Benign Bone Tumors

Osteochondroma: Osteochondromas (osteocartilaginous exostoses), the most common benign bone tumors, may arise from any bone but tend to occur near the ends of long bones. These tumors manifest most often in people aged 10 to 20 and may be single or multiple. Multiple osteochondromas tend to run in families. Secondary malignant chondrosarcoma develops in well under 1% of patients with single osteochondromas, but in about 10% of patients with multiple osteochondromas. Patients with multiple hereditary osteochondromas have more tumors and are more likely to develop a chondrosarcoma than patients with a single osteochondroma. Osteochondromas rarely cause the bone to fracture.

On imaging studies, the lesion appears as a bony prominence with a cartilage cap (< 2 cm) off the surface of the bone with no underlying cortex under the prominence. The medullary canal is in continuity with the base of the exostosis. The medullary canal and exostosis are confluent, and there is no true underlying cortex at the base of the exostosis. Excision is needed if the tumor is compressing a large nerve; causes pain (especially when impinging on muscle and creating an inflammatory bursa); disturbs growth; or on imaging study has a destructive appearance, soft-tissue mass, or thickened cartilaginous cap (> 2 cm) suggesting transformation into malignant chondrosarcoma. An enlarging tumor in an adult should raise concern of chondrosarcoma and the possible need for excision or biopsy. Enchondroma: Enchondromas may occur at any age but tend to manifest in people aged 10 to 40. They are usually located within the medullary bone metaphyseal-diaphyseal region. These tumors are usually asymptomatic but may enlarge and become painful. They are often found when x-rays are taken for another reason.

On x-ray, the tumor may appear as a lobulated calcified area within bone; some lesions are less calcified, with areas of stippled calcification on either plain films or CT. If adjacent to the cortex, enchondromas show minor endosteal scalloping. Almost all enchondromas have increased uptake on a bone scan and thus create concern of cancer. X-ray findings, including MRI and CT, may be diagnostic; if they are not, and especially if the tumor (not the associated joint) is painful, the diagnosis should be confirmed by biopsy. To help differentiate bone pain from joint pain, the joint can be injected, usually with a long-lasting anesthetic (eg, bupivacaine); if pain persists, it may be caused

by the bone lesion. An asymptomatic enchondroma does not need biopsy, excision, or other treatment (usually curettage); however, follow-up imaging studies are indicated to rule out the rare disease progression to chondrosarcoma. These studies are done at 6 mo and again at 1 yr or whenever symptoms develop. Patients with multiple enchondromas (Ollier's disease) and especially multiple enchondromatosis with soft-tissue hemangiomas (Maffucci's syndrome) have a much higher risk of chondrosarcoma. Chondroblastoma: Chondroblastoma is rare and occurs most commonly among people aged 10 to 20. Arising in the epiphysis, this tumor may continue to grow and destroy bone and the joint. It appears on imaging studies as a sclerotic marginated cyst containing spots of punctate calcification. MRI can help diagnostically by showing characteristic changes well away from the lesion.

The tumor must be surgically removed by curettage, and the cavity must be bone grafted. Local recurrence rate is about 10 to 20%, and recurrent lesions often resolve with repeat bone curettage and bone grafting. Chondromyxofibroma: Chondromyxofibroma is very rare and usually occurs before age 30. The appearance on imaging studies, which is usually eccentric, sharply circumscribed, lytic, and located near the end of long bones, suggests the diagnosis. Treatment after biopsy is surgical excision or curettage.

Osteoid osteoma: Osteoid osteoma, which tends to affect young people (commonly aged 10 to 35), can occur in any bone but is most common among long bones. It can cause pain (usually worse at night, reflecting increased nocturnal prostaglandin-mediated inflammation). Pain is typically relieved by mild analgesics (particularly aspirin

or other NSAIDs) that target prostaglandins. In growing children, the inflammatory response and associated hyperemia, if close to the open growth plate, may cause overgrowth and limb length discrepancy. Physical examination may reveal atrophy of regional muscles because the pain causes

muscle disuse.

Characteristic appearance on imaging studies is a small radiolucent zone surrounded by a larger sclerotic zone. If a tumor is suspected, a technetium-99m bone scan should be done; an osteoid osteoma appears as an area of increased uptake. CT with fine image sequences is also done and is most helpful in distinguishing the lesion. Removal of the small radiolucent zone with percutaneous radiofrequency ablation provides permanent relief. Most osteoid osteomas are treated by an interventional musculoskeletal radiologist using percutaneous techniques and anesthesia. Less often, osteoid osteomas are surgically curetted or excised. Surgical removal may be preferred when the osteoid osteoma is near a nerve or close to the skin (eg, spine, hands, feet) because the heat produced by radiofrequency ablation may cause damage. Nonossifying fibroma (fibrous cortical defect): Nonossifying fibroma (fibrous cortical defect, fibroxanthoma) is a benign fibrous lesion of bone that appears as a well-defined lucent cortical defect on x-ray. A very small nonossifying fibroma is called a fibrous cortical defect. These lesions are developmental defects in which parts of bone that normally ossify are instead filled with fibrous tissue. They commonly affect the metaphyses, and the most commonly affected sites are, in order, the distal femur, distal tibia, and proximal tibia. They can progressively enlarge and become multiloculated. Nonossifying fibromas are common among children. Most lesions eventually ossify and undergo remodeling, often resulting in dense, sclerotic areas. However, some lesions enlarge.

Small nonossifying fibromas are asymptomatic. However, lesions that involve nearly 50% of the bone diameter tend to cause pain and increase the risk of pathologic fracture. Nonossifying fibromas are generally first noted incidentally on imaging studies (eg, after trauma). They typically are radiolucent, single, < 2 cm in diameter, and have an oblong lucent appearance with a well-defined sclerotic border in the cortex. They can also be mutiloculated. Small nonossifying fibromas require no treatment and limited follow-up. Lesions that cause pain or are close to 50% of the bone diameter may warrant curettage and bone grafting to decrease risk of a pathologic fracture through the lesion. Benign giant cell tumor of bone: Benign giant cell tumors of bone, which most commonly affect people in their 20s and 30s, occur in the epiphyses. These tumors are considered locally aggressive. They tend to continue to enlarge,

destroy bone, and may eventually erode the rest of the bone and extend into the soft tissues. They may cause pain. These tumors are notorious for their tendency to recur. Rarely, a giant cell tumor of bone may metastasize to the lung, even though it remains histologically benign.

Benign giant cell tumors of bone appear as expansile lytic lesions on imaging. On imaging studies, there is a margin without a sclerotic rim where the tumor ends and normal trabecular bone begins. Most benign giant cell tumors of bone are treated by curettage and packing with methyl methacrylate or by bone graft. To reduce recurrence rate, surgeons often prefer using an adjuvant such as thermal heat (provided by the hardening of methyl methacrylate) or treating the tumors chemically withphenol or freezing with liquid nitrogen. If a tumor is very large and destructive to the joint, complete excision with joint reconstruction may be necessary.
Last full review/revision May 2012 by Michael J. Joyce, MD Content last modified May 2012

Primary Malignant Bone Tumors

(see also Leukemias.) Multiple myeloma: Multiple myeloma is the most common primary malignant bone tumor but is often considered a marrow cell tumor within the bone rather than a bone tumor. It is of hematopoietic derivation (see also Multiple Myeloma) and occurs mostly in older adults. Tumor development and progression is usually multicentric and often involves the bone marrow so diffusely that bone marrow aspiration is diagnostic. Imaging studies usually show sharply circumscribed lytic lesions or diffuse demineralization. Rarely, the lesion can appear as sclerotic or as diffuse osteopenia, especially in a vertebral body. An isolated single myeloma lesion without systemic marrow involvement is called a plasmacytoma. Certain bony lesions respond quite well to radiation therapy.

Osteosarcoma:

Osteosarcoma (osteogenic sarcoma) is the 2nd most common primary bone tumor and is highly malignant. It is most common among people aged 10 to 25, although it can occur at any age. Osteosarcoma produces malignant osteoid (immature bone) from tumor bone cells. Osteosarcoma usually develops around the knee (distal femur more often than proximal tibia) or in other long bones, particularly the metaphyseal-diaphyseal area, and may metastasize, usually to lung or other bone. Pain and swelling are the usual symptoms.

Findings on imaging studies vary and may include sclerotic or lytic features. Diagnosis requires biopsy. Patients need a chest x-ray and CT to detect lung metastases and a bone scan to detect bone metastases. Treatment is a combination of chemotherapy and surgery. Use of adjuvant chemotherapy increases survival from < 20% to > 65% at 5 yr. Chemotherapy usually begins before any surgery. Decreased tumor size on x-ray, decreased pain level, and decreased serum alkaline phosphatase indicate some response, but the desired response is for > 95% tumor necrosis on mapping of the resected specimen. After several courses of chemotherapy (over several months), limb-sparing surgery and limb reconstruction can proceed. In limbsparing surgery, the tumor is resected en bloc, including all surrounding reactive tissue and a rim of surrounding normal tissue; to avoid microscopic spillage of tumor cells, the tumor is not violated. More than 85% of patients can be treated with limb-sparing surgery without decreasing the long-term survival rate. Continuation of chemotherapy after surgery is usually necessary. If there is nearly complete tumor necrosis (about 95%) from preoperative chemotherapy, 5-yr survival rate is > 90%. Variants of conventional osteosarcoma that occur much less frequently include surface cortical lesions, such as parosteal osteosarcoma and periosteal osteosarcoma. Parosteal osteosarcomas most often involve the posterior cortex of the distal femur and usually are fairly well differentiated. Periosteal osteosarcoma is more of a cartilage surface tumor that is malignant. It is often located on the mid-shaft femur and appears as a sunburst on x-ray. Likelihood of metastases for periosteal osteosarcomas is much greater than for welldifferentiated parosteal osteosarcomas, but somewhat less than for typical osteosarcomas. Parosteal osteosarcomas require surgical en bloc resection but no chemotherapy. Most of the time, periosteal osteosarcomas are treated similarly to conventional osteosarcomas with chemotherapy and surgical en bloc resection.

Fibrosarcoma: Fibrosarcomas have similar characteristics to osteosarcomas but produce fibrous tumor cells (rather than bone tumor cells), affect the same age group, and pose similar problems. Treatment and outcome for high-grade lesions are similar to osteosarcoma.

Malignant fibrous histiocytoma: Malignant fibrous histiocytoma is clinically similar to osteosarcoma and fibrosarcoma, although malignant fibrous histiocytomas have been classified as different from the osteosarcoma group because of a different histology (no tumor bone production). Malignant fibrous histiocytomas tend to occur in children and adolescents but can also occur in older adults as secondary lesions in bone infarcts and radiation fields. Treatment and outcome are similar to that of conventional osteosarcoma.

Chondrosarcoma: Chondrosarcomas are malignant tumors of cartilage. They differ from osteosarcomas clinically, therapeutically, and prognostically. Of chondrosarcomas, 90% are primary tumors. Chondrosarcomas arise in other preexisting conditions, particularly multiple osteochondromas and multiple enchondromatosis (eg, in Ollier's disease and Maffucci's syndrome). Chondrosarcomas tend to occur in older adults. They often develop in flat bones (eg, pelvis, scapula) but can develop in any portion of any bone and can implant in surrounding soft tissues.

X-rays often reveal punctate calcifications. Primary chondrosarcomas often also exhibit cortical bone destruction and loss of normal bone trabeculae. Secondary chondrosarcoma may be suggested by the appearance of punctate calcifications or an increase in size of an osteochondroma. Technetium-99m bone scintigraphy is a helpful screening study; all cartilaginous lesions show increased uptake on the scan, although chondrosarcomas exhibit particularly high uptake. Biopsy is required for diagnosis and can also determine the tumor's grade (probability of metastasizing). Low-grade chondrosarcomas (grade 1/2 or grade 1) are often treated

intralesionally (wide curettage) with addition of an adjuvant (often freezing liquid nitrogen, argon beam, heat of methyl methacrylate, radiofrequency, or phenol). Other tumors are treated with total surgical resection. When surgical resection with maintenance of function is impossible, amputation may be necessary. Because of the potential to implant the tumor, meticulous care must be taken to avoid spillage of tumor cells into the soft tissues during a biopsy or surgery. Recurrence is inevitable if tumor cells spill. If no spillage occurs, the cure rate depends on the tumor grade. Low-grade tumors are nearly all cured with adequate treatment. Because these tumors have limited vascularity, chemotherapy and radiation therapy have little efficacy. Ewing's sarcoma of bone: Ewing's sarcoma of bone is a round-cell bone tumor with a peak incidence between 10 yr and 25 yr. Most tumors develop in the extremities, but any bone may be involved. Ewing's sarcoma tends to be extensive, sometimes involving the entire bone shaft, most often the diaphyseal region. About 15 to 20% occur around the metaphyseal region. Pain and swelling are the most common symptoms.

Lytic destruction, particularly a permeative infiltrating pattern without clear borders, is the most common finding on imaging, but multiple layers of subperiosteal reactive new bone formation may give an onion-skin appearance. X-rays do not usually reveal the full extent of bone involvement, and a large soft-tissue mass usually surrounds the affected bone. MRI better defines disease extent, which can help guide treatment. Many other benign and malignant tumors can appear very similarly, so diagnosis is made by biopsy. At times this type of tumor may be confused with an infection. Accurate histologic diagnosis can be accomplished with molecular markers, including evaluation for a typical clonal chromosomal abnormality. Treatment includes various combinations of surgery, chemotherapy, and radiation therapy. Currently, >60% of patients with primary localized Ewing's sarcoma may be cured by this multimodal approach. Cure is sometimes possible even with metastatic disease. Chemotherapy in conjunction with surgical en bloc resection, if applicable, often yields better long-term results. Lymphoma of bone: Lymphoma of bone (previously known as reticulum cell sarcoma) affects adults, usually in their 40s and 50s. It may arise in any bone. The tumor consists of

small round cells, often with a mixture of reticulum cells, lymphoblasts, and lymphocytes. It can develop as an isolated primary bone tumor, in association with similar tumors in other tissues, or as a metastasis from known soft-tissue lymphomatous disease. Pain and swelling are the usual symptoms. Pathologic fracture is common.

Imaging studies reveal bone destruction, which may be in a mottled or patchy or even infiltrating, permeative pattern, often with a clinical and radiographic large soft-tissue mass. In advanced disease, the entire outline of the affected bone may be lost. In isolated primary bone lymphoma, the 5-yr survival rate is 50%. Combination radiation therapy and chemotherapy is as curative as amputation or other extensive ablative surgery. Stabilization of long bones is often necessary to prevent pathologic fracture. Amputation is indicated only rarely, when function is lost because of pathologic fracture or extensive soft-tissue involvement that cannot be managed otherwise. Malignant giant cell tumor: Malignant giant cell tumor, which is rare, is usually located at the extreme end of a long bone. X-ray reveals classic features of malignant destruction (predominantly lytic destruction, cortical destruction, soft-tissue extension, and pathologic fracture). A malignant giant cell tumor that develops in a previously benign giant cell tumor is characteristically radioresistant. Treatment is similar to that of osteosarcoma, but the cure rate is low.

Chordoma: Chordoma, which is rare, develops from the remnants of the primitive notochord. It tends to occur at the ends of the spinal column, usually in the middle of the sacrum or near the base of the skull. A chordoma in the sacrococcygeal region causes nearly constant pain. A chordoma in the base of the skull can cause deficits in a cranial nerve, most commonly in nerves to the eye.

Symptoms may exist for months to several years before diagnosis. A chordoma appears on imaging studies as an expansile, destructive bone lesion that may

be associated with a soft-tissue mass. Metastasis is unusual, but local recurrence is not. Chordomas in the sacrococcygeal region may be cured by radical en bloc excision. Chordomas in the base of the skull are usually inaccessible to surgery but may respond to radiation therapy.
Last full review/revision May 2012 by Michael J. Joyce, MD Content last modified May 2012

Metastatic Bone Tumors

Any cancer may metastasize to bone, but metastases from carcinomas are the most common, particularly those arising in the following areas:

Breast Lung Prostate Kidney Thyroid Colon

Prostate cancer in men and breast cancer in women are the most common types of cancers. Lung cancer is the most common cause of cancer death in both sexes. Breast cancer is the most common cancer to metastasize to bone. Any bone may be involved with metastases. Metastatic disease does not commonly spread to bone below the mid forearm or mid calf, but when it occurs in those sites, it results most often from lung or sometimes kidney cancer.

Symptoms and Signs

Metastases manifest as bone pain, although they may remain asymptomatic for some time. Bone metastases may cause symptoms before the primary tumor is suspected or may appear in patients with a known diagnosis of cancer.

Diagnosis

X-ray Radionuclide scanning to identify all metastases Clinical evaluation and testing to diagnose the primary tumor (if unknown)

Often biopsy if the primary tumor is unknown after assessment

Metastatic bone tumors are considered in all patients with unexplained bone pain, but particularly in patients who have

Known cancer Pain at more than one site Findings on imaging studies that suggest metastases

Prostate cancer is most often blastic, lung cancer is most often lytic, and breast cancer may be blastic or lytic. CT and MRI are highly sensitive for specific metastases. However, if metastases are suspected, a radionuclide whole-body scan, which is not quite as sensitive, is usually done. Bone scan is more sensitive for early and asymptomatic bone metastases than plain x-rays and can be used to scan the entire body. Lesions on the scan are usually presumed to be metastases if the patient has a known primary cancer. Metastases should be suspected in patients who have multiple lesions on bone scan. Although metastases are suspected in patients with known cancer and a single bone lesion, the lesion may not be a metastasis; thus, a needle biopsy of the lesion is often done to confirm the diagnosis of a metastasis. PET for almost whole-body scanning is now often used for some tumors; it is more specific for bone metastases than is radionuclide bone scan and can identify many extraskeletal metastases. If bone metastases are suspected because multiple lytic lesions are found, assessment for the primary tumor can begin with clinical evaluation for primary cancers (particularly focused on the breast, prostate, and thyroid), chest x-ray, mammography, and measurement of prostate-specific antigen level. Initial CT of the chest, abdomen, and pelvis may also reveal the primary tumor. However, bone biopsy, especially fine-needle or core biopsy, is necessary if metastatic tumor is suspected and the primary tumor has not been otherwise diagnosed. Biopsy with use of immunohistologic stains may give clues to the primary tumor type.

Treatment

Usually radiation therapy Surgery to stabilize bone at risk of pathologic fracture Kyphoplasty or vertebraplasty for certain painful vertebral fractures

Treatment depends on the type of tissue involved (which organ tissue type). Radiation therapy, combined with selected chemotherapeutic or hormonal drugs, is the most common treatment modality. Early use of radiation (30 Gy) and bisphosphonates (eg, zoledronate, pamidronate

) slows bone destruction. Some tumors are more likely to heal after radiation therapy; eg, blastic lesions of prostate and breast cancer are more likely to heal than lytic destructive lesions of lung cancer and renal cell carcinoma. Drugs used to treat receptor activator of nuclear factor kappa-B ligand (RANKL)

are now being used to reduce bone destruction. If bone destruction is extensive, resulting in imminent or actual pathologic fracture, surgical fixation or resection and reconstruction may be required to provide stabilization and help minimize morbidity. When the primary cancer has been removed and only a single bone metastasis remains (especially if the metastatic lesion appears 1 yr after the primary tumor), en bloc excision sometimes combined with radiation therapy, chemotherapy, or both rarely may be curative. Insertion of methyl methacrylate into the spine (kyphoplasty or vertebraplasty) relieves pain and expands and stabilizes compression fractures that do not have epidural soft-tissue extension.

Key Points

Carcinomas of breast, lung, and prostate are the most common sources of metastatic bone tumors. Bone metastases should be suspected in patients with known cancer, when pain is at more than one site, and/or when findings on imaging studies suggest metastases. Bone biopsy is needed if the primary tumor is unknown after clinical and radiographic evaluation. Most often, radiation therapy and a bisphosphonate are used to slow bone destruction. Pathologic fractures may require treatment with surgery, kyphoplasty, or vertebraplasty.
Last full review/revision May 2012 by Michael J. Joyce, MD Content last modified September 2013

Ewing's sarcoma
Ewing's sarcoma or Ewing sarcoma (/ju/) is a malignant small, round, blue cell tumour. It is a rare disease in which cancer cells are found in thebone or in soft tissue. The most common areas in which it occurs are the pelvis, the femur, the humerus, the ribs and clavicle (collar bone). Because a common genetic locus is responsible for a large percentage of Ewing's sarcoma and primitive neuroectodermal tumors, these are sometimes grouped together in a category known as the Ewing family of tumors.[1] 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's sarcoma occurs most frequently in teenagers and young adults, with a male/female ratio of 1.6:1.[2] Although usually classified as a bone tumour, Ewing's sarcoma can have characteristics of both mesodermal and ectodermal origin, making it difficult to classify.[3] James Ewing (18661943) first described the tumour, establishing that the disease was separate from lymphoma and other types of cancer known at that time.[4][5]

Causes
Genetic exchange between chromosomes can cause cells to become cancerous. Most cases of Ewing's sarcoma (85%) are the result of a translocation between chromosomes 11

and 22, which fuses the EWS gene of chromosome 22 to the FLI1 gene of chromosome 11.[6] EWS/FLI functions as the master regulator.[7] Other translocations are at t(21;22)[8] and t(7;22).[9] Ewing's sarcoma cells are positive for CD99 and MIC2,[6] and negative for CD45.[10]

Clinical findings[edit]

Distribution of Ewing's sarcoma. Most frequent locations are the large long bones and the pelvis.

Ewing's 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. Patients usually experience extreme bone pain. Signs and symptoms include: intermittent fevers, anemia, leukocytosis, increased sedimentation rate, and other symptoms of inflammatory systemic illness.[6] Also, depending on the type, progression, and location of the tumor - great pain may occur. 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.[11]

Imaging findings[edit]

X-Ray of a child with Ewing sarcoma of thetibia.

Magnetic resonance imaging slice showing Ewing's sarcoma of the left hip (white area shown right).

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 tumors. MRI 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. 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. In the group of malignant small round cell tumors 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. A grouping of three unrelated teenagers in Wake Forest NC have diagnosed with Ewing's 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.[12]

Clinical differential diagnosis

Other entities that may have a similar clinical presentation include osteomyelitis, osteosarcoma (especially telangiectatic osteosarcoma) andeosinophilic granuloma. Soft tissue neoplasms such as pleomorphic undifferentiated sarcoma (malignant fibrous histiocytoma) that erode into adjacent bone may also have a similar appearance.

Diagnosis

Micrograph of a metastatic Ewing's 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's sarcoma is a small 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. 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).[13][14] The pathologic differential diagnosis is the grouping of Small, round, blue cell tumours, which includes lymphoma, alveolar rhabdomyosarcoma anddesmoplastic small round cell tumor, among others.

Epidemiology
Ewing's sarcomas represent 16% of primary bone sarcomas.[6] Ewing's sarcoma in the United States is most common in the second decade of life,[6] 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 1519 years. Internationally, the annual incidence rate averages less than 2 cases per million children.[15] 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. The oldest known patient diagnosed was at age 76, He was from the Mercer County, New Jersey Area.

Treatment[edit]
Almost all patients require multidrug chemotherapy (often including ifosfamide and etoposide)[16] as well as local disease control with surgery and/or radiation.[17] An aggressive approach is necessary because almost all patients with apparently localized disease at the time of diagnosis actually have asymptomatic metastatic disease. Treatment often consists of neo-adjuvant chemotherapy, which may include vincristine, doxorubicin,and cyclophosphamide with ifosfamide and etoposide.[6] After about three months of chemotherapy, the remaining tumor is surgically resected, irradiated, or both.[6] 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. 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 612 months and radiation therapy for 58 weeks.[citation needed] Radiotherapy has been used for localised 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 downregulating the expression of the oncogenic fusion protein associated with the development of Ewing's sarcoma resulting from the EWS-ETS gene translocation.[18][19] 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 vitroand to delay growth of Ewing sarcoma xenografts in in vivo mouse models.[20][21]

Fertility preservation[edit]
In women, chemotherapy may damage the ovaries and cause infertility. To avail 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.[22] 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.[22]

Prognosis[edit]
Staging attempts to distinguish patients with localized from those with metastatic disease.[23] Most commonly, metastases occur in the chest, bone and/or bone marrow. Less common sites include the central nervous system and lymph nodes. Five-year survival for localized disease is 70% to 80% when treated with chemotherapy.[24] Long term survival for metastatic disease may be less than 10%. However, some sources state it is 25-30%.[25]