The Ewing family of tumors (ET) comprises a heterogeneous group of sarcomas that mainly develop in the skeleton of adolescents and young adults, and encompasses the entities of Ewing sarcoma and primitive neuroectodermal tumor. The clinical presentation of ET is unspecific; most patients present with a visible or palpable mass, tenderness and pain. Diagnosis of ET relies on imaging studies and subsequent histological examination of tissue samples. Potentially curative surgery or radiotherapy, preceded and followed by chemotherapy, constitute the most common approach to therapy. ET patients have a favorable prognosis if the disease is diagnosed during during early stages, but survival rates diminish in case of metastatic disease.
While the majority of ET originate from the diaphysis of the long bones, from the ribs or pelvis, about a third of these tumors develop in extraskeletal sites, most frequently in soft tissues of the trunk and extremities  . The most common presenting symptoms, independent of the anatomical location of the tumor, are the presence of a growing mass, tenderness and pain. Tumors that compress peripheral nerves may also cause paresthesias and dysesthesias such as numbness, tingling, and increased sensitivity to stimuli. Some patients present with fever, a symptom suggestive of acute osteomyelitis, although ET are not per se associated with infection . Fever presumably results from tumor necrosis . Anemia and leukocytosis are often seen in ET patients . Serum concentrations of alkaline phosphatase and lactate dehydrogenase may be increased.
Up to a third of ET patients suffers from metastatic disease at the time of diagnosis. ET are most likely to metastasize to the bone, bone marrow, and lungs. Accordingly, additional symptoms may be present.
Imaging studies and the histological examination of tissue samples are key steps for the diagnosis of ET. In radiographic images, osseous ET present as ill-defined osteolytic lesions that confer a moth-eaten appearance to the diaphysis or diaphyseal-metaphyseal transition, that evoke notable cortical changes and an onion-skin-like, multi-layered periostal reaction . By contrast, magnetic resonance imaging allows for the display of well-defined lesion margins . After the administration of contrast agents, soft tissue enhancement can be observed. Cystic or necrotic changes as well as hemorrhages are common. Of note, definite lesion margins, cortical destruction, contrast-enhancing soft tissue, cystic lesions, and necrotic foci are not characteristic of acute osteomyelitis .
Still, tissue samples have to be obtained to confirm the tentative diagnosis of ET . With regard to the histological features of ET, these tumors are commonly referred to as "small-blue-round-cell tumors": ET usually consist of uniformly small, round tumor cells with large nuclei and scant clear or eosinophilic cytoplasm that often contains PAS-positive glycogen. In case of soft-tissue ET, tumor cells may occasionally be spindle-shaped. Neither nucleoli nor cytoplasmic membranes are prominent structures. ET cells stain blue on hematoxylin and eosin staining. ET frequently express CD99, which preferentially locates to the membrane, vimentin, neuron-specific enolase and other neural markers .
In order to distinguish Ewing sarcoma from primitive neuroectodermal tumors, light and electron microscopic as well as immunohistochemical features have to be considered. In detail, Ewing sarcoma lack evidence of neuroectodermal differentiation while primitive neuroectodermal tumors show a certain degree of neuroectodermal differentiation .
Genetic studies complement the aforementioned diagnostic tools. Chromosome banding analysis, interphase fluorescence in situ hybridization, real-time polymerase chain reaction and Southern blotting may all be carried out to determine chromosomal and gene aberrations that underlie ET development in an individual case. The detection of transcripts of determined fusion genes in peripheral blood or bone marrow is a good marker of minimal residual disease, and the results of genetic analyses may further gain in importance as molecular targeted therapies become available  .
Local disease control with surgery and/or radiation, and chemotherapy are the mainstays of treatment. In case of localized disease, surgery and radiation may be performed with a curative intent, but they are usually part of a palliative therapy in patients with metastatic ET. Radiotherapy is preferred over surgical interventions in case of unresectable tumors or tumors located at anatomical sites that are difficult to access or to resect, e.g., skull, facial bones, and spine. Chemotherapy may precede surgery and radiation, and is typically also applied in an adjuvant manner. Commonly applied regimens comprise vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide for localized disease, and vincristine, doxorubicin, and cyclophosphamide for metastatic disease . Other cytostatic agents are currently tested for their efficacy in ET, e.g. busulfan, irinotecan and temozolomide, but they are not the only active compounds on trial: Tyrosine kinase inhibitors cabozantinib and erlotinib, PARP inhibitors olaprib and niraprib as well as TK216, an inhibitor of protein-protein interactions involving the EWS-FLI-1 fusion protein, shall be mentioned exemplarily for molecular targeted drugs whose efficacy in ET is assessed in on-going clinical trials . Additionally, the administration of biophosphonate zoledronic acid has been proposed as a measure to counteract ET-related osteoclast-induced bone resorption .
When scheduling follow-up examinations, it should be noted that ET may relapse several years after their initial diagnosis. New tumors may arise at the original or distant sites, and patients should be monitored for at least ten years after their therapy has been completed.
According to a large retrospective study comprising more than 1,800 cases of ET, the median survival of ET patients is 8.5 years, with five-year and ten-year survival rates amounting to 55 and 49%, respectively . Elsewhere, five-year and ten-year survival rates of 68 and 63%, respectively, have been indicated . Poor prognostic factors include metastatic disease, axial location of the neoplasm, and large tumor size, but also male gender and old age . With regard to the former, distant metastases are detected in up to 28% of ET patients. Their chance of five-year survival is <40% .
Genetic abnormalities related to the EWS gene on the long arm of chromosome 22 are assumed to trigger ET development . EWS is a protein-coding gene whose product is involved in gene expression, RNA processing and transport, and intracellular signaling cascades. Chromosomal translocations between the EWS gene and genes encoding for transcription factors result in the synthesis of abnormal, chimeric proteins that usually comprise the N-terminal domain of the original EWS protein and the C-terminal DNA-binding domain of the transcription factor.
In 1993, chromosomal translocation t(11;22)(q24;q12) has been related to tumorigenesis of ET . It leads to the formation of the EWS-FLI-1 oncogenic fusion protein and is present in 85% of ET patients . The transduction of the gene encoding for chimeric protein EWS-FLI-1 has been shown to suffice to transform fibroblasts in vitro . By now, additional chromosomal aberrations have been determined as triggers of ET development, e.g., t(21;22)(q22;q12) causing the production of the EWS-ERG fusion protein in 10 to 15% of all cases  , and t(7;22)(p22;q12) inducing the generation of the EWS-ETV1 fusion protein . FLI-1, ERG, ETV1, and more than two dozen other genes encoding for transcription factors constitute the family of ETS transcription factors, which is why the term EWS-ETS fusion protein is sometimes used to refer to the trigger of ET development in a general manner.
At first glance, it seems obvious that the ETS gene implicated in the chromosomal translocation underlying ET formation in an individual patient determines the tumor type. While this rule applies to most pathologies, numerous exceptions are known: The same translocation may indeed be present in different clinicopathological entities. Possibly, distinct tumor types characterized by expression of more or less the same fusion protein differ with regard to the location of the breakpoint in that protein. It may also be speculated that secondary events such as additional mutations eventually pave the way towards a specific tumor type, but neither hypothesis has been confirmed yet .
For the United States, the annual incidence of ET has been estimated to 2.9 per million inhabitants . It is diagnosed at a mean age of 18 years and is the third most common type of sarcoma in minors, but may affect patients of all age groups  . ET patients may be of either gender and ethnicity, but male predominance with a male-to-female ratio of about 1.4 to 1 has been reported .
The pathogenesis of ET remains poorly understood. ET are assumed to derive from primitive mesenchymal cells with a limited potential for neural differentiation . The neoplastic degeneration of these cells is caused by chromosomal translocations as described above; EWS-ETS fusion proteins have been shown to have potent oncogenic activity . They may function as aberrant transcription factors binding to the targets of their ETS component. This way, they may enhance the expression of proto-oncogenes, limit that of tumor suppressor genes like TGF-β receptor type 2, or alter the expression of other genes related to apoptosis, differentiation, angiogenesis, and invasion  . In case of repression of TGF-β receptor type 2, the survival benefit of the tumor cell rests on the avoidance of programmed cell death.
Via as-of-yet unknown mechanisms, ET cells enhance osteoclastogenesis and increase osteoclast activitation . This results in excessive bone resorption, which explains the moth-eaten appearance of ET on radiographic images. Bone resorption facilitates tumor growth and spread to neighboring tissues.
Due to considerable knowledge gaps regarding the causes of chromosomal translocations implicated in ET development, no recommendations can be given to prevent the disease. Familial ET have been reported in isolated cases  , and affected families might eventually benefit from genetic counseling if the underlying chromosomal or genetic aberration were identified. However, data on an inherited predisposition to ET are currently not available.
The entities Ewing sarcoma and primitive neuroectodermal tumor share important molecular and histological features, are treated in a similar manner, and are associated with a similar prognosis , so they are grouped in a single family . While this family is referred to as "Ewing sarcoma and primitive neuroectodermal tumor" by the World Health Organization , the term "Ewing family of tumors" is preferred by others . The latter may, indeed, be understood as a more general term comprising additional entities characterized by non-random chromosomal translocations involving the EWS gene and genes encoding for members of the family of ETS transcription factors. Besides Ewing sarcoma and primitive neuroectodermal tumor, that would be Askin tumor, angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic round cell tumor, extraskeletal myxoid chondrosarcoma, myxoid or round cell liposarcoma, and myoepithelial carcinoma  .
The term Ewing family of tumors (ET) refers to a heterogeneous group of malignant neoplasms that most commonly affect people in their second decade of life. Ewing sarcoma and primitive neuroectodermal tumor shall be named as two examples of neoplasms belonging to the aforementioned family. Most frequently, ET develop in the skeleton, but they may also originate from soft tissues such as muscles, and rarely from internal organs.
ET patients often present with a visible or palpable mass, claim tenderness or pain. There may be additional symptoms that depend on the anatomical location of the tumor and the involvement of neighboring tissues. For instance, ET may compress peripheral nerves and thereby cause numbness or a tingling sensation. In general, clinical symptoms are unspecific and patients are recommended for imaging studies. Radiography, computed tomography, and magnetic resonance imaging may all be employed to determine the site and size of the tumor. There are certain features, e.g., excess bone resorption, cortical and periostal reaction, that support the suspicion of ET. However, the tentative diagnosis of ET requires the histological examination of tissue samples to be obtained by biopsy. Once the diagnosis is confirmed, a treatment plan is set up. Most patients receive neoadjuvant chemotherapy to reduce the size of the tumor before undergoing surgery or being recommended for radiotherapy. Both surgery and radiotherapy may be curative, but in order to avoid a relapse, another round of chemotherapy is usually started after these interventions.
An individual patient's prognosis depends on several factors: tumor size and stage, location of the neoplasm, gender, and age. Large tumors and metastatic disease considerably worsen the outcome, but patients who are diagnosed during early stages of the disease have a favorable prognosis.