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Ewing Family of Tumors

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.


Presentation

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 [1] [2]. 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 [2]. Fever presumably results from tumor necrosis [3]. Anemia and leukocytosis are often seen in ET patients [1]. 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.

Fever
  • 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.[symptoma.com]
  • Slight fever. The tumour is composed of compact, uniform cells with large, round, or ovoid nuclei containing scattered chromatin. Miotic changes are common; small vascular channels may be present.[whonamedit.com]
  • Swelling, this can be seen if it is on a bone near the surface of the body but in other places, like on the pelvis, it may not be visible Less common symptoms, rare and very rare symptoms, fever (pyrexia), tiredness or feeling weary, (lethargy), pain[web.archive.org]
  • Fever may also be present. If a tumor is suspected, tests to locate the primary tumor and any spread (metastasis) often include: Bone scan Chest x-ray CT scan of the chest MRI of the tumor X-ray of the tumor A biopsy of the tumor will be done.[nlm.nih.gov]
Swelling
  • The most common presenting symptoms of ESFT are pain or swelling. Treatment for ESFT consists of a multimodal approach, including chemotherapy, radiation therapy, and surgery.[doi.org]
  • Symptoms may include swelling and pain at the site of the tumor, fever, and a bone fracture. The most common areas where it begins are the legs, pelvis, and chest wall.[en.wikipedia.org]
  • Swelling, this can be seen if it is on a bone near the surface of the body but in other places, like on the pelvis, it may not be visible Less common symptoms, rare and very rare symptoms, fever (pyrexia), tiredness or feeling weary, (lethargy), pain[web.archive.org]
  • The most common is pain and sometimes swelling at the site of the tumor. Children may also break a bone at the site of the tumor after a minor injury. Fever may also be present.[nlm.nih.gov]
Anemia
  • 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.[symptoma.com]
  • Rarely, it can develop in the vagina.Signs and symptoms include: intermittent fevers, anemia, leukocytosis, increased sedimentation rate, and other symptoms of inflammatory systemic illness.According to the Bone Cancer Research Trust (BCRT), the most[en.wikipedia.org]
  • In some cases, affected individuals may also experience fever, lack of energy, weight loss, low levels of circulating red blood cells (anemia), and increased levels of circulating white blood cells (leukocytosis). A palpable mass is often present.[rarediseases.org]
Localized Pain
  • pain, swelling, and sporadic bone pain with variable intensity.[en.wikipedia.org]
  • Signs and symptoms Signs and symptoms of Ewing sarcoma may include the following: Localized pain Back pain, which may indicate a paraspinal, retroperitoneal, or deep pelvic tumor Palpable mass Systemic symptoms of fever and weight loss, which often indicate[emedicine.com]
Limited Mobility
  • Low bone mineral density (BMD) and risk of fractures can occur owing in part to chemotherapy and limited mobility from local control of the primary tumor.[ncbi.nlm.nih.gov]
Cough
  • A 70-year-old man sought care because of a progressing cough and dyspnea. Chest computed tomography revealed a circumscribed mass of 6 cm in the left upper lobe.[ncbi.nlm.nih.gov]
Dyspnea
  • A 70-year-old man sought care because of a progressing cough and dyspnea. Chest computed tomography revealed a circumscribed mass of 6 cm in the left upper lobe.[ncbi.nlm.nih.gov]
Nausea
  • Etoposide - Can result in pancytopenia, as well as anaphylactic reactions, and it is implicated in the development of second malignancies, particularly acute myelogenous leukemia Combination chemotherapy - Results, in general, in alopecia, nausea, vomiting[emedicine.com]
Vomiting
  • Etoposide - Can result in pancytopenia, as well as anaphylactic reactions, and it is implicated in the development of second malignancies, particularly acute myelogenous leukemia Combination chemotherapy - Results, in general, in alopecia, nausea, vomiting[emedicine.com]
Bone Pain
  • Clinical presentation is usually dominated by local bone pain and a mass. Imaging reveals a technetium pyrophosphate avid lesion that, on plain radiograph, is destructive, diaphyseal and classically causes layered periosteal calcification.[doi.org]
  • Most common symptoms reported: Localised pain: bone pain; may come and go and vary in its intensity.[web.archive.org]
  • People usually experience extreme bone pain.[en.wikipedia.org]
Seizure
  • Seizures and hemiparesis were the main neurologic complications. CONCLUSIONS: The rate of parenchymal brain involvement in our patients with EF was 8.8%. Spread was mainly hematogenous.[ncbi.nlm.nih.gov]
Dysesthesia
  • Tumors that compress peripheral nerves may also cause paresthesias and dysesthesias such as numbness, tingling, and increased sensitivity to stimuli.[symptoma.com]

Workup

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 [1]. By contrast, magnetic resonance imaging allows for the display of well-defined lesion margins [3]. 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 [3].

Still, tissue samples have to be obtained to confirm the tentative diagnosis of ET [3]. 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 [1].

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 [1].

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 [1] [4].

Treatment

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 [5]. 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 [6]. Additionally, the administration of biophosphonate zoledronic acid has been proposed as a measure to counteract ET-related osteoclast-induced bone resorption [7].

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.

Prognosis

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 [8]. Elsewhere, five-year and ten-year survival rates of 68 and 63%, respectively, have been indicated [9]. Poor prognostic factors include metastatic disease, axial location of the neoplasm, and large tumor size, but also male gender and old age [8]. With regard to the former, distant metastases are detected in up to 28% of ET patients. Their chance of five-year survival is <40% [9].

Etiology

Genetic abnormalities related to the EWS gene on the long arm of chromosome 22 are assumed to trigger ET development [2]. 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 [10]. It leads to the formation of the EWS-FLI-1 oncogenic fusion protein and is present in 85% of ET patients [11]. The transduction of the gene encoding for chimeric protein EWS-FLI-1 has been shown to suffice to transform fibroblasts in vitro [12]. 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 [1] [11], and t(7;22)(p22;q12) inducing the generation of the EWS-ETV1 fusion protein [13]. 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 [14].

Epidemiology

For the United States, the annual incidence of ET has been estimated to 2.9 per million inhabitants [9]. 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 [2] [8]. 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 [1].

Sex distribution
Age distribution

Pathophysiology

The pathogenesis of ET remains poorly understood. ET are assumed to derive from primitive mesenchymal cells with a limited potential for neural differentiation [2]. 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 [1]. 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 [12] [14]. 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 [7]. 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.

Prevention

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 [15] [16], 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.

Summary

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 [8], so they are grouped in a single family [5]. While this family is referred to as "Ewing sarcoma and primitive neuroectodermal tumor" by the World Health Organization [1], the term "Ewing family of tumors" is preferred by others [2]. 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 [1] [2].

Patient Information

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.

References

Article

  1. Fletcher C, Bridge J, Hogendoorn P, Mertens F. World Health Organization classification of tumours of soft tissue and bone: pathology and genetics of tumours of soft tissue and bone. 4 ed. Lyon, France: IARC Press; 2013.
  2. Tsokos M, Alaggio RD, Dehner LP, Dickman PS. Ewing sarcoma/peripheral primitive neuroectodermal tumor and related tumors. Pediatr Dev Pathol. 2012; 15(1 Suppl):108-126.
  3. Henninger B, Glodny B, Rudisch A, et al. Ewing sarcoma versus osteomyelitis: differential diagnosis with magnetic resonance imaging. Skeletal Radiol. 2013; 42(8):1097-1104.
  4. Jiang Y, Ludwig J, Janku F. Targeted therapies for advanced Ewing sarcoma family of tumors. Cancer Treat Rev. 2015; 41(5):391-400.
  5. Valdes M, Nicholas G, Verma S, Asmis T. Systemic Therapy Outcomes in Adult Patients with Ewing Sarcoma Family of Tumors. Case Rep Oncol. 2017; 10(2):462-472.
  6. Brown HK, Schiavone K, Gouin F, Heymann MF, Heymann D. Biology of Bone Sarcomas and New Therapeutic Developments. Calcif Tissue Int. 2018; 102(2):174-195.
  7. Odri GA, Dumoucel S, Picarda G, et al. Zoledronic acid as a new adjuvant therapeutic strategy for Ewing's sarcoma patients. Cancer Res. 2010; 70(19):7610-7619.
  8. Verma V, Denniston KA, Lin CJ, Lin C. A Comparison of Pediatric vs. Adult Patients with the Ewing Sarcoma Family of Tumors. Front Oncol. 2017; 7:82.
  9. Esiashvili N, Goodman M, Marcus RB, Jr. Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol. 2008; 30(6):425-430.
  10. Downing JR, Head DR, Parham DM, et al. Detection of the (11;22)(q24;q12) translocation of Ewing's sarcoma and peripheral neuroectodermal tumor by reverse transcription polymerase chain reaction. Am J Pathol. 1993; 143(5):1294-1300.
  11. Sorensen PH, Lessnick SL, Lopez-Terrada D, Liu XF, Triche TJ, Denny CT. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet. 1994; 6(2):146-151.
  12. Hahm KB, Cho K, Lee C, et al. Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein. Nat Genet. 1999; 23(2):222-227.
  13. Jeon IS, Davis JN, Braun BS, et al. A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene. 1995; 10(6):1229-1234.
  14. Ordoñez JL, Osuna D, Herrero D, de Alava E, Madoz-Gúrpide J. Advances in Ewing's sarcoma research: where are we now and what lies ahead? Cancer Res. 2009; 69(18):7140-7150.
  15. Hutter RV, Francis KC, Foote FW, Jr. Ewing's sarcoma in siblings: Report of the second known occurrence. Am J Surg. 1964; 107:598-603.
  16. Joyce MJ, Harmon DC, Mankin HJ, Suit HD, Schiller AL, Truman JT. Ewing's sarcoma in female siblings. A clinical report and review of the literature. Cancer. 1984; 53(9):1959-1962.

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Last updated: 2018-06-22 00:13