Ewing sarcoma
Encyclopedia
Ewing sarcoma is a malignant round-cell tumour. It is a rare disease in which cancer
cells are found in the bone
or in soft tissue
. The most common areas in which it occurs are the pelvis
, the femur
, the humerus
, the ribs and clavicle.
Because a common genetic locus is responsible for a large percentage of Ewing sarcoma and primitive neuroectodermal tumor
s, these are sometimes grouped together in a category known as the Ewing family of tumors
. The diseases are, however, considered to be different: peripheral primitive neuroectodermal tumours are generally not associated with bones, while Ewing sarcomas are most commonly related to bone.
Ewing sarcoma occurs most frequently in male teenagers, with a male/female ratio of 1.6:1.
Although usually classified as a bone tumour, Ewing sarcoma can have characteristics of both mesoderm
al and ectoderm
al origin, making it difficult to classify.
James Ewing (1866–1943) first described the tumour, establishing that the disease was separate from lymphoma
and other types of cancer known at that time.
gene of chromosome 11.
EWS/FLI functions as the master regulator.
Other translocations are at t(21;22) and t(7;22).
the most common symptoms reported are:
Localised pain: bone pain; may come and go and vary in its intensity.
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.
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. Patients usually experience extreme bone pain.
It is positive for CD99
and negative for CD45
.
On conventional radiographs
, the most common osseous presentation is a permeative lytic lesion with periosteal
reaction. The classic description of lamellated or "onion skin" type periosteal
reaction is often associated with this lesion. 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.
MRI
should be routinely used in the work-up of malignant tumours. MRI will show the full bony and soft tissue extent and relate the tumour 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 tumour, thus help in determining response to treatment prior to surgery.
CT can also be used to define the extraosseous extent of the tumour, 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 tumour response to therapy.
In the group of malignant small round cell tumours which include Ewing's sarcoma, bone lymphoma and small cell osteosarcoma, the cortex may appear almost normal radiographically, while there is permeative growth throughout the Haversian channels.
These tumours may be accompanied by a large soft tissue mass while there is almost no visible bone destruction.
The radiographs frequently do not shown any signs of cortical destruction.
Radiographically Ewing's Sarcoma presents as "Moth-eaten" destructive radiolucencies of the medulla and erosion of the cortex with expansion.
, 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.
and molecular pathology
.
Ewing sarcoma is a small round cell tumor, that typically has a clear cytoplasm on H&E stain
ing, 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
. Morphologic and immunohistochemical findings are corroborated with an associated chromosomal translocation
, of which there are several. The most common translocation, present in approximately 90% of Ewing sarcoma cases, is t(11;22)(q24;q12).
The pathologic differential diagnosis is the grouping of Small, round, blue cell tumours, which includes lymphoma
, alveolar rhabdomyosarcoma
and desmoplastic small round cell tumor
, among others.
Due to the prevalence of diagnosis during teenage years, there may possibly be a link between the onset of puberty and the early stages of this disease, although no research is currently being conducted to confirm this hypothesis.
(often including ifosfamide
and etoposide
) as well as local disease control with surgery and/or radiation is indicated in the treatment of all patients.
Treatment often consists of neo-adjuvant chemotherapy
generally followed by a limb salvage or an amputation
and may also include radiotherapy. Complete excision at the time of biopsy may be performed if malignancy is confirmed at the time it is examined. Treatment lengths vary depending on location and stage of the disease at diagnosis. Radical chemotherapy may be as short as 6 treatments at 3 week cycles, however most patients will undergo chemotherapy for 6–12 months and radiation therapy for 5–8 weeks.
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. 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 Ewing sarcoma xenografts in vivo mouse models.
. To avail for future pregnancies, the woman may preserve oocytes or ovarian tissue by oocyte cryopreservation
or ovarian tissue cryopreservation
prior to starting chemotherapy. However, the latter may reseed the cancer upon reinsertion of the ovarian tissue. If it is performed, the ovarian tissue should be examined for traces of malignancy at both the pathological and molecular levels prior to the grafting of the cryopreserved tissue.
occur in the chest, bone and/or bone marrow. Less common sites include the central nervous system
and lymph node
s.
Five-year survival for localized disease is 70% to 80% when treated with chemotherapy
. Long term survival for metastatic disease can be less than 10% but some sources state it is 25-30%.
funds research and provides information on Ewing sarcoma and other bone cancers. This includes information for teenagers who have this condition.
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
cells are found in the bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
or in soft tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
. The most common areas in which it occurs are the pelvis
Pelvis
In human anatomy, the pelvis is the lower part of the trunk, between the abdomen and the lower limbs .The pelvis includes several structures:...
, the femur
Femur
The femur , or thigh bone, is the most proximal bone of the leg in tetrapod vertebrates capable of walking or jumping, such as most land mammals, birds, many reptiles such as lizards, and amphibians such as frogs. In vertebrates with four legs such as dogs and horses, the femur is found only in...
, the humerus
Humerus
The humerus is a long bone in the arm or forelimb that runs from the shoulder to the elbow....
, the ribs and clavicle.
Because a common genetic locus is responsible for a large percentage of Ewing sarcoma and primitive neuroectodermal tumor
Primitive neuroectodermal tumor
Primitive neuroectodermal tumor is a neural crest tumor. It is a rare tumor, usually occurring in children and young adults under 25 years of age...
s, these are sometimes grouped together in a category known as the Ewing family of tumors
Ewing family of tumors
The Ewing family of tumors is a group of cancers that includes Ewing tumor of bone , extraosseous Ewing tumors , primitive neuroectodermal tumors , and Askin tumors . These tumors all come from the same type of stem cell...
. The diseases are, however, considered to be different: peripheral primitive neuroectodermal tumours are generally not associated with bones, while Ewing sarcomas are most commonly related to bone.
Ewing sarcoma occurs most frequently in male teenagers, with a male/female ratio of 1.6:1.
Although usually classified as a bone tumour, Ewing sarcoma can have characteristics of both mesoderm
Mesoderm
In all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and...
al and ectoderm
Ectoderm
The "ectoderm" is one of the three primary germ cell layers in the very early embryo. The other two layers are the mesoderm and endoderm , with the ectoderm as the most exterior layer...
al origin, making it difficult to classify.
James Ewing (1866–1943) first described the tumour, establishing that the disease was separate from lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
and other types of cancer known at that time.
Causes
Genetic exchange between chromosomes can cause cells to become cancerous. Ewing sarcoma is the result of a translocation between chromosomes 11 and 22, which fuses the EWS gene of chromosome 22 to the FLI1FLI1
Friend leukemia integration 1 transcription factor , also known as proto-oncogene Fli-1 or transcription factor ERGB, is a protein that in humans is encoded by the human FLI1 gene. - Function :...
gene of chromosome 11.
EWS/FLI functions as the master regulator.
Other translocations are at t(21;22) and t(7;22).
Symptoms
According to The Bone Cancer Research Trust (BCRT)The Bone Cancer Research Trust (BCRT)
The Bone Cancer Research Trust is a charity providing funding for research into primary bone cancer, raising awareness of the disease, providing patient information and support services...
the most common symptoms reported are:
Localised pain: bone pain; may come and go and vary in its intensity.
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.
Clinical findings
Ewing sarcoma is more common in males 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 pelvisPelvis
In human anatomy, the pelvis is the lower part of the trunk, between the abdomen and the lower limbs .The pelvis includes several structures:...
and proximal long tubular bones, especially around the growth plates. The diaphyses of the femur
Femur
The femur , or thigh bone, is the most proximal bone of the leg in tetrapod vertebrates capable of walking or jumping, such as most land mammals, birds, many reptiles such as lizards, and amphibians such as frogs. In vertebrates with four legs such as dogs and horses, the femur is found only in...
are the most common sites, followed by the tibia
Tibia
The tibia , shinbone, or shankbone is the larger and stronger of the two bones in the leg below the knee in vertebrates , and connects the knee with the ankle bones....
and the humerus
Humerus
The humerus is a long bone in the arm or forelimb that runs from the shoulder to the elbow....
. Thirty percent are overtly metastatic
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
at presentation. Patients usually experience extreme bone pain.
It is positive for CD99
CD99
CD99 antigen also known as MIC2 or single-chain type-1 glycoprotein is a protein that in humans is encoded by the CD99 gene. The protein has a mass of 32 kD...
and negative for CD45
CD45
Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene. PTPRC is also known as CD45 antigen , which was originally called leukocyte common antigen.- Function :The protein encoded by this gene is a member of the protein tyrosine...
.
Imaging findings
Radiography
Radiography is the use of X-rays to view a non-uniformly composed material such as the human body. By using the physical properties of the ray an image can be developed which displays areas of different density and composition....
, the most common osseous presentation is a permeative lytic lesion with periosteal
Periosteum
Periosteum is a membrane that lines the outer surface of all bones, except at the joints of long bones. Endosteum lines the inner surface of all bones....
reaction. The classic description of lamellated or "onion skin" type periosteal
Periosteum
Periosteum is a membrane that lines the outer surface of all bones, except at the joints of long bones. Endosteum lines the inner surface of all bones....
reaction is often associated with this lesion. 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.
MRI
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
should be routinely used in the work-up of malignant tumours. MRI will show the full bony and soft tissue extent and relate the tumour to other nearby anatomic structures (e.g. vessels). Gadolinium
Gadolinium
Gadolinium is a chemical element with the symbol Gd and atomic number 64. It is a silvery-white, malleable and ductile rare-earth metal. It is found in nature only in combined form. Gadolinium was first detected spectroscopically in 1880 by de Marignac who separated its oxide and is credited with...
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 tumour, thus help in determining response to treatment prior to surgery.
CT can also be used to define the extraosseous extent of the tumour, especially in the skull, spine, ribs and pelvis. Both CT and MRI can be used to follow response to radiation and/or chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
.
Bone scintigraphy
Scintigraphy
Scintigraphy is a form of diagnostic test used in nuclear medicine, wherein radioisotopes are taken internally, and the emitted radiation is captured by external detectors to form two-dimensional images...
can also be used to follow tumour response to therapy.
In the group of malignant small round cell tumours which include Ewing's sarcoma, bone lymphoma and small cell osteosarcoma, the cortex may appear almost normal radiographically, while there is permeative growth throughout the Haversian channels.
These tumours may be accompanied by a large soft tissue mass while there is almost no visible bone destruction.
The radiographs frequently do not shown any signs of cortical destruction.
Radiographically Ewing's Sarcoma presents as "Moth-eaten" destructive radiolucencies of the medulla and erosion of the cortex with expansion.
Clinical differential diagnosis
Other entities that may have a similar clinical presentation include osteomyelitisOsteomyelitis
Osteomyelitis simply means an infection of the bone or bone marrow...
, osteosarcoma
Osteosarcoma
Osteosarcoma is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid...
(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.
Diagnosis
The definitive diagnosis is based on histomorphologic findings, immunohistochemistryImmunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
and molecular pathology
Molecular pathology
Molecular pathology is an emerging discipline within pathology which is focused in the study and diagnosis of disease through the examination of molecules within organs, tissues or bodily fluids....
.
Ewing sarcoma is a small round cell tumor, that typically has a clear cytoplasm on H&E stain
H&E stain
H&E stain, HE stain or hematoxylin and eosin stain is a popular staining method in histology. It is the most widely used stain in medical diagnosis; for example when a pathologist looks at a biopsy of a suspected cancer, the histological section is likely to be stained with H&E and termed H&E...
ing, due to glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
. The presence of the glycogen can be demonstrated with positive PAS staining and negative PAS diastase
PAS diastase
PAS diastase is a histological stain often used by pathologists as an ancillary study in making a diagnosis on paraffin-embedded tissue samples. Diastase is an enzyme that breaks down glycogen and PAS is a stain that typically gives a magenta color in the presence of glycogen. When the two are used...
staining. The characteristic immunostain is CD99
CD99
CD99 antigen also known as MIC2 or single-chain type-1 glycoprotein is a protein that in humans is encoded by the CD99 gene. The protein has a mass of 32 kD...
which diffusely marks the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. Morphologic and immunohistochemical findings are corroborated with an associated chromosomal translocation
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
, of which there are several. The most common translocation, present in approximately 90% of Ewing sarcoma cases, is t(11;22)(q24;q12).
The pathologic differential diagnosis is the grouping of Small, round, blue cell tumours, which includes lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
, alveolar rhabdomyosarcoma
Rhabdomyosarcoma
A rhabdomyosarcoma is a type of cancer, specifically a sarcoma , in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location...
and desmoplastic small round cell tumor
Desmoplastic small round cell tumor
Desmoplastic small-round-cell tumor is classified as a soft tissue sarcoma. It is an aggressive and rare tumor 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...
, among others.
Epidemiology
The frequency in the United States depends on the patient's age, with a rate of 0.3 case per 1,000,000 children in those younger than 3 years of age to as high as 4.6 cases per 1,000,000 in adolescents aged 15–19 years. Internationally the annual incidence rate averages less than 2 cases per 1,000,000 children. In the United Kingdom an average of six children per year are diagnosed, mainly males in early stages of puberty.Due to the prevalence of diagnosis during teenage years, there may possibly be a link between the onset of puberty and the early stages of this disease, although no research is currently being conducted to confirm this hypothesis.
Treatment
Because almost all patients with apparently localized disease at diagnosis have occult metastatic disease, multidrug chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
(often including ifosfamide
Ifosfamide
Ifosfamide is a nitrogen mustard alkylating agent used in the treatment of cancer.It is sometimes abbreviated "IFO".-Uses:It is given as a treatment for a variety of cancers, including:...
and etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
) as well as local disease control with surgery and/or radiation is indicated in the treatment of all patients.
Treatment often consists of neo-adjuvant chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
generally followed by a limb salvage or an amputation
Amputation
Amputation is the removal of a body extremity by trauma, prolonged constriction, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventative surgery for...
and may also include radiotherapy. Complete excision at the time of biopsy may be performed if malignancy is confirmed at the time it is examined. Treatment lengths vary depending on location and stage of the disease at diagnosis. Radical chemotherapy may be as short as 6 treatments at 3 week cycles, however most patients will undergo chemotherapy for 6–12 months and radiation therapy for 5–8 weeks.
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. 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 Ewing sarcoma xenografts in vivo mouse models.
Fertility preservation
In women, chemotherapy may damage the ovaries and cause infertilityInfertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
. To avail for future pregnancies, the woman may preserve oocytes or ovarian tissue by oocyte cryopreservation
Oocyte cryopreservation
Human oocyte cryopreservation is a novel technology in which a woman’s eggs are extracted, frozen and stored. Later, when she is ready to become pregnant, the eggs can be thawed, fertilized, and transferred to the uterus as embryos.-History:Cryopreservation itself has always played a central role...
or ovarian tissue cryopreservation
Ovarian tissue cryopreservation
Ovarian tissue cryopreservation is cryopreservation of tissue of the ovary of a female.-Indications:Cryopreservation of ovarian tissue is of interest to women who want fertility preservation beyond the natural limit, or whose reproductive potential is threatened by cancer therapy, for example in...
prior to starting chemotherapy. However, the latter may reseed the cancer upon reinsertion of the ovarian tissue. If it is performed, the ovarian tissue should be examined for traces of malignancy at both the pathological and molecular levels prior to the grafting of the cryopreserved tissue.
Prognosis
Staging attempts to distinguish patients with localized from those with metastatic disease. Most commonly, metastasesMetastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
occur in the chest, bone and/or bone marrow. Less common sites include the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s.
Five-year survival for localized disease is 70% to 80% when treated with chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. Long term survival for metastatic disease can be less than 10% but some sources state it is 25-30%.
Research, Information and Support
In the UK and Ireland The Bone Cancer Research Trust (BCRT)The Bone Cancer Research Trust (BCRT)
The Bone Cancer Research Trust is a charity providing funding for research into primary bone cancer, raising awareness of the disease, providing patient information and support services...
funds research and provides information on Ewing sarcoma and other bone cancers. This includes information for teenagers who have this condition.
External links
- Cancer.Net: Ewing Family of Tumors, Childhood
- Ewing family of tumors entry in the public domain NCI Dictionary of Cancer Terms