Ewing Sarcoma

 Ewing sarcoma (ES) and primitive peripheral neuroectodermal tumor (PNET) were originally described in the early 1900s as distinct clinicopathologic entities. It become evident that these entities are actually part of a spectrum of neoplastic diseases known as the Ewing sarcoma family of tumors (EFT), which also includes extraosseous ES (EES), adult neuroblastoma, malignant small-cell tumor of the thoracopulmonary region (Askin's tumor), paravertebral small-cell tumor, and atypical ES. 




Because of their similar histologic and immunohistochemical characteristics and shared nonrandom chromosomal translocations, these tumors are considered to be derived from a common cell of origin. Although the histogenetic origin has been debated over the years, evidence from immunohistochemical, cytogenetic, and molecular genetic studies supports a neuroectodermal origin for all EFT


The EFT can develop in almost any bone or soft tissue, but is most common in the flat and long flat bones; patients typically present with localized pain and swelling. Although overt metastatic disease is found in fewer than 25 percent at the time of diagnosis, subclinical metastatic disease is assumed to be present in nearly all patients because of the 80 to 90 percent relapse rate in patients undergoing local therapy alone. As a result, systemic chemotherapy has evolved as an important component of treatment


Advances in multidisciplinary management of EFT over the past 30 years have resulted in a marked improvement in survival and a greater likelihood of limb-sparing surgery rather than amputation
In data derived from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute, five year survival rates for patients with ES rose from 36 to 56 percent during the periods 1975 to 1984 and 1985 to 1994  .


With modern multidisciplinary treatment, long-term survival can be achieved in 70 to 80 percent of patients presenting with nonmetastatic disease


Clinical Presentation:


Primary sites — ES most often arises in the long bones of the extremities (predominantly the femur, but also the tibia, fibula and humerus), and the bones of the pelvis. The spine, hands, and feet are affected considerably less often  . 


Within the axial skeleton, tumors arose from the pelvis, chest wall, spine/paravertebral region, or head and neck in 45, 34, 12, and 9 percent of cases, respectively. Compared to undifferentiated ES of bone, PNET and EES more often arise within the axial rather than the appendicular skeleton




Approximately 25 percent of patients have a soft tissue primary.


Signs and Symptoms :


Patients with EFT typically present with localized pain or swelling of a few weeks or months duration
Trauma, often minor, may be the initiating event that calls attention to the lesion. The pain may be mild at first, but intensifies fairly rapidly; it may be aggravated by exercise, and is often worse at night. A distinct soft tissue mass can sometimes be appreciated. When present, it is usually firmly attached to the bone and moderately to markedly tender to palpation  . Swelling of the affected limb with erythema over the mass is not uncommon.
Patients with juxta-articular lesions may present with loss of joint motion, while lesions involving the ribs can be associated with direct pleural extension and large extraosseous masses .
When the spine or sacrum are involved, nerve root irritation or compression can result in back pain, radiculopathy, or symptoms of spinal cord compression (eg, weakness or loss of bowel and/or bladder control).
Constitutional symptoms or signs, such as fever, fatigue, weight loss, or anemia, are present in about 10 to 20 percent of patients at presentation  . Fever is related to cytokines produced by the tumor cells, and along with other systemic symptoms, is associated with advanced disease.
Approximately 80 percent of patients present with clinically localized disease, although as noted previously, subclinical metastatic disease is presumed to be present in nearly all. Overt metastases may become evident within weeks to months in the absence of effective therapy. The significance of this lies in the frequent delay between the onset of symptoms and diagnosis, which in one report averaged over nine months .
Patients with primary pelvic tumors are significantly more likely to present with metastatic disease compared to other sites .Other factors associated with clinically evident metastatic disease at presentation include high level of lactic dehydrogenase (LDH), the presence of fever, an interval between onset of symptoms and diagnosis less than three months, and age older than 12 years


Sites of metastatic disease at diagnosis are similar to those seen with recurrent disease; lung and bone metastases predominate, in roughly equal proportions. The spine is the most frequently involved bone.
Lung metastases represent the first site of distant spread in 70 to 80 percent of cases, and are the leading cause of death for patients with EFT. 
Lymph node, liver, and brain involvement are distinctly uncommon.


Radiographic Studies :


The diagnostic work-up is usually initiated with a plain radiograph of the affected area. ES involving bone typically presents as a poorly marginated destructive lesion, most often associated with a soft tissue mass. The tumors tend to be large, and in long bones are metaphyseal or diaphyseal in location.
The radiographic appearance has been described as "permeative" or "moth-eaten", indicative of a series of finely destructive lesions that become confluent over time. The cortex at the site of the lesion is often expanded, and the periosteum displaced by the underlying tumor, resulting in the clinical sign of Codman's triangle. The characteristic periosteal reaction produces layers of reactive bone, deposited in an "onion peel" appearance.

The soft tissue component of the tumor rarely shows any calcification or ossification. Sclerosis, if present, represents a secondary bone reaction rather than the primary bone formation that characterizes osteosarcoma. A pathologic fracture is present at diagnosis in 10 to 15 percent of cases.


Compared to plain radiographs, a CT scan of the primary site better delineates the extent of cortical destruction and soft tissue disease
However, definition of tumor size, local intraosseous and extraosseous extent, and the relationship of the tumor to fascial planes, vessels, nerves, and organs is best achieved by magnetic resonance imaging (MRI)
Imaging of the entire involved bone is necessary to exclude the presence of skip lesions (ie, medullary disease within the same bone, but not in direct contiguity with the primary lesion)


Prognostic Factors :


--Disease Extent: Presence or absence of metastases,patients with bones and lungs metastases fared worse than patients with bone metastases alone
--Tumor site and size : For patients presenting with localized disease, those with axial primary tumors (ie, pelvis, rib, spine, scapula, skull, clavicle, sternum) have a worse treatment outcome than those with extremity lesions
--Response to therapy: Patients with apparently localized disease have only a 10 to 20 percent likelihood of cure if treated with surgery or radiotherapy alone; this is improved dramatically when chemotherapy is added to treatment.Both the completeness of surgical resection and the response to induction therapy are important prognostic factors. Patients who are left with significant amounts of viable tumor in the resected specimen following neoadjuvant chemotherapy do worse than those with minimal or no residual tumor.
--Histology:In most but not all studies, neither the presence of neural differentiation (eg, as in PNETs) nor extraosseous origin has a significant adverse influence on outcome
--Age: contraversy about age as prognostic factor, the five-year relapse-free survival was significantly better for children younger than 10 compared to older children
--Molecular findings:deletion of the short arm of chromosome 1p, homozygous deletions of CDKN2A and p16/p14ARF, and p53 mutations have all been associated with poor response to chemotherapy and a worse prognosis


Treatment:


 Systemic chemotherapy is the mainstay of therapy ,often being used before surgery .Doxorubicin ,cyclophosphamide or ifosfamide,etoposide ,vincristine and dactinomycin are active drugs .Local treatment for the primary tumor includes surgical resection ,usually with limb salvage or radiation therapy .Patients with lesions below the elbow and below the mid-calf  have a 5-year survivl rate of 80% with effective treatment .Ewing sarcoma is a curable tumor even in the presesnce of obvious metastatic disease,especially in children<11 years old. 








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Harrison's Internal Medicine 2008