Ewing's sarcoma (SE) is a rare, undifferentiated round cell tumor that originates in connective tissue and mainly affects children, adolescents and young adults. The average age of onset of the disease is 15 years.
Males are more affected than females, with a ratio of 1.6 to 1.0, although in the age group between 0 and 14 years Ewing's sarcoma appears in males and females equally.
After osteosarcoma, Ewing's sarcoma is the second most common bone cancer in children and adolescents. It accounts for 2% of all pediatric cancers. Approximately 1 case occurs in 1.5 million people each year.
It originates mainly in the bones (85%); it can develop in any type of bone in the skeleton (long, short, flat bones), affecting both the bones of the limbs (femur, humerus and other bones) and those of the pelvis and thorax (pelvis, ribs, other bones). In 15% of patients, it can originate in the soft tissues (mainly at the paravertebral and thorax level); in this case it is called "extraosseous" and is more frequent in adults than in children.
The disease can present in a localized form (primary tumor) or spread to other organs (secondary or metastatic tumor). At the time of assessment (diagnosis), about 25-30% of patients have metastases (Video). Metastases arise mainly in 3 sites: lungs, other bones, bone marrow. The 5-year survival of people with localized disease is around 70%; it is reduced by up to 30% in those with metastases.
Ewing's sarcoma is part of a group of cancers known as Ewing's Sarcoma family which comprises:
- Ewing's sarcoma, with origin in the bone
- extraosseous Ewing's sarcoma, with origin in the soft tissues
- Askin's tumor, with origin in the chest wall
- Primary Neuroectodermal tumor (PNET)
All these tumors present a set of specific genetic alterations (chromosomal translocations) that lead to the fusion of genes of the FET family (mainly the EWS gene) with genes of the ETS family (which encode transcription factors) usually FLI1 and less frequently ERG, ETV1, E1A-F, FEV.
EWS fusion can also occur with genes not belonging to the ETS family (non-ETS): it is found in undifferentiated round cell tumors, which resemble Ewing's sarcoma (Ewing-like).
The new classification of bone and soft tissue tumors of the World Health Organization (WHO) identifies, precisely on the basis of molecular alterations, a group of "Ewing-like sarcomas" which includes three types:
- round cell sarcomas with gene fusion between EWS and non-ETS family genes
- sarcomas with CIC gene rearrangement
- sarcomas with BCOR hangup
Despite an overlap in their structural features, most of the cells in these sarcomas have a shape that suggests the underlying molecular alteration. Ewing's sarcoma, for example, is the prototype of round cell sarcoma, while sarcoma cells CICs mostly have shape characteristics close to those of the epithelium, and BCOR cells are spindle-shaped.
All sarcomas of the Ewing family are highly malignant.
The rarity and complexity of the disease require that patients always be treated in specialized centers for sarcomas (referral centers).Symptoms
The disorders (symptoms) caused by Ewing's sarcoma are usually not specific. In any case, they depend on the size and the site affected.
- intermittent pain, that is that it can come and go in the affected area (bone or close to the bone), making itself felt more during the night. The pain can be very severe if the tumor compresses the nerves or, conversely, not be present until the disease it is not already in an advanced stage
- mass or swelling around the bone orto the joint, not visible, however, if the tumor is in a deep location such as, for example, in the pelvis
- limitation in movement at the level of the joints
- spontaneous fracture of the affected bone (pathological fracture)
Other less common disorders can be:
- fatigue, tiredness
- weight loss
- difficult breathing
The type of disturbance and the intensity can vary from person to person; they can be milder at the onset of the disease, appear suddenly or present and disappear and then reappear suddenly.
The suspicion of the disease is almost never immediate both for the rarity and because the non-specific disorders can resemble those present in other conditions / diseases:
- sports trauma
- inflammation of the tendons (tendinitis)
- bone infection (osteomyelitis)
- growing pains in children
The disease affects during periods of rapid bone growth but at the moment its possible causes and risk factors are not known. Hereditary factors capable of increasing the risk of disease have not been identified. Nor are environmental risk factors known.
Almost 95% of cases of Ewing's sarcoma have a "chromosomal translocation", that is, an error in rearrangement of parts of chromosomes: in practice, a part of a chromosome breaks down and attaches itself to a chromosome other than that of membership. Each human cell contains 23 pairs of chromosomes, each of which is made up of "genes" which in turn are made up of chains of DNA, molecules that contain the information needed by the cell. Genes contain instructions on cell growth and division. If some of them are damaged, they lead to tumor development.
People with Ewing's sarcoma have the same type of genetic damage (chromosomal translocation), particularly of the pair of chromosomes 11 and 22 (11; 22); to a lesser extent than the pair 21 and 22 (21; 22) and than that 7 and 22 (7; 22). The translocation between chromosomes 11 and 22 results in the union of 2 genes, one called EWS and the other FLI1, and the formation of a new “fusion gene”, called EWS-FLI1, specific to the Ewing's sarcoma family.
The presence of this gene is used to ascertain the disease. The EWS-FLI1 gene carries the instruction for the production of a protein called "transcription factor" which acts on other genes, activating or not activating them, with the result of modifying the growth and division of the cell.
However, the possible causes underlying the genetic damage (chromosomal translocation) or the risk factors are not yet known. Therefore, it is not possible, at the moment, to be able to prevent the disease.Diagnosis
The assessment (diagnosis) of Ewing's sarcoma requires a biopsy and an analysis of the collected tissue (morphological, immunohistochemical and molecular analysis) which must be carried out by experienced pathologists.
Usually, when symptoms appear, people go to their doctor or pediatrician.
However, the non-specificity of the disorders (symptoms) and the rarity of the disease generally tend to delay detection, because the doctor does not suspect it. Disorders are often traced back to "growing pains" or sports trauma.
Generally, it is their duration over time that prompts people to go back to the doctor several times or to go to a specialist. Some go straight to the emergency room, especially in case of fractures.
The diagnostic process includes a set of investigations:
- radiography(X-ray) initial, if the result does not exclude the suspicion of tumor, or on the contrary there are some uncritical elements of Ewing's sarcoma, such as the "onion-like" appearance at the level of the periosteum, decrease in bone tissue (lytic lesions of the "bone), it is necessary to continue with further radiological investigations
- magnetic nuclear resonance (RNM); scintigraphy bone and / or PET if the MRI confirms the suspicion of tumor, computed tomography of the chest (CT), all these tests are performed due to the high risk of lung metastases already at the beginning of the disease and allow to have detailed images of internal tissues and organs and to understand the spread of cancer in the body (staging of the disease)
- blood testsAlthough there are no specific tests associated with the tumor, high levels of 2 enzymes, alkaline phosphatase and lactic dehydrogenase (LDH) are found in patients. Rarely there is a decrease in white blood cells, hemoglobin, platelets unless there is major involvement of the bone marrow
- biopsy, that is the removal of a fragment (sample) of tissue which will then be analyzed in the laboratory. The biopsy must be performed in specialized centers. Two types of biopsy are possible, needle biopsy and incisional biopsy. The first is less invasive than the second. During the needle biopsy, a sample of tissue is taken under local anesthesia with an instrument similar to a large needle. During the incisional biopsy, the tissue sample is extracted after a small incision. It is a real surgery that requires an "adequate anesthesia. The biopsy allows to obtain the necessary tissue to ascertain (diagnose) the disease.
- diagnosis on the tissue taken in the biopsy, consists of the combination of morphological, immunohistochemical and molecular analysis. The latter makes use of new and sophisticated technologies, such as HGS sequencing. The diagnosis, given the rarity and complexity of the disease, must be performed by experienced pathologists. The differential diagnosis between Ewing's sarcoma and Ewing-like sarcomas is important in consideration of the diversity of both response to therapy and survival.
Therapies require a multidisciplinary approach, through a team of specialists (MDT), in centers of reference for sarcomas.
The treatments are "multimodal" which means they include a combination of:
- chemotherapy (drug treatment that acts on the whole body)
- surgery and / or radiotherapy (used locally)
In localized disease, chemotherapy is usually used both before surgery (induction chemotherapy), to reduce the tumor mass to be removed and target any micrometastases, and after surgery (consolidation chemotherapy), to eliminate tumor cells which may have spread throughout the body.Chemotherapy consists mainly of the combination of several drugs including doxorubicin, ifosfamide, vincristine, cyclophosphamide but also etoposide and actinomycin D, with courses of administration lasting several months.
The treatment schemes, that is the combinations of drugs, the number of cycles and the interval between administrations are mainly related to the stage of the disease but also to the age of the patients. In children and adolescents, for example, clinical studies with administration at short intervals between courses show better results in localized disease and less toxicity.
Chemotherapy in some people and if the necessary conditions are present, can be carried out, in clinical trials, with some drugs (such as melphalan, treosulfan) at high doses followed by bone marrow transplantation, ie re-infusion of autologous hematopoietic stem cells (taken from the patient's own bone marrow).
For patients in whom there is a "relapse" of the disease, ie Ewing's sarcoma recurs within 2 years of diagnosis, no specific treatments are currently available; however, there are "clinical studies", in which patients can participate in some cases, the possibilities of cure are very limited. Possibilities include high expert consensus for using temozolomide and irinotecan as a first option.
When metastases are present, limited to the lungs or spread to other bones or to the bone marrow, treatment basically consists of the combination of the same drugs used in the localized forms.
Patients, however, whenever possible, should be invited to participate in specific clinical trials, through which quality and careful monitoring of the therapies administered is ensured. Clinical trials are currently underway for a promising new drug for metastatic Ewing's tumor that has come back over time. The new molecule under study, TK216, acts by binding to EWS-FLI1 thus preventing the initiation of tumor transformation.
Other drugs under study are tyrosine kinase inhibitors (IGF-IR) and inhibitory drugs of enzymes involved in DNA repair (PARP) that are very present in cancer cells.
The so-called "wide-margin" surgery, that is, surgery that completely removes the tumor, remains the main treatment at the local level. The improvement of surgical techniques allows today, especially at the level of the limbs, a conservative and reconstructive surgery of almost 90% of cases, avoiding demolition interventions (amputations).
However, it is not always possible to remove the tumor en bloc as, at times, it could be in places that are not easily accessible (for example, spine, pelvis); others, its elimination could cause serious damage; still others, it may have spread to nearby tissues. In these cases, radiotherapy is used and sometimes hadrontherapy, a highly specialized type of radiotherapy that uses protons / carbon ions.
Ewing's sarcoma, unlike other sarcomas, is sensitive to radiotherapy which is used both after surgery, if the margins of the removed tumor still have cancer cells, and in the case of an inoperable tumor. The radiotherapy used to prevent its reappearance. local cancer is usually followed by courses of consolidation chemotherapy.Surgery can be used to remove metastases to the lungs or other sites in the body.Complications
Complications of chemotherapy and radiotherapy can be short-term and long-term.
In the short term, the following may occur:
- nausea, vomiting
- hair loss (alopecia)
- anemia (reduced number of red blood cells)
- bleedingresulting from a reduction in the number of platelets
- reduction in the number of white blood cells (leukopenia), associated with an increased risk of infections
- tiredness, fatigue
- oral mucositis, or inflammation of the mucous membranes of the mouth and the appearance of canker sores in the mouth
In the long term, damage to different organs can occur, depending on the type of treatments (therapies) used. Some drugs, for example, can cause damage to the kidneys, others to the heart, others still cause infertility problems or cause a second tumor.Living with
After surgery, physiotherapy is required to recover muscle and joint tone and function. Rehabilitation, especially in the case of prosthesis implantation, must begin as soon as possible.
Check-ups and examinations (radiographs, nuclear magnetic resonance and CT scan of the chest) must be performed periodically according to a specific schedule for at least 5 years.
Those affected by the disease should maintain an active network of relationships and interests that can support them on a psychological and motivational level during and after treatment. Psychological support may be needed during illness and for resuming daily activities.
In addition, there are groups / associations that can provide support to patients through the exchange of experiences in a mutual-help relationship.
Trent JC, Rosenberg AE et al. Sarcomas. Evidence-Based Diagnosis and Management. Springer, 2021
Riggi N, Suvà ML, Stamenkovic I. Ewing's Sarcoma [Summary]. The New England Journal of Medical. 2021; 384: 154-64
Casali PG, Bielack S,, Abecassis N et al. Bone sarcomas: ESMO – PaedCan – EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2018; 29 (Suppl 4): iv79 – iv95
World Health Organization (WHO). Soft Tissue and Bone Tumors WHO Classification of Tumors. 5th Edition, vol. 3
Picci P, Manfrini M, Fabbri N, Cambarotti M, Vanel D. Atlas of Muskuloskeletal tumors and tumorlike lesions. The Rizzoli Case Archive - Springer, 2014In-depth link
Euro Ewing Consortium (EEC). (English)
Sarcoma UK. (English)
Bone Cancer Research Trust. Ewing sarcoma. (English)
Trust Paola Gonzato - Sarcoma ONLUS Network. The sarcoma
Trust Paola Gonzato - Sarcoma ONLUS Network. Ewing