Ewing’s sarcoma is a tumor that forms in bone or soft tissue. Undifferentiated round cell sarcoma can also occur in bone or soft tissue. It occurs mainly in children and young adults, often appearing during adolescence.

Ewing sarcomas are the second most common malignant primary bone tumors of childhood after osteosarcoma, generally originating from the marrow cavity with invasion of the Haversian system.

This sarcoma was first described by James Ewing, a pioneer in the field of cancer research, in 1921.

Dr. James Ewing, pathologist (1866-1943) Wikipedia

Sarcoma affects long bones:

  • Femur
  • Tibia
  • Humerus

Ewing’s sarcoma can spread (metastasize) to other parts of the body. This cancer is relatively rare. Around 1.7 children under the age of 15 will have this cancer.

Contents

Pathophysiology of Ewing sarcoma

The pathophysiology of Ewing sarcoma is closely linked to specific genetic abnormalities that lead to tumor formation. The underlying mechanism usually involves a characteristic chromosomal translocation between chromosomes 11 and 22, leading to the creation of an EWSR1-FLI1 fusion gene. Here is a more detailed description of the pathophysiology of Ewing sarcoma:

  1. Chromosome translocation: The key genetic feature of Ewing sarcoma is the t(11;22)(q24;q12) translocation. This translocation involves the genes EWSR1 (Ewing Sarcoma breakpoint region 1) on chromosome 22 and FLI1 (Friend Leukemia Integration 1) on chromosome 11. The fusion of these two genes results in the creation of a new fusion gene, EWSR1- FLI1.
  2. Fusion gene formation: The EWSR1-FLI1 fusion gene produces a fusion protein that acts as an abnormal transcription factor. This modified fusion protein interferes with normal gene regulation mechanisms, leading to inappropriate expression of genes involved in cell growth, differentiation and survival.
  3. Activation of signaling pathways: The EWSR1-FLI1 fusion protein activates various cellular signaling pathways, such as the Wnt/β-catenin pathway and the Hedgehog pathway, which are crucial for normal cell growth. This uncontrolled activation can promote the uncontrolled cell proliferation characteristic of cancer.
  4. Inhibition of cell differentiation: The fusion protein disrupts normal cell differentiation, meaning that tumor cells lose their ability to differentiate into specialized cells. This contributes to the formation of an undifferentiated tumor.
  5. Angiogenesis: Ewing sarcoma is often characterized by increased vascularization, that is, the formation of new blood vessels (angiogenesis). This ensures an adequate supply of nutrients and oxygen to the growing tumor.

In summary, the pathophysiology of Ewing sarcoma is mainly linked to genetic alterations, in particular to the characteristic chromosomal translocation, which leads to the creation of an EWSR1-FLI1 fusion gene. This genetic abnormality leads to changes in gene regulation, promoting tumor growth and other characteristics associated with cancer. A better understanding of these mechanisms may contribute to the development of new targeted therapeutic approaches against Ewing sarcoma.

Causes of Ewing Sarcoma

The exact causes of Ewing’s sarcoma are not completely understood, but it is widely accepted that this tumor results from specific genetic mutations. Ewing sarcoma is associated with a characteristic chromosomal abnormality, mainly a t(11;22)(q24;q12) translocation, involving the genes EWSR1 (Ewing Sarcoma breakpoint region 1) on chromosome 22 and FLI1 (Friend Leukemia Integration 1). ) on chromosome 11. This translocation generates a new fusion gene EWSR1-FLI1, which plays a key role in tumor development.

Other factors and genetic predispositions may also contribute to the occurrence of Ewing sarcoma, including:

  1. Age: Ewing sarcoma is most common in children and young adults, usually between the teens and 20s. However, it can also occur in older adults.
  2. Race: There is a slight prevalence of Ewing sarcoma in Caucasian individuals.
  3. Gender: Ewing sarcoma has been observed to affect men slightly more frequently than women.
  4. Family history: Although Ewing sarcoma is not generally considered heritable, a family history of bone cancers may increase the risk in some individuals.
  5. Radiation Exposure: Prior exposure to radiation, although rare, has been identified as a potential risk factor for the development of Ewing sarcoma.

Symptoms of Ewing Sarcoma

  1. Bone pain: Pain in the affected area is one of the most common symptoms of Ewing sarcoma. The pain may be persistent and gradually increase over time.
  2. Swelling: Swelling or swelling in the affected area may be observed. This may be due to the growth of the tumor and the reaction of surrounding tissues.
  3. Joint stiffness: If the tumor affects a joint, joint stiffness may develop. This can lead to decreased mobility in the affected area.
  4. Fever: Some patients may experience a fever, although this is not a symptom specific to Ewing’s sarcoma. Fever may indicate a systemic inflammatory reaction.
  5. Fatigue: Persistent fatigue may accompany Ewing’s sarcoma, often associated with the presence of a malignancy and immune system response.
  6. Weight loss: Unexplained weight loss may occur, primarily due to the systemic effects of the disease.
  7. Spontaneous fractures: In some cases, the tumor can weaken the bone to the point of spontaneous fractures or cracks.
  8. Neurological symptoms: If the tumor compresses the nerves or spinal cord, neurological symptoms such as numbness, tingling, or weakness may occur.

Differential diagnosis of Ewing sarcoma

  1. Osteomyelitis: A bone infection can present with similar symptoms, such as bone pain and fever. X-rays may show lytic lesions, but blood test results, such as blood counts, can help differentiate osteomyelitis from Ewing’s sarcoma.
  2. Chondrosarcoma: A chondrosarcoma is a type of cartilage cancer that can affect the bones. It can sometimes be difficult to distinguish chondrosarcoma from Ewing’s sarcoma radiologically due to similarities in lesions and periosteal reactions.
  3. Osteosarcoma: An osteosarcoma is another type of bone cancer that can be confused with Ewing’s sarcoma due to the presence of destructive bone lesions. However, lesion location and histologic features can help differentiate the two.
  4. Nonossifying fibroma (cortical fibrous lesion): This benign condition can cause lytic lesions similar to those seen in Ewing sarcoma. Radiological features, as well as the absence of systemic symptoms, can guide the diagnosis.
  5. Eosinophilic granuloma: This benign lesion may be confused with Ewing’s sarcoma due to its radiological features, but it generally does not exhibit the same aggressiveness and does not have malignant potential.
  6. Malignant neurogenic tumors: Some malignant neurogenic tumors, such as neuroblastoma or rhabdomyosarcoma, may also be considered in differential diagnoses, particularly when they occur in the same anatomical areas.

X-ray signs of Ewing’s sarcoma

  1. Lytic lesions: On x-rays, Ewing’s sarcoma may appear as areas of destroyed bone showing lytic lesions. These areas appear dark and irregular, indicating destruction of bone tissue.
  2. Soft tissue infiltration: Ewing sarcoma can spread to surrounding soft tissues. On x-rays, this may appear as an increase in the density of the soft tissues adjacent to the affected bone.
  3. Periosteal reaction: A periosteal reaction, characterized by the formation of new bone in the periosteum (the outer membrane of bones), may be visible on x-rays. This can give the bone an “onion” appearance or cause thickening of the periosteum.
  4. Mass formation: In advanced cases, bone mass formation may be noticeable on x-rays. This mass can disrupt the normal structure of the bone and surrounding tissues.
  5. Pervasive Destruction: Ewing sarcoma X-rays may reveal widespread, pervasive destruction of the affected bone. This characteristic contributes to the understanding of the aggressiveness of the tumor in its capacity to invade bone tissue.
  6. Aggressive periosteal reaction: In addition to the periosteal reaction mentioned previously, Ewing’s sarcoma may exhibit a particularly aggressive periosteal reaction, marked by thickening and exacerbated osteoblastic activity.
  7. “Onion Skin” Appearance: The “onion skin” appearance refers to the layered or ring-like arrangement of lytic and sclerosing areas on radiographs. This appearance may be the result of rapid tumor growth and alternation between destroyed areas and areas where new bone is being formed.

These radiographic features, combined with other clinical and diagnostic features, contribute to establishing the diagnosis of Ewing sarcoma. It is crucial to note that these signs are not specific to Ewing’s sarcoma and can also be seen in other bone pathologies. A definitive diagnosis requires a multidisciplinary approach with the participation of specialists in oncology, radiology and pathology.

The multilayer periosteal reaction, also known as the lamellar or onion skin periosteal reaction, shows multiple concentric parallel layers of new bone adjacent to the cortex, reminiscent of the layers of an onion. The layers would be the result of periods of variable growth 2 and would indicate a pathological process of intermediate aggressiveness.Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org . From the case rID: 7844
Ewing sarcoma, onion skin appearance
Ewing sarcoma, Case courtesy of Dr Samir Benoudina, Radiopaedia.org . From the case rID: 75437

Références

  1. Ludwig JA. Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. Curr Opin Oncol. 2008 Jul;20(4):412-8. [PubMed]2.
  2. Riggi N, Stamenkovic I. The Biology of Ewing sarcoma. Cancer Lett. 2007 Aug 28;254(1):1-10. [PubMed]3.
  3. Van Mater D, Wagner L. Management of recurrent Ewing sarcoma: challenges and approaches. Onco Targets Ther. 2019;12:2279-2288. [PMC free article] [PubMed]4.
  4. Esiashvili N, Goodman M, Marcus RB. 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 Jun;30(6):425-30. [PubMed]5.
  5. Lessnick SL, Ladanyi M. Molecular pathogenesis of Ewing sarcoma: new therapeutic and transcriptional targets. Annu Rev Pathol. 2012;7:145-59. [PMC free article] [PubMed]6.
  6. Burchill SA. Ewing’s sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol. 2003 Feb;56(2):96-102. [PMC free article] [PubMed]7.
  7. Ozaki T. Diagnosis and treatment of Ewing sarcoma of the bone: a review article. J Orthop Sci. 2015 Mar;20(2):250-63. [PMC free article] [PubMed]8.
  8. Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am. 2000 May;82(5):667-74. [PubMed]9.
  9. Biermann JS, Chow W, Reed DR, Lucas D, Adkins DR, Agulnik M, Benjamin RS, Brigman B, Budd GT, Curry WT, Didwania A, Fabbri N, Hornicek FJ, Kuechle JB, Lindskog D, Mayerson J, McGarry SV, Million L, Morris CD, Movva S, O’Donnell RJ, Randall RL, Rose P, Santana VM, Satcher RL, Schwartz H, Siegel HJ, Thornton K, Villalobos V, Bergman MA, Scavone JL. NCCN Guidelines Insights: Bone Cancer, Version 2.2017. J Natl Compr Canc Netw. 2017 Feb;15(2):155-167. [PubMed]10.
  10. Ross KA, Smyth NA, Murawski CD, Kennedy JG. The biology of ewing sarcoma. ISRN Oncol. 2013;2013:759725. [PMC free article] [PubMed]11.
  11. Hoshi M, Takami M, Ieguchi M, Aono M, Takada J, Oebisu N, Iwai T, Nakamura H. Fertility following treatment of high-grade malignant bone and soft tissue tumors in young adults. Mol Clin Oncol. 2015 Mar;3(2):367-374. [PMC free article] [PubMed]12.
  12. Woo SH, Sung MJ, Park KS, Yoon TR. Three-dimensional-printing Technology in Hip and Pelvic Surgery: Current Landscape. Hip Pelvis. 2020 Mar;32(1):1-10. [PMC free article] [PubMed]13.
  13. Fan H, Fu J, Li X, Pei Y, Li X, Pei G, Guo Z. Implantation of customized 3-D printed titanium prosthesis in limb salvage surgery: a case series and review of the literature. World J Surg Oncol. 2015 Nov 04;13:308. [PMC free article] [PubMed]14.
  14. Schuck A, Ahrens S, Paulussen M, Kuhlen M, Könemann S, Rübe C, Winkelmann W, Kotz R, Dunst J, Willich N, Jürgens H. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys. 2003 Jan 01;55(1):168-77. [PubMed]15.
  15. Yock TI, Krailo M, Fryer CJ, Donaldson SS, Miser JS, Chen Z, Bernstein M, Laurie F, Gebhardt MC, Grier HE, Tarbell NJ., Children’s Oncology Group. Local control in pelvic Ewing sarcoma: analysis from INT-0091–a report from the Children’s Oncology Group. J Clin Oncol. 2006 Aug 20;24(24):3838-43. [PubMed]16.
  16. DuBois SG, Krailo MD, Gebhardt MC, Donaldson SS, Marcus KJ, Dormans J, Shamberger RC, Sailer S, Nicholas RW, Healey JH, Tarbell NJ, Randall RL, Devidas M, Meyer JS, Granowetter L, Womer RB, Bernstein M, Marina N, Grier HE. Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children’s Oncology Group. Cancer. 2015 Feb 01;121(3):467-75. [PMC free article] [PubMed]17.
  17. Gerrand C, Bate J, Seddon B, Dirksen U, Randall RL, van de Sande M, O’Donnell P, Tuckett J, Peake D, Jeys L, Saifuddin A, Grainger M, Whelan J. Seeking international consensus on approaches to primary tumour treatment in Ewing sarcoma. Clin Sarcoma Res. 2020 Nov 17;10(1):21. [PMC free article] [PubMed]18.
  18. Ren Y, Zhang Z, Shang L, You X. Surgical Resection of Primary Ewing’s Sarcoma of Bone Improves Overall Survival in Patients Presenting with Metastasis. Med Sci Monit. 2019 Feb 16;25:1254-1262. [PMC free article] [PubMed]19.
  19. Raciborska A, Bilska K, Rychłowska-Pruszyńska M, Duczkowski M, Duczkowska A, Drabko K, Chaber R, Sobol G, Wyrobek E, Michalak E, Rodriguez-Galindo C, Wożniak W. Management and follow-up of Ewing sarcoma patients with isolated lung metastases. J Pediatr Surg. 2016 Jul;51(7):1067-71. [PubMed]20.
  20. Rodriguez-Galindo C, Billups CA, Kun LE, Rao BN, Pratt CB, Merchant TE, Santana VM, Pappo AS. Survival after recurrence of Ewing tumors: the St Jude Children’s Research Hospital experience, 1979-1999. Cancer. 2002 Jan 15;94(2):561-9. [PubMed]21.
  21. Hillmann A, Ozaki T, Rübe C, Hoffmann C, Schuck A, Blasius S, Haas A, Jürgens H, Winkelmann W. Surgical complications after preoperative irradiation of Ewing’s sarcoma. J Cancer Res Clin Oncol. 1997;123(1):57-62. [PubMed]22.
  22. Hesla AC, Papakonstantinou A, Tsagkozis P. Current Status of Management and Outcome for Patients with Ewing Sarcoma. Cancers (Basel). 2021 Mar 10;13(6) [PMC free article] [PubMed]23.
  23. Ahmed SK, Randall RL, DuBois SG, Harmsen WS, Krailo M, Marcus KJ, Janeway KA, Geller DS, Sorger JI, Womer RB, Granowetter L, Grier HE, Gorlick RG, Laack NNI. Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children’s Oncology Group. Int J Radiat Oncol Biol Phys. 2017 Dec 01;99(5):1286-1294. [PMC free article] [PubMed]24.
  24. Dunst J, Jürgens H, Sauer R, Pape H, Paulussen M, Winkelmann W, Rübe C. Radiation therapy in Ewing’s sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):919-30. [PubMed]25.
  25. Ladenstein R, Pötschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin O, van den Berg H, Dirksen U, Hjorth L, Michon J, Lewis I, Craft A, Jürgens H. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol. 2010 Jul 10;28(20):3284-91. [PubMed]26.
  26. O’Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, Wunder J, Kandel R, Goddard K, Sadura A, Pater J, Zee B. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002 Jun 29;359(9325):2235-41. [PubMed]

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