Ewing sarcoma

Last updated
Ewing sarcoma
Other names
  • Ewing's sarcoma
  • Peripheral primitive neuroectodermal tumor and Askin tumor (not recommended) [1]
  • Ewing sarcoma family of tumors [2]
Ewing sarcoma - PAS - very high mag.jpg
Micrograph of metastatic Ewing sarcoma (right of image) in normal lung (left of image). PAS stain.
Pronunciation
Specialty Oncology
Symptoms Swell and pain near the tumor [2]
Complications Pleural effusion, paraplegia [3]
Usual onset10 to 20 years old [4] [3]
CausesUnknown [3]
Diagnostic method Tissue biopsy [2]
Differential diagnosis Osteosarcoma, neuroblastoma, osteomyelitis, eosinophilic granuloma [3]
Treatment Chemotherapy, radiation therapy, surgery, stem cell transplant [2]
Prognosis Five-year survival ~ 70% [4]
Frequency1 per 1 million people (US) [4]

Ewing sarcoma is a type of pediatric cancer [5] that forms in bone or soft tissue. [1] Symptoms may include swelling and pain at the site of the tumor, fever, and a bone fracture. [2] The most common areas where it begins are the legs, pelvis, and chest wall. [4] In about 25% of cases, the cancer has already spread to other parts of the body at the time of diagnosis. [4] Complications may include a pleural effusion or paraplegia. [3]

Contents

It is a type of small round cell sarcoma. [1] The cause of Ewing sarcoma is unknown, most cases appearing to occur randomly. [3] Though not strongly associated with known hereditary cancer syndromes, accumulating evidence suggests a strong inherited risk factor, [6] identifying a genetic component having multiple chromosome loci associated with Ewing sarcoma susceptibility. [5] Sometimes Ewing sarcoma is associated with a germline mutation. [1] The underlying mechanism often involves a genetic change known as a reciprocal translocation. [4] Diagnosis is based on biopsy of the tumor. [2]

Treatment often includes chemotherapy, radiation therapy, surgery, and stem cell transplant. [7] [2] Targeted therapy and immunotherapy are being studied. [2] Five-year survival is about 70%. [4] A number of factors, however, affect this estimate. [4]

In 1920, James Ewing discerned that these tumors are a distinct type of cancer. [8] [9] It affects approximately one in a million people per year in the United States. [4] Ewing sarcoma occurs most often in teenagers and young adults and represents 2% of childhood cancers. [2] [3] Caucasians are affected more often than African Americans or Asians, while males are affected more often than females. [10] [4]

Signs and symptoms

Distribution of Ewing sarcoma: The most frequent locations are the large long bones and the pelvis. Distribution of Ewing's sarcoma.jpg
Distribution of Ewing sarcoma: The most frequent locations are the large long bones and the pelvis.

Ewing sarcoma is more common in males (1.6 male:1 female) and usually presents in childhood or early adulthood, with a peak between 10 and 20 years of age. It can occur anywhere in the body but most commonly in the pelvis and proximal long tubular bones, especially around the growth plates. The diaphyses of the femur are the most common sites, followed by the tibia and the humerus. Thirty percent are overtly metastatic at presentation, while 10–15% of people present with a pathologic fracture at the time of diagnosis. [11] People usually experience extreme bone pain. Rarely, it can develop in the vagina. [12] [13]

Signs and symptoms include intermittent fevers, anemia, leukocytosis, increased sedimentation rate, and other symptoms of inflammatory systemic illness. [14]

According to the Bone Cancer Research Trust (BCRT), the most common symptoms are localized pain, swelling, and sporadic bone pain with variable intensity. The swelling is most likely to be visible if the sarcoma is located on a bone near the surface of the body, but when it occurs in other places deeper in the body, like on the pelvis, it may not be visible. [15]

Genetics

Genetic exchange between chromosomes can cause cells to become cancerous. Most cases of Ewing sarcoma (about 85%) are the result of a defining genetic event; a reciprocal translocation between chromosomes 11 and 22, t(11,22), which fuses the Ewing Sarcoma Breakpoint Region 1 ( EWSR1 ) gene of chromosome 22 (which encodes the EWS protein) to the Friend Leukemia Virus Integration 1 ( FLI1 ) gene (which encodes Friend Leukemia Integration 1 transcription factor (FLI1), a member of the ETS transcription factor family) of chromosome 11. [14] [11] The resultant chromosomal translocation causes the EWS trans-activation domain (which is usually silent in the wild type) to become very active, this leads to the translation of a new EWS-FLI1 fusion protein. [11] EWS proteins are involved in meiosis, B-lymphocyte maturation, hematopoietic stem cell renewal, DNA repair and cell senescence. [11] ETS transcription factors are involved in cell differentiation and cell cycle control. [11] The EWS-FLI1 fusion protein has phase transition properties allowing it to transition into a liquid-like phase, separated by compartments consisting of membrane-less organelles. This phase transition property allows the fusion protein to access and activate micro-satellite regions of the genome that would otherwise be inaccessible. This fusion protein can convert usually silent chromatin regions into fully active enhancers leading to oncogenesis of the cells. [11]

The EWS-FLI1 fusion protein also causes variable expression of the genome via epigenetic mechanisms. The fusion protein does this by recruiting enzymes that affect DNA methylation, histone acetylation and direct inhibition of non-coding microRNA. [11] EWS-FLI1 promotes histone acetylation, which leads to uncoiling of DNA (which is usually tightly wound around histones); this chromatin relaxation leads to the DNA being more accessible to transcription factors and thus enhancing the expression of the associated genes. [11] DNA methylation leads to gene silencing as it prevents transcription factor binding. EWS-FLI1 reduces DNA methylation (which occurs mostly in areas corresponding to transcription enhancers), leading to increased gene expression. [11] The EWS-FLI1 fusion protein inhibits certain microRNAs of cells (such as miRNA-145). MiRNA-145 normally activates RNA-induced silencing complexes (RISCs) to inhibit or degrade mRNA that is involved in cell pluripotency. [11] Thus, ESW-FLI1 inhibition of the microRNA miRNA-145 leads to increased pluripotency, decreased differentiation of cells and increased oncogenesis. [11]

A 2012 genome-wide association study (GWAS) identified three susceptibility loci located on chromosomes 1, 10 and 15. [16] A 2015 continuative study discovered that the Ewing sarcoma susceptibility gene EGR2 , which is located within the chromosome 10 susceptibility locus, is regulated by the EWSR1-FLI1 fusion oncogene via a GGAA-microsatellite. [17] [18] A 2018 GWAS (Machiela, et al, 2018) [5] reaffirmed the susceptibility loci on chromosomes 1, 10 and 15 and added 3 additional loci on chromosomes 6 and 20; totaling 1p36.22, 6p25.1, 10q21.3, 15q15.1, 20p11.22 and 20p11.23. The latter locus is near NKX2-2, a highly overexpressed gene in Ewing sarcoma. [5]

EWS/FLI functions as the master regulator. [19] Other translocations are at t(21;22) [20] and t(7;22). [21] Ewing sarcoma cells are positive for CD99 and MIC2, [14] and negative for CD45. [22]

Diagnosis

Micrograph of a metastatic Ewing sarcoma with the characteristic cytoplasmic clearing on H&E staining, which was showing to be PAS positive Ewing sarcoma - intermed mag.jpg
Micrograph of a metastatic Ewing sarcoma with the characteristic cytoplasmic clearing on H&E staining, which was showing to be PAS positive

The definitive diagnosis is based on histomorphologic findings, immunohistochemistry and molecular pathology.

Ewing sarcoma is a small-blue-round-cell tumor that typically has a clear cytoplasm on H&E staining, due to glycogen. The presence of the glycogen can be demonstrated with positive PAS staining and negative PAS diastase staining. The characteristic immunostain is CD99, which diffusely marks the cell membrane. However, as CD99 is not specific for Ewing sarcoma, several auxiliary immunohistochemical markers can be employed to support the histological diagnosis. [23] Morphologic and immunohistochemical findings are corroborated with an associated chromosomal translocation, of which several occur. The most common translocation, present in about 90% of Ewing sarcoma cases, is t(11;22)(q24;q12), [24] [25] which generates an aberrant transcription factor through fusion of the EWSR1 gene with the FLI1 gene. [26]

The pathologic differential diagnosis is the grouping of small-blue-round-cell tumors, which includes lymphoma, alveolar rhabdomyosarcoma, and desmoplastic small round cell tumor, among others.[ citation needed ]

Medical imaging

X-ray of a child with Ewing sarcoma of the tibia Ewing sarcoma tibia child.jpg
X-ray of a child with Ewing sarcoma of the tibia

On conventional radiographs, typical findings of Ewing sarcoma consist of multiple confluent lytic bone lesions that have a "moth eaten" pattern due to permeative destruction of bone. [11] There will also be a displaced periosteum as the new sub-periosteal layer of bone begins to grow on top of the tumor. This raised or displaced periosteum is consistent with the classic radiographic finding of the Codman triangle. [11] The proliferative reaction of bone can also create delicate laminations constituting the periosteal layers and giving the radiographic appearance of an onion peel. [11] Plain films add valuable information in the initial evaluation or screening. The wide zone of transition (e.g. permeative) is the most useful plain film characteristic in differentiation of benign versus aggressive or malignant lytic lesions.

Magnetic resonance imaging slice showing Ewing sarcoma of the left hip (white area shown right) Ewing's sarcoma MRI nci-vol-1832-300.jpg
Magnetic resonance imaging slice showing Ewing sarcoma of the left hip (white area shown right)

Magnetic resonance imaging (MRI) should be routinely used in the work-up of malignant tumors. It will show the full bony and soft tissue extent and relate the tumor to other nearby anatomic structures (e.g. vessels). Gadolinium contrast is not necessary as it does not give additional information over noncontrast studies, though some current researchers argue that dynamic, contrast-enhanced MRI may help determine the amount of necrosis within the tumor, thus help in determining response to treatment prior to surgery. [27]

Computed axial tomography (CT) can also be used to define the extraosseous extent of the tumor, especially in the skull, spine, ribs, and pelvis. Both CT and MRI can be used to follow response to radiation and/or chemotherapy. Bone scintigraphy can also be used to follow tumor response to therapy. [28]

In the group of malignant small round cell tumors that includes Ewing sarcoma, bone lymphoma, and small cell osteosarcoma, the cortex may appear almost normal radiographically, while permeative growth occurs throughout the Haversian channels. These tumors may be accompanied by a large soft-tissue mass while almost no bone destruction is visible. The radiographs frequently do not show any signs of cortical destruction.

Radiographically, Ewing sarcoma presents as "moth-eaten" destructive radiolucencies of the medulla and erosion of the cortex with expansion. [29]

Differential diagnosis

Other entities with similar clinical presentations include osteomyelitis, osteosarcoma (especially telangiectatic osteosarcoma), and eosinophilic granuloma. Soft-tissue neoplasms such as pleomorphic undifferentiated sarcoma (malignant fibrous histiocytoma) that erode into adjacent bone may also have a similar appearance. Accumulating evidence suggests that EWSR1-NFATc2 positive sarcomas, which were previously considered to possibly belong to the Ewing family of tumors, differ from Ewing sarcoma in their genetics, transcriptomes, and epigenetic and epidemiological profiles, indicating that they might represent a distinct tumor entity. [30] [31] [32] [33]

Treatment

Almost all people receive multidrug chemotherapy (most often vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide), [34] as well as local disease control with surgery and/or radiation. [35] An aggressive approach is necessary because almost all people with apparently localized disease at the time of diagnosis actually have asymptomatic metastatic disease.[ citation needed ]

The surgical resection may involve limb salvage or amputation. Complete excision at the time of biopsy may be performed if malignancy is confirmed at the time it is examined.[ citation needed ] Treatment lengths vary depending on location and stage of the disease at diagnosis. Radical chemotherapy may be as short as six treatments at three-week cycles, but most people undergo chemotherapy for 6–12 months and radiation therapy for 5–8 weeks.[ citation needed ] Radiotherapy has been used for localized disease. The tumor has a unique property of being highly sensitive to radiation, sometimes acknowledged by the phrase "melting like snow", but the main drawback is that it recurs dramatically after some time.[ citation needed ]

Antisense oligodeoxynucleotides have been proposed as possible treatment by down-regulating the expression of the oncogenic fusion protein associated with the development of Ewing sarcoma resulting from the EWS-ETS gene translocation. [36] [37] In addition, the synthetic retinoid derivative fenretinide (4-hydroxy(phenyl)retinamide) has been reported to induce high levels of cell death in Ewing sarcoma cell lines in vitro and to delay growth of xenografts in in vivo mouse models. [38] [39]

In most pediatric cancers including sarcoma, proton beam radiation (also known as proton therapy) delivers an equally effective dose to the tumor with less damage to the surrounding normal tissue compared to photon radiation. [40]

Prognosis

Staging attempts to distinguish people with localized from those with metastatic disease. [41] The most common areas of metastasis are the lungs, bone and bone marrow with less common areas of metastasis being the lymph nodes, liver and brain. [11] The presence of metastatic disease is the most important prognostic factor in Ewing Sarcoma with the 5 year survival rate being only 30% when metastasis is present at the time of diagnosis as compared to a 70% 5 year survival rate with no metastasis present. [11] Another important prognostic factor is the location of the primary tumor; proximal tumors (located in the pelvis and sacrum) are worse prognostic indicators as compared to more distal tumors. [11] Other factors associated with a poor prognosis include a large primary neoplasm, older age at diagnosis (older than 18 years of age) and increased lactate dehydrogenase (LDH) levels. [11]

Five-year survival for localized disease is greater than 70% after therapy. [42] Prior to the use of multi-drug chemotherapy, long-term survival was less than 10%. The development of multi-disciplinary therapy with chemotherapy, irradiation, and surgery has increased current long-term survival rates in most clinical centers to greater than 50%. [43] However, some sources state it is 25–30%. [44]

Retrospective research showed that two chemokine receptors, CXCR4 and CXCR7, can be used as molecular prognosis factors. People who express low levels of both chemokine receptors have the highest odds of long-term survival with >90% survival at five years post-diagnosis versus <30% survival at five years for patients with very high expression levels of both receptors. [45] A recent study also suggested a role for SOX2 as an independent prognostic biomarker that can be used to identify patients at high risk for tumor relapse. [46]

Epidemiology

Ewing sarcomas represent 16% of primary bone sarcomas. [14] In the United States, they are most common in the second decade of life, [14] with a rate of 0.3 cases per million in children under 3 years of age, and as high as 4.6 cases per million in adolescents aged 15–19 years. Nearly 80% of patients are aged less than 20 years of age. [47] It is uncommon in patients younger than 5 years and older than 30 years. [47]

Internationally, the annual incidence rate averages less than 2 cases per million children. [48] In the United Kingdom, an average of six children per year are diagnosed; mainly males in early stages of puberty. With occurrences primarily arising in older children and teenagers, one causal theory is puberty, e.g. its rapid growth spurts making bone tissue more cancer susceptible during development years. [49]

A grouping of three unrelated teenagers in Wake Forest, North Carolina, have been diagnosed with Ewing sarcoma. All three children were diagnosed in 2011 and all attended the same temporary classroom together while the school underwent renovation. A fourth teenager living nearby was diagnosed in 2009. The odds of this grouping are considered significant. [50] Ewing sarcoma occurs about 10- to 20-fold more commonly in people of European descent compared to people of African descent. [51] [11]

Ewing sarcoma is the second most common bone cancer in children and adolescents, with poor prognosis and outcome in ~70% of initial diagnoses and 10–15% of relapses. [52]

Related Research Articles

<span class="mw-page-title-main">Sarcoma</span> Type of malignant tumor (cancer)

A sarcoma is a malignant tumor, a type of cancer that arises from cells of mesenchymal origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or other structural tissues, and sarcomas can arise in any of these types of tissues. As a result, there are many subtypes of sarcoma, which are classified based on the specific tissue and type of cell from which the tumor originates. Sarcomas are primary connective tissue tumors, meaning that they arise in connective tissues. This is in contrast to secondary connective tissue tumors, which occur when a cancer from elsewhere in the body spreads to the connective tissue. Sarcomas are one of five different types of cancer, classified by the cell type from which they originate. The word sarcoma is derived from the Greek σάρκωμα sarkōma 'fleshy excrescence or substance', itself from σάρξsarx meaning 'flesh'.

<span class="mw-page-title-main">Desmoplastic small-round-cell tumor</span> Aggressive and rare cancer

Desmoplastic small-round-cell tumor (DSRCT) is an aggressive and rare cancer that primarily occurs as masses in the abdomen. Other areas affected may include the lymph nodes, the lining of the abdomen, diaphragm, spleen, liver, chest wall, skull, spinal cord, large intestine, small intestine, bladder, brain, lungs, testicles, ovaries, and the pelvis. Reported sites of metastatic spread include the liver, lungs, lymph nodes, brain, skull, and bones. It is characterized by the EWS-WT1 fusion protein.

<span class="mw-page-title-main">Alveolar soft part sarcoma</span> Medical condition

Alveolar soft part sarcoma, abbreviated ASPS, is a very rare type of soft-tissue sarcoma, that grows slowly and whose cell of origin is unknown.

<span class="mw-page-title-main">NFATC2</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the NFATC2 gene.

<span class="mw-page-title-main">FLI1</span> Protein-coding gene in the species Homo sapiens

Friend leukemia integration 1 transcription factor (FLI1), also known as transcription factor ERGB, is a protein that in humans is encoded by the FLI1 gene, which is a proto-oncogene.

<span class="mw-page-title-main">ATF1</span> Protein-coding gene in humans

Cyclic AMP-dependent transcription factor ATF-1 is a protein that in humans is encoded by the ATF1 gene.

<span class="mw-page-title-main">ETV4</span> Protein-coding gene in the species Homo sapiens

ETS translocation variant 4 (ETV4), also known as polyoma enhancer activator 3 (PEA3), is a member of the PEA3 subfamily of Ets transcription factors.

<span class="mw-page-title-main">Mesoblastic nephroma</span> Medical condition

Congenital mesoblastic nephroma, while rare, is the most common kidney neoplasm diagnosed in the first three months of life and accounts for 3-5% of all childhood renal neoplasms. This neoplasm is generally non-aggressive and amenable to surgical removal. However, a readily identifiable subset of these kidney tumors has a more malignant potential and is capable of causing life-threatening metastases. Congenital mesoblastic nephroma was first named as such in 1967 but was recognized decades before this as fetal renal hamartoma or leiomyomatous renal hamartoma.

<span class="mw-page-title-main">RNA-binding protein EWS</span> Human protein and coding gene

RNA-binding protein EWS is a protein that in humans is encoded by the EWSR1 gene on human chromosome 22, specifically 22q12.2. It is one of 3 proteins in the FET protein family.

<i>ERG</i> (gene) Protein-coding gene in the species Homo sapiens

ERG is an oncogene. ERG is a member of the ETS family of transcription factors. The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis.

<span class="mw-page-title-main">RNA-binding protein FUS</span> Human protein and coding gene

RNA-binding protein FUS/TLS, also known as heterogeneous nuclear ribonucleoprotein P2 is a protein that in humans is encoded by the FUS gene.

<span class="mw-page-title-main">TAF15</span> Protein-coding gene in the species Homo sapiens

TATA-binding protein-associated factor 2N is a protein that in humans is encoded by the TAF15 gene.

The Ewing family of tumors (EFTs) is a group of small cell sarcomas including Ewing sarcoma of the bone, extra osseous Ewing tumors, and primitive neuroectodermal tumors. They are rare cancers, usually diagnosed in peoples' twenties. The sarcoma of bone is the most common of the variants. All forms are predisposed to metastasis and have had historically high rates of mortality. The family of tumors shares a common translocation mutation of the EWS gene on chromosome 22 to an ETS-type gene, most commonly the FLI1 gene. EFTs are highly malignant, with 5-year survival for patients with metastatic disease at 20%. The current standard of care includes resection, radiation, and chemotherapy.

<span class="mw-page-title-main">Myxoid liposarcoma</span> Medical condition

A myxoid liposarcoma is a malignant adipose tissue neoplasm of myxoid appearance histologically.

<span class="mw-page-title-main">Clear cell sarcoma</span> Rare form of cancer

Clear cell sarcoma is a rare form of cancer called a sarcoma. It is known to occur mainly in the soft tissues and dermis. Rare forms were thought to occur in the gastrointestinal tract before they were discovered to be different and redesignated as gastrointestinal neuroectodermal tumors.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare low-grade malignant mesenchymal neoplasm of the soft tissues, that differs from other sarcomas by unique histology and characteristic chromosomal translocations. There is an uncertain differentiation and neuroendocrine differentiation is even possible.

In molecular biology mir-708 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms. miR-708 is located on chromosome 11q14.1 and is endcoded in intron 1 of the ODZ4 gene. It is most highly expressed in the brain and eyes, and has a supposed role in endoplasmic reticular stress of the eye.

EWS/FLI1 is an oncogenic protein that is pathognomonic for Ewing sarcoma. It is found in approximately 90% of all Ewing sarcoma tumors with the remaining 10% of fusions substituting one fusion partner with a closely related family member.

Sclerosing epithelioid fibrosarcoma (SEF) is a very rare malignant tumor of soft tissues that on microscopic examination consists of small round or ovoid neoplastic epithelioid fibroblast-like cells, i.e. cells that have features resembling both epithelioid cells and fibroblasts. In 2020, the World Health Organization classified SEF as a distinct tumor type in the category of malignant fibroblastic and myofibroblastic tumors. However, current studies have reported that low-grade fibromyxoid sarcoma (LGFMS) has many clinically and pathologically important features characteristic of SEF; these studies suggest that LGSFMS may be an early form of, and over time progress to become, a SEF. Since the World Health Organization has classified LGFMS as one of the malignant fibroblastic and myofibroblastic tumors that is distinctly different than SEF, SEF and LGFMS are here regarded as different tumor forms.

The FET protein family consists of three similarly structured and functioning proteins. They and the genes in the FET gene family which encode them are: 1) the EWSR1 protein encoded by the EWSR1 gene located at band 12.2 of the long arm of chromosome 22; 2) the FUS protein encoded by the FUS gene located at band 16 on the short arm of chromosome 16; and 3) the TAF15 protein encoded by the TAF15 gene located at band 12 on the long arm of chromosome 7 The FET in this protein family's name derives from the first letters of FUS, EWSR1, and TAF15.

References

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