgery or radiation therapy alone; this is improved dramatically when chemotherapy is added to treatment. Systemic therapy for ES is evolving [55] and discussed in detail separately. (See "Treatment of Ewing sarcoma".).
Both the completeness of surgical resection and the response to induction therapy are important prognostic factors. Patients who are left with significant amounts of viable tumor in the resected specimen following neoadjuvant chemotherapy do worse than those with minimal or no residual tumor [2,56-60]. These topics are discussed in detail separately. (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management" and "Radiation therapy for Ewing sarcoma family of tumors", section on 'Adjuvant radiation therapy'.)
Histology — In most, but not all studies, the presence of neural differentiation (eg, as in tumors historically known as peripheral primitive neuroectodermal tumors) does not have an adverse influence on survival [4,61-63].
Age — Older age has been linked to a poor prognosis in some reports [64-66] but not others [67-69]. As an example, in one report, the five-year relapse-free survival was significantly better for children younger than 10 compared with older children (86 versus 55 percent, respectively) [65]. Similarly, data from three consecutive studies of the Children's Oncology Group (COG) showed that age >18 years, pelvic site, size >8 cm, and chemotherapy without ifosfamide/etoposide were all associated with significantly worse outcomes [70].
The situation for adults is less clear. Although many series have reported a less favorable outcome in adults (particularly older adults [64]) as compared with children [71], a greater tumor bulk in adults or use of lower doses of alkylating agents [72] may explain some of these observations. Others have noted that adults fare as well as children, particularly when full dose chemotherapy protocols are utilized [69,73-75].
Molecular findings — Ewing sarcoma (ES) is characterized by distinct nonrandom chromosomal translocations, which all involve the Ewing sarcoma gene (EWS) on chromosome 22. These translocations result in the fusion of distinct genes on different chromosomes, and these fused genes then encode hybrid proteins, which are thought to be involved in tumorigenesis. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma", section on 'Molecular genetics'.)
At least 18 different structural possibilities for gene fusions have been reported in these tumors. There are two sources of variability: the EWS fusion partner (eg, FLI1, ERG, ETV1, E1A, or FEV) and the breakpoint locations within the genes. This molecular heterogeneity may have some influence on the prognosis of ES [76-79]. As an example, a better outcome has been reported for patients with localized tumors expressing the most common chimeric transcript (the so-called type I transcript in which EWS exon 7 is fused to FLI1 exon 6, which is present in approximately 60 percent of cases) compared with other fusion types [77,78]. However, more recent treatment protocols appear to have eliminated prognostic differences based upon fusion type [80].
Studies evaluating the prognostic significance of other cytogenetic and molecular alterations in ES are limited. However, deletion of the short arm of chromosome 1p, homozygous deletions of CDKN2A and p16/p14ARF, and p53 mutations have all been associated with poor response to chemotherapy and a worse prognosis [76,81,82]. Another study identified high levels of SOX2 (sex determining region Y box 2) expression in about 16 to 20 percent of patients, which was found to be an independent prognostic biomarker for poor outcomes in Ewing sarcoma patients [83]. Despite the supposed homogeneity of EWS related translocations, increasing molecular heterogeneity is now appreciated among the Ewing sarcoma family of tumors. Further data on newer prognostic and predictive molecular markers are needed to help shape future treatment strategies for these patients.
Use of prognostic factors for treatment stratification — As noted previously, there is no widely accepted formal staging system for ES. One of the most important uses of a staging system is to stratify patients for treatment purposes, based upon expected outcome. Because of the very powerful prognostic power of the presence of metastatic disease, most studies in ES have stratified patients by the presence or absence of metastatic disease. Although the primary site (ie, extremity versus pelvis or spine) also has prognostic significance, only a few studies have used site as the basis for determining the aggressiveness of therapy. (See "Treatment of Ewing sarcoma".)
Some investigators consider patients with localized disease, but who show features of poor prognosis (eg, pelvic primary site, older age), as "advanced" or "high-risk," grouping them for the purposes of treatment with others who have overt metastatic disease. The selection of treatment based upon individual prognostic factors is referred to as risk-adapted therapy [56]. Using several indicators of prognosis in addition to the presence of metastatic disease, a prognostic model was developed using data from the Surveillance, Epidemiology, and End Results (SEER) database and applied to 1680 patients who were enrolled in COG trials for Ewing sarcoma [84]. These investigators were able to identify five distinct prognostic groups based upon age, pelvic location, ethnicity, and the presence of metastatic disease. (See "Treatment of Ewing sarcoma", section on 'Treatment for metastatic disease'.)
The data indicating prognostic differences among patients with varying fusion genes raise the possibility that heterogeneity in the structure of chimeric transcripts may also be used to define clinically distinct risk groups. As an example, a direct comparison between treatment response and EWS fusion type may reveal a role of certain chimeras in therapy resistance. However, prospective clinical studies are just beginning to be performed to address this hypothesis. Inclusion of EWS fusion type determination into future clinical trials is appropriate.
Other prognostic factors — One report identified abnormal body mass index (BMI) as predictive of inferior tumor necrosis after chemotherapy and a worse overall survival [85].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Ewing sarcoma (The Basics)" and "Patient education: Bone cancer (The Basics)")
SUMMARY
●Primary disease sites – Ewing sarcoma (ES) most often arises in the long bones of the extremities (predominantly the femur, tibia, fibula, and humerus) and the flat bones of the pelvis (such as the ilium). The spine, hands, and feet are affected less often. (See 'Primary sites' above.)
●Clinical presentation – Patients with ES typically present with localized pain or swelling of a few weeks' or months' duration. Trauma, often minor, may be the initiating event that calls attention to the lytic lesion and may affect strength. Constitutional symptoms or signs, such as fever, fatigue, weight loss, or anemia, are present in approximately 10 to 20 percent of patients at presentation. (See 'Signs and symptoms' above.)
●Diagnostic evaluation – The goals of the initial evaluation are to establish the diagnosis, evaluate local disease extent, and determine the presence and sites of metastatic spread. (See 'Staging evaluation' above.)
•Evaluation of the primary tumor – The diagnostic work-up is usually initiated with a plain radiograph of the affected area. ES involving bone typically presents as a poorly marginated destructive lesion with a permeative or "moth-eaten" appearance, most often associated with a soft tissue mass (image 1). While computed tomography (CT) scan better delineates the extent of cortical destruction and soft tissue disease, definition of tumor size, local intraosseous and extraosseous extent, and the relationship of the tumor to fascial planes, vessels, nerves, and organs is best achieved by magnetic resonance imaging (MRI) (image 4). (See 'Radiographic studies' above.)
•Evaluation for metastatic disease – The metastatic work-up includes a CT scan of the chest to evaluate the thorax for metastatic disease (table 3) and a radionuclide bone scan to evaluate the entire skeleton for the presence of multiple lesions. Positron emission tomography (PET) or PET/CT is increasingly used for the initial staging and response assessment of ES and may be able to replace radionuclide bone scan for detection of bone metastases in selected patients with lytic disease. (See 'Metastatic work-up' above.)
•Bone marrow biopsy – Some clinicians advocate bone marrow biopsy (at least unilateral) in all patients to exclude widespread metastatic disease. (See 'Bone marrow aspirate and biopsy' above.)
•Biopsy of the primary tumor – A biopsy should be carefully planned to obtain adequate diagnostic tissue without compromising a later operation, particularly the opportunity for limb salvage. (See 'Tumor biopsy' above.)
●Prognostic factors – Several clinical and biologic characteristics can assist in defining prognosis and directing the intensity of therapy. These include the presence or absence of metastases, the primary tumor location and size, response to therapy, and the presence of certain chromosomal translocations. (See 'Prognostic factors' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Henry J Mankin, MD, and Thomas F DeLaney, MD, who contributed to earlier versions of this topic review.
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