Ewing family of tumors

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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. [1]  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. [2]

Contents

Genetic and demographic predisposition

Ewing’s sarcoma is most common in Caucasians and typically diagnosed during the first several decades of life, most often in someone’s teens.  The cancer also affects males at twice the rate compared to females. [1]

Despite EFTs appearing more often in younger patients, they have not been linked to any common cancer predisposing syndromes, such as Li-Fraumeni Syndrome.  EFTs have also not been shown to correlate with any environmental risk factor. [3]  The defining genetic mutation of EFTs is the translocation of EWS gene located on chromosome 22 to an ETS-type gene, most often FLI1.  Other potential fusion genes include ERG, ETV1, E1A-F, or FEV. [4]

Types

The Ewing Family of Tumors are small cell sarcomas most commonly occurring within the bone, but may also occur within soft tissues or as a primitive neuroendocrine tumor.

Ewing's sarcoma of bone

Ewing’s sarcoma of bone is the most common of the EFTs and tends to occur in the trunk and long bones.  The cancer most often occurs in the shaft, or diaphysis, of bones, as compared to other common bone cancers.  The most common presenting symptom is pain in the bone, and the initial diagnostic step is imaging, often both MRI and radiograph.  Due to the high chance of metastasis, full body PET/CT is often performed to look for cancer spread.  Confirming diagnosis of Ewing’s sarcoma requires biopsy and genetic testing.  The current practice for treatment is first neoadjuvant radiation to shrink the cancer, resection, and follow up chemotherapy. [1] [5]

Extra-osseous Ewing's sarcoma

Extra-osseous Ewing’s sarcoma accounts for roughly 20% of Ewing’s sarcoma cases, and most commonly occurs in the glutes, shoulders, and arms.  The presentation is nonspecific, with most patients first reporting a painful mass.  Initial workup is similar to Ewing’s sarcoma of bone, beginning with imaging.  However, ultrasound is often used in conjunction with CT and MRI.  Biopsy is again required to confirm diagnosis.  Treatment also consists of surgical removal followed by chemotherapy, however patients seem to do better overall when compared to Ewing’s sarcoma of the bone. [6] [7]  

Primitive neuroendocrine tumors (PNETs)

Primitive neuroendocrine tumors are rare forms of EFTs that originate from neuroendocrine cells, with the differentiation varying from tumor to tumor.  PNETs were first discovered in peripheral nerves and considered distinct from EFTs, until genetic studies showed the same translocation of EWS-FLI1 in PNETs.  PNETs and Ewing’s sarcoma are described as appearing on the same histologic spectrum. [8] [9]  Treatment of PNETs is the same as extra-osseous Ewing’s sarcoma, with resection of the whole tumor alongside chemotherapy and radiation.  Outcomes however are poor as PNET remains an aggressive cancer as a member of the Ewing Family of Tumors. [9]

Related Research Articles

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

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">Bone tumor</span> Medical condition

A bone tumor is an abnormal growth of tissue in bone, traditionally classified as noncancerous (benign) or cancerous (malignant). Cancerous bone tumors usually originate from a cancer in another part of the body such as from lung, breast, thyroid, kidney and prostate. There may be a lump, pain, or neurological signs from pressure. A bone tumor might present with a pathologic fracture. Other symptoms may include fatigue, fever, weight loss, anemia and nausea. Sometimes there are no symptoms and the tumour is found when investigating another problem.

<span class="mw-page-title-main">Osteosarcoma</span> Cancerous tumour in a bone

An osteosarcoma (OS) or osteogenic sarcoma (OGS) is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchymal origin and that exhibits osteoblastic differentiation and produces malignant osteoid.

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

Rhabdomyosarcoma (RMS) is a highly aggressive form of cancer that develops from mesenchymal cells that have failed to fully differentiate into myocytes of skeletal muscle. Cells of the tumor are identified as rhabdomyoblasts.

<span class="mw-page-title-main">Dermatofibrosarcoma protuberans</span> Medical condition

Dermatofibrosarcoma protuberans (DFSP) is a rare locally aggressive malignant cutaneous soft-tissue sarcoma. DFSP develops in the connective tissue cells in the middle layer of the skin (dermis). Estimates of the overall occurrence of DFSP in the United States are 0.8 to 4.5 cases per million persons per year. In the United States, DFSP accounts for between 1 and 6 percent of all soft-tissue sarcomas and 18 percent of all cutaneous soft-tissue sarcomas. In the Surveillance, Epidemiology and End Results (SEER) tumor registry from 1992 through 2004, DFSP was second only to Kaposi sarcoma.

<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.

A blastoma is a type of cancer, more common in children, that is caused by malignancies in precursor cells, often called blasts. Examples are nephroblastoma, medulloblastoma, and retinoblastoma. The suffix -blastoma is used to imply a tumor of primitive, incompletely differentiated cells, e.g., chondroblastoma is composed of cells resembling the precursor of chondrocytes.

<span class="mw-page-title-main">Primitive neuroectodermal tumor</span> Medical condition

Primitive neuroectodermal tumor is a malignant (cancerous) neural crest tumor. It is a rare tumor, usually occurring in children and young adults under 25 years of age. The overall 5 year survival rate is about 53%.

<span class="mw-page-title-main">Ewing sarcoma</span> Type of cancer

Ewing sarcoma is a type of pediatric cancer that forms in bone or soft tissue. 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. In about 25% of cases, the cancer has already spread to other parts of the body at the time of diagnosis. Complications may include a pleural effusion or paraplegia.

<span class="mw-page-title-main">Atypical teratoid rhabdoid tumor</span> Medical condition

An atypical teratoid rhabdoid tumor (AT/RT) is a rare tumor usually diagnosed in childhood. Although usually a brain tumor, AT/RT can occur anywhere in the central nervous system (CNS), including the spinal cord. About 60% will be in the posterior cranial fossa. One review estimated 52% in the posterior fossa, 39% are supratentorial primitive neuroectodermal tumors (sPNET), 5% are in the pineal, 2% are spinal, and 2% are multifocal.

<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">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">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">Esthesioneuroblastoma</span> Medical condition

Esthesioneuroblastoma is a rare cancer of the nasal cavity. Arising from the upper nasal tract, esthesioneuroblastoma is believed to originate from sensory neuroepithelial cells, also known as neuroectodermal olfactory cells.

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.

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.

Myxofibrosarcoma (MFS), although a rare type of tumor, is one of the most common soft tissue sarcomas, i.e. cancerous tumors, that develop in the soft tissues of elderly individuals. Initially considered to be a type of histiocytoma termed fibrous histiocytoma or myxoid variant of malignant fibrous histiocytoma, Angervall et al. termed this tumor myxofibrosarcoma in 1977. In 2020, the World Health Organization reclassified MFS as a separate and distinct tumor in the category of malignant fibroblastic and myofibroblastic tumors.

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

  1. 1 2 3 Iwamoto Y (February 2007). "Diagnosis and treatment of Ewing's sarcoma". Japanese Journal of Clinical Oncology. 37 (2): 79–89. doi:10.1093/jjco/hyl142. PMID   17272319.
  2. ↑ Yu H, Ge Y, Guo L, Huang L (January 2017). "Potential approaches to the treatment of Ewing's sarcoma". Oncotarget. 8 (3): 5523–5539. doi:10.18632/oncotarget.12566. PMC   5354928 . PMID   27740934.
  3. ↑ Gargallo P, Yáñez Y, Juan A, Segura V, Balaguer J, Torres B, et al. (October 2020). "Review: Ewing Sarcoma Predisposition". Pathology & Oncology Research. 26 (4): 2057–2066. doi:10.1007/s12253-019-00765-3. PMID   31656020. S2CID   204907655.
  4. ↑ Baldauf MC, Orth MF, Dallmayer M, Marchetto A, Gerke JS, Rubio RA, et al. (January 2018). "Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets". Oncotarget. 9 (2): 1587–1601. doi:10.18632/oncotarget.20098. PMC   5788584 . PMID   29416716.
  5. ↑ Zöllner SK, Amatruda JF, Bauer S, Collaud S, de Álava E, DuBois SG, et al. (April 2021). "Ewing Sarcoma-Diagnosis, Treatment, Clinical Challenges and Future Perspectives". Journal of Clinical Medicine. 10 (8): 1685. doi: 10.3390/jcm10081685 . PMC   8071040 . PMID   33919988.
  6. ↑ Abboud A, Masrouha K, Saliba M, Haidar R, Saab R, Khoury N, et al. (May 2021). "Extraskeletal Ewing sarcoma: Diagnosis, management and prognosis". Oncology Letters. 21 (5): 354. doi:10.3892/ol.2021.12615. PMC   7967932 . PMID   33747211.
  7. ↑ Galyfos G, Karantzikos GA, Kavouras N, Sianou A, Palogos K, Filis K (February 2016). "Extraosseous Ewing Sarcoma: Diagnosis, Prognosis and Optimal Management". The Indian Journal of Surgery. 78 (1): 49–53. doi:10.1007/s12262-015-1399-0. PMC   4848231 . PMID   27186040.
  8. ↑ Bosman FT (2018-07-27). "Book review—Rosai and Ackerman's surgical pathology-2 volume set, 11th edition". Virchows Archiv. 473 (3): 389–390. doi:10.1007/s00428-018-2421-2. ISSN   0945-6317. S2CID   51726143.
  9. 1 2 Patel D, Nandu NS, Reddy A (April 2020). "Extraosseus[sic] Ewing's Sarcoma in Pancreas: A Review". Cureus. 12 (4): e7505. doi: 10.7759/cureus.7505 . PMC   7195206 . PMID   32373408.

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