by Madison Weg
The 2017-2018 Rein in Sarcoma Scholars are each writing a detailed article about a particular sarcoma cancer sub-type. Madison grew up in Worthington, MN and attended college at the University of Minnesota, Twin Cities. She was first exposed to the world of cancer as a student volunteer during her time as an undergraduate and then worked as a research assistant for a year after graduating, looking into osteosarcoma and various other cancers. Madison attends the University of Minnesota Medical School and is applying for residency in internal medicine with plans to specialize in hematology/oncology.
Ewing sarcoma is a rare malignancy that most often presents as an undifferentiated primary bone tumor; less commonly it arises in soft tissue (extraosseous Ewing sarcoma). Both are part of a spectrum of neoplastic diseases known as the ESFT because of their similar histologic, cytogenetic and immunohistochemical characteristics. This family of tumors includes primitive neuroectodermal tumor (PNET), malignant small-cell tumors of the thoracopulmonary region (Askin tumor), desmoplastic small round cell tumors, CIC-DUX4 and BCOR-CCNB3 fusion sarcomas and atypical ES.
Ewing sarcoma is the second most common primary bone cancer. Nonetheless, it is an infrequent cancer, with 225 cases diagnosed per year in patients less than 20 years old in North America. The incidence is 0.3 cases per 100,000 people per year in Caucasians. They are most common in children age 10-20 years, with 20-30% of cases being diagnosed before age 10. However, 30 percent of cases arise in children under the age of 10, and another 30 percent are in adults over the age of 20. They are more common in Caucasians than in Asian or African American patients. The male to female ratio is 1.5:1.
Histology describes the morphologic appearance of the tumor cells under the microscope. Most cases of ESFT are composed of uniform small round cells with round nuclei containing fine chromatin, scanty clear or eosinophilic cytoplasm, and indistinct cytoplasmic membranes, whereas in others the tumor cells are larger, have prominent nucleoli, and irregular contours.
In addition to the morphology of the cells, there are also special immunostains that pathologists use to definitively diagnose ESFT.
- CD99 is expressed in almost all cases in a characteristic membranous fashion
- Vimentin stains most tumor cells
- Neural markers such as neuron specific enolase (NSE), are frequently expressed
- ES/PNET has been shown to stain with keratin in some cases
Ewing sarcomas are characterized by specific non-random translocations, which are the main drivers of the cancer.
- 85% of cases due to translocation between chromosomes 22 and 11, t(11;22)(q24;q12)
- 10% of cases due to translocation between chromosome 22 and 21
- Rare causes (<1% of cases each) are translocations between chromosome 22 and 7, 17 or 2
The ESFT most often arise in the long bones of the extremities (predominantly the femur but also the tibia, fibula and humerus) and bones of the pelvis. The spine, hands and feet are affected considerably less often.
- Axial skeleton: 54% (pelvis 25%, ribs 12%, spine 8%, scapula 3.8%, skull 3.8%, clavicle 1.2%)
- Appendicular skeleton: 42% (femur 16.4%, fibula 6.7%, tibia 7.6%, humerus 4.8%, foot 2.4%, radius 1.9%, hand 1.2%)
- Often arises from the diaphysis rather than metaphysis
- Other bones: 0.7%
A minority of Ewing sarcomas arise in soft tissue. Compared to those that arise in the bone, patients with extraosseous ES are more frequently older, more likely to be female and arise more often within bones of the trunk versus the extremities.
Signs and Symptoms
Patients typically present with localized pain or swelling of a few weeks or months duration. Often minor trauma may be the initiating event that calls attention to the lesion. The pain may begin as mild but intensify rapidly. It is often worse at night and may be aggravated by exercise. A distinct soft tissue mass may or may not be appreciated. When present, it is usually firmly attached to the bone and moderately to markedly tender to palpation. The affected limb may also be may also be swollen and red. Constitutional symptoms (fever, fatigue, weight loss or anemia) are present in approximately 10 – 20% of patients.
Approximately 80% of patients present with clinically localized disease, however, subclinical metastatic disease is presumed to be present in nearly all patients. Overt metastases may become evident within weeks to months of the absence of effective therapy. This becomes significant when considering the all too frequent delay between onset of symptoms and correct diagnosis, which can be over nine months.
Patients with primary pelvic tumors are significantly more likely to present with metastatic disease compared to other sites (25% vs. 16%). Other factors that may be associated with clinically evident metastatic disease at presentation include:
- High LDH
- Interval between onset of symptoms and diagnosis <3 months
- Age > 12 years
Sites of metastatic disease at diagnosis are similar to those seen with recurrent disease, with lung and bone/bone marrow metastases being most common. The spine is the most frequently involved bone. Lung metastases are the first site of distant spread in 70-80% of cases and are the leading cause of death for patients with ESFT. Lymph node, liver and brain involvement have been reported, but are uncommon.
The goals of the initial evaluation are to establish the diagnosis, evaluate local disease extent and determine the presence and sites of metastases. This is done using the results of physical exam, imaging, laboratory tests, and tissue biopsy prior to the initiation of definitive therapy.
- The diagnostic work-up usually starts with an x-ray of the affected area. Ewing sarcoma (ES) involving bones has a characteristic appearance that your oncologist and radiologist will be looking for.
- Compute Tomography (CT)
- Compared with standard x-rays, a CT scan of the primary site better delineates the extent of cortical destruction and soft tissue disease.
- Once the diagnosis of ESFT is established a chest CT will usually be done to evaluate the lungs and surrounding tissues for metastatic disease.
- Preferred in most cases over CT for initial imaging because of its superior definition of tumor size, local intraosseous and extraosseous extent, and the relationship of the tumor to fascial planes, vessels, nerves, and other organs.
- Bone scan
- While not usually part of the original diagnostic work-up, once the diagnosis of EFT is confirmed a bone scan is recommended as part of the metastatic work-up.
- A radionucleotide bone scan is done to evaluate the entire skeleton for the presence of multiple lesions.
- A test to look at basic blood counts that will be helpful in diagnosis as well as providing a baseline that will be followed throughout treatment.
- A test measuring kidney function, which is helpful in guiding chemotherapy choices and dosing.
- Liver function tests (AST, bilirubin, alkaline phosphatase)
- These tests evaluate liver function and are also used to determine options for treatment with chemotherapy.
- Positron Emission Tomography (PET)/or Integrated PET-CT
- A PET scan is another way to evaluate the rest of the skeleton to detect bone metastasis, as well as other sites of disease in the body.
- PET may also be used for monitoring response to chemotherapy and/or radiation therapy and in the postoperative evaluation for possible recurrence.
- Lactate dehydrogenase (LDH)
- A known prognostic factor for patients with ESFT. See below.
- Tumor biopsy
- In order to confirm the diagnosis, further work up and cancer staging, a sample from the tumor is required.
- This will be done by a specialized surgeon or interventional radiologist who can carefully plan the procedure to obtain adequate tissue without compromising a later operation.
- This biopsy will be done after the completion of imaging studies of the primary site.
- With the tissue obtained, the pathologist will play a critical role in establishing the diagnosis as they are able to identify microscopic features and lab markers (immunostains) that are characteristic of ESFT (mentioned above).
- Bone marrow biopsy
- Because of the predilection of ESFT for spread to the bone marrow, the oncologist may recommend a bone marrow biopsy to exclude bone marrow involvement.
Treatment will be overseen by an oncologist who will work with many other health care providers that are experts in ESFT to determine the best treatment plan. These specialists may include a pediatrician, surgical oncologist, orthopedic oncologist and/or radiation oncologist.
Although overt metastatic disease is found in less than 25% at the time of diagnosis, subclinical metastatic disease is presumed to be present in nearly all patients because of the 80-90% relapse rate in patients undergoing local therapy alone. As a result, systemic chemotherapy has evolved as an important component of treatment. Local treatment can be achieved by surgery, radiation or both.
Chemotherapy uses powerful drugs given through an indwelling central venous catheter to kill or stop the sarcoma cells from growing. The goal is that this will successfully eradicate the microscopic areas of metastatic disease along with shrinking the primary tumor prior to definitive local therapy. Virtually all current regimens employ three to six cycles of initial chemotherapy after biopsy, followed by local therapy and then another six to ten cycles of chemotherapy. The cycles are spaced apart, usually two weeks, to allow time for blood counts to rebound in between. The most commonly used agents are vincristine, cyclophosphamide, ifosfamide, etoposide and doxorubicin. The physician may also be able to enroll the patient in a clinical trial with new chemotherapies.
Local therapy is usually done after several cycles of chemotherapy have reduced the cancer to a point where surgery can be most effective. The choice of radiation therapy or surgery usually represents a tradeoff between functional result and the risk of a secondary radiation-induced malignancy. The decision is made with the help of your team of doctors giving careful consideration of the potential harm and benefits of treatment options, patient characteristics and preferences.
- The preferred option for potentially resectable lesions and for those arising in dispensable bones (e.g. fibula, rib, small lesions of the hands or feet).
- Avoids risk of secondary radiation-induced malignancies.
- In young children whose skeleton is immature, resection may be associated with less morbidity than RT.
- Limb salvage is almost always attempted, although there remain a small number of lesions for which either limb salvage surgery or irradiation would lead to an unsatisfactory orthopedic result, and in whom amputation is warranted.
- Radiation therapy (RT)
- Used to kill or decrease cancer cells that cannot be removed surgically, often followed by more chemotherapy to eradicate any remaining cells.
- Radiation therapy uses high-energy X-rays and/or other types of radiation to target the cancer cells. There are two main types:
- External radiation (External beam radiation) – Uses machines outside of the body to deliver the radiation dose.
- Internal radiation (Brachytherapy) – Uses needles, seeds, wires or catheters to deliver the radiation directly into or very close to the cancer.
Commonly used staging systems do not exist for the ESFT as they do for most other solid tumors. There are tumor, node, and metastasis (TNM) staging systems for primary tumors of both bone and soft tissue available, however they are not in widespread use for the ESFT. Instead prognosis is defined with several clinical and biologic characteristics that help to direct intensity of therapy.
- Disease extent
- The presence or absence of metastasis is the key prognostic factor for ESFT.
- Approximate five-year survival rates for patients with localized disease are 70%, while they average 33% for those who have overt metastasis at diagnosis.
- The location of metastasis also matters. Patients with bone and lung metastasis fare significantly worse than those with bone metastasis alone, who in turn, fared worse than those with isolated lung metastasis.
- Tumor site and size
- For patients with localized disease, those with axial primary tumors (e.g. pelvis, rib, spine, scapula, skull, clavicle, sternum) have a worse treatment outcome than those with extremity lesions.
- Patients with small primary tumors (<100 mL) fare better than those with larger tumors.
- Fever, anemia, and elevated serum LDH all correlate with a greater volume of disease at presentation and a poorer prognosis.
- Tumors that arise in skin or subcutaneous sites have a generally favorable prognosis.
- Response to therapy
- Both the completeness of surgical resection and the response to induction chemotherapy are important prognostic factors.
- Patients left with significant amounts of viable tumor in the resected specimen following neoadjuvant chemotherapy do worse than those with minimal or no residual tumor.
- Older age has been linked to a poorer prognosis in some studies.
The majority of recurrences occur within two years of initial diagnosis, but later relapse although uncommon, can occur. Any symptoms at the primary site or elsewhere should raise concern and prompt investigation. Sites of recurrence, prior treatment and relapse-free interval affect remaining treatment choices at that time. It is important to recognize that prognosis and long-term outlook are predicted on an individualized basis by the team of physicians.
1. Bernstein M, Kovar H, Paulussen M, et al. Ewing's sarcoma family of tumors: current management. Oncologist. 2006 May;11(5):503-19
2. Schiffman JD, Wright J. Ewing’s Sarcoma and Second Malignancies. Sarcoma. 2010; 2011: 736841.
3. Paulussen M, Bielack S, Jürgens H, Casali PG, ESMO Guidelines Working Group. Ewing's sarcoma of the bone: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009 May;20 Suppl 4:140-2
4. Rodriguez-Galindo C, Navid F, Liu T, Billups CA, Rao BN, Krasin MJ. Prognostic factors for local and distant control in Ewing sarcoma family of tumors. Annals of Oncology. 2007May;19(4):814–20.
5. Hui JY. Epidemiology and Etiology of Sarcomas. Surgical Clinics of North America. 2016;96(5):901–14.
6. Fletcher CDM, Unni KK, Mertens F, World Health Organization., International Agency for Research on Cancer. Pathology and genetics of tumours of soft tissue and bone. Lyon: IARC Press; 2002.
7. Pappo AS, Dirkesen U. Rhabdomyosarcoma, Ewing Sarcoma, and Other Round Cell Sarcomas. Journal of Clinical Oncology. 2017; 36: 168-179.