Ewing Sarcoma

Ewing Sarcoma

PKGhatak,MD

In 1921 Dr. James Ewing, Professor of Clinical Pathology at Cornell University of New York and a pioneer researcher in Memorial Hospital (now called Memorial Sloan Kettering Hospital) reported a new kind of malignant tumor of bone, named after him - Ewing tumor or Ewing sarcoma. It is a malignancy of small, round, bluish color cells with clear cytoplasm, originates in the connective tissue of bone or soft tissue close to the bone. It often arises in long bones, pelvis, ribs and shoulder blades and rarely in the skull.

Incidence:

Ewing Sarcoma (ES) is a rare cancer. About 2 cases are seen in 1 million children. It accounts for about 2 % of all childhood cancer, the second most common bone sarcoma. Most of the children with Ewing sarcoma are between 10 to 20 years of age, only 15 % are below 10 years of age. 
The incidence of ES in Caucasians is 10 to 20 times higher compared with Asian and African children.

The male Vs female ratio is 1.6 to 1. Most ES originate in bones, only about 15 % are of soft tissue origin.

Why and how ES originates:

Ewing sarcoma does not run in families. There are no known external factors like toxins, drugs, or radiation that are implicated in its origin. Only one incidence of a cluster of ES in school children was reported but no case was ascertained.

About 85 % of ES are associated with a fusion of genes, a chromosomal translocation between chromosome no.22 and Chromosome no.11, t (22,11). Fusion results in EWSR1/ FLI1 fusion gene and it functions as a master regulator of cell division, it also regulates the EGR2 gene of chromosome 10.

In very rare occasions translocation of genes between ch.21 and ch.22, t(21,22) and translocation of genes between ch.7 and ch.22, t(7,22) are seen.

The lymphocytes of Ewing sarcoma exhibit CD99 and MIC2 markers and are negative for CD45.

Chemokine Receptors CXCR4 and CXCR7 are present in tumor cells.  As the tumor grows in size these two receptors began to appear in the blood. The levels of CXCR4 and CXCR7 run parallel to the tumor mass. When patients respond to therapy these levels fall. These makers become important tools for monitoring disease and prognostic trackers. High levels are associated with poor outcomes, low levels indicate a high chance of cure with treatment.

There are three other sarcomas that behave like Ewing sarcoma and are similarly treated.

1.BCOR-CCNB2 rearrangements. These tumors originate in the pelvis, arms and legs.

2.CIC-DUX4 rearrangements. Sarcoma is seen in males 21 to 40 yrs. old, tumors located in the trunk, arms and legs.

3. CIC- NUTMI rearrangements. Sarcoma is seen in the central nervous system and trunk in younger patients.

Location of Tumor at the time of diagnosis.

In bones. In order of frequency: femur, homers, pelvis, ribs and shoulder blades.

In soft tissues – tendons at the point of attachment to bones, cartilage near growing areas, muscles, nerve tissue of ribs, retroperitoneal area, any abdominal organ or abdominal wall.

Special names of Ewing tumor- tumors originating in soft tissue in contact with bones.

1. Peripheral primitive neuroectodermal tumors ( pPNET ). These tumors originate in nerve tissue in contact with bone anywhere in the body.
2. Askin Tumor. When pPNET originates in the chest wall. 

Symptoms:

It may grow without any symptoms if deep seated, in places like the pelvis or chest wall.

If close to the skin – a visible swelling, warm to the touch. Muscle stiffness and intermittent bone pain, specially after activities. The pain is often neglected as sports injuries.

Intermittent low grade fever. Night leg pain.

Unexplained weight loss, tired feeling. Fracture of bone without an injury.

Urinary incontinence when the tumor is in the pelvis.

Diagnosis:

Physical examination may or may not detect any abnormality but

1. X-Rays of involved bone will show lytic lesions (hollowed out), with local swelling of bone and onion- skin like appearance of the periosteum (outer layer over bones).
2. Moth-eaten appearance of the pelvic bone.
3. CT scan – will show the areas involved much more clearly.
4. MRI – changes in soft tissue are easily detected.
5. Bone scan. Not usually done nowadays.
6. PET-Scan. It lights up areas of distant spread of the tumor.
7. Elevated LDH (lactic dehydrogenase) – a blood test.
8. Bone marrow biopsy. It is an essential part of an investigation. The presence of malignant cells in bone marrow means widespread metastasis.

Definitive diagnosis:

Biopsy of the tumor. There are 3 types of tissue biopsies: Needle biopsy.

Incision biopsy. A small portion of the tumor is removed for microscopic examination and immunological tests.

Excision biopsy. The entire tumor mass is removed at the time of surgery.

Other investigations:

Cytogenic analysis. The chromosomes are systematically analyzed for the presence of any abnormalities - broken chromosomes, missing genes, rearrangements of genes and extra genes.

Immunohistochemistry: Antibodies to tumor antigen bind with the tumor cells. For easier identification, the antibodies are tagged with a fluorescence dye.

Flow Cytometry: This method detects tumor cells, abnormal cells in shape, size and numbers.

Staging:

Ewing's sarcomas are not staged like malignant tumors.

They are categorized as Local, Metastatic or Recurrent tumors.

Treatment:

Chemotherapy. It is often the first treatment modality in all newly diagnosed ES because the small cells spread locally and are not easy to detect.

These are the common chemotherapeutic agents used in the treatment of ES;

Vincristine, Doxorubicin, Cyclophosphamide, Podophyllotoxin (etoposide), Ifosfamide.
Melphalan and Busulfan are older drugs are also in use.
Newer drugs are Irinotectan, Temozolamide, Mesna, Dexrazoxane

There is no one protocol for Chemotherapy. Major institutions use one protocol over another based on the results of their own clinical experience.

In a usual setting - Three of the above drugs, usually vincristine, doxorubicin and cyclophosphamide alternate with Ifosfamide and etoposide. Drugs are administered via a central vein in cycles, repeated every 2 or 3 weeks, for a period of 6 to 12 months.

The Second Phase:

If the tumor is located in a limb – amputation of the limb is done.

If the tumor has reduced to a small size – the remaining tumor with a thin layer of normal tissue is removed by an operation. A tissue graft may be required to close the resulting large wound.

After surgery, the patients generally require further therapy and are treated with chemotherapy, radiation, or a combination of both.
Surgery may not be possible in some cases because of location or due to large tumor size. ES cells are very sensitive to radiation and Proton therapy is more lethal to tumors and spares the normal surrounding tissue.

The Third Phase:

Radiation / Proton therapy.

As discussed above.

Treatment of Metastasis:

Chemotherapy.

At times a combination of Radiotherapy and Chemotherapy.

Recurrent Tumors. The tumor may reappear at the initial location or at a different location.

Often recurrence occurs at 2 years after successful initial treatment. Recurrent tumors are treated with chemotherapy and/or radiation therapy.

Prognosis:

A female child, below 10 yr. old at the time of diagnosis and with a small localized tumor has the best outlook. A cure rate of 80 % is expected. A low LDH level and low Chemokines CXCR4 and CXCR7 levels assure a good prognosis.

Recent Advances in Treatment:

Targeted therapy.

1. Monoclonal antibody. These antibodies are obtained from a single type of Immune cell. The antibodies may be combined with drugs, toxins and radioactive material. Ganitumab is a monoclonal antibody used in Metastatic ES.
2. Kinase Inhibitor Therapy. This agent blocks the protein required for cancer cell division.
   Cabozantinib is a kinase inhibitor used in Recurrent ES.
3. NEDD8-Activating Enzyme (NAE). These groups of drugs block the NEDD8 enzyme and thereby stop cell division of malignant cells. Pevonedistat is used in recurrent ES.

Immunotherapy. Also known as Biotherapy or Biologic agents:

It utilizes patients' own immune cells and increases their potency to attack malignant cells.

1. Immune Checkpoint Inhibitors.: A group of T- cells produces a protein which promotes cell deaths and is known as PD1(programmed cell deaths). Another T-cell population blocks excessive PD1 action. ES tumor cells developed a protein that acts precisely like the second T-cells. Antibodies to PD1 are available and used in this condition and are called Checkpoint inhibitors.
   
   Nivolumab and Ipilimumab are currently available for ES treatment.
2. Chimeric Antigen Receptor (CAR) T: Patients' T-cells are incubated with special cell receptors. These receptors attach to malignant cells and facilitate killing them when injected back to the patient.
   It is still in an experimental stage of development.

A new approach to treatment:

Small molecule YK-4-279 interferes with binding the FL1 gene to RNA Helical A and kills Ewing sarcoma cells in animal models.
Insulin like growth factor antibodies (IGFR 1). It is known tumor cells use Insulin for growth and cell division, when it is blocked malignant cells die.
IGFR 1 is a new small molecule that has shown promise in the animal model.
Anti-sense oligonucleotide- Genetic sequence directed against particular genes. In animal models, ES antisense oligonucleotide acts against the ES translocation gene.

Stem cell transplantation:

This treatment modality is used when the first line of treatment fails and in younger patients.  

There are 3 possible sources of stem cells.1. From the patient: Stem cells are harvested from the bone marrow of the patient. It is called Homologous stem cells or Autologous stem cell transplantation.

2. From family members or friends: The donor of stem cells must match the ABO blood group and HLA (Human Leukocyte Antigen). This process is called Heterologous stem cell transplantation.

3. Cord Blood stem cells: Properly matched stem cells are also available from special centers where cord blood is stored.

Complications of stem cell transplants.

Infection is the primary concern immediately after transplants, then rejection reactions should be watched for.

Side effects of chemotherapy.
General: Intense nausea due to the action of drugs on nausea/ vomiting center in the brain. Loss of appetite, loss of taste of food. Diarrhea, weakness and fatigue. Anemia and frequent infections.
Hair loss. Depression and anxiety. IV access site infection.
Bone marrow depression and development of Acute Myelocytic Leukemia. A second malignancy at a later date. Sarcoma at the radiation site.
Specific side effects of some agents.
Peripheral neuropathy in Vincristine, Cardiac toxicity and skin discoloration in Doxorubicin, Frequency of urination and hematuria in Etoposide. Hemorrhagic cystitis in Cyclophosphamide,

Sites of metastasis: Lungs, bone and bone marrow.
Metastasis in the lung if a single one - can be removed by surgery. Multiple metastases are often treated with chemotherapy and radiation.

Ewing Sarcoma is a childhood malignancy, mainly affecting the white population. Translocation of the gene between chromosomes no.11 and 22 results in the formation of the WESR1-FLI1 fusion gene that encodes a chimeric protein. This protein initiates the malignant transformation of connective tissue of bone and also the alteration of other genes resulting in the alteration of various cellar functions. The diagnosis of ES requires the detection of chromosomal abnormality and histochemical examination of biopsy tissue. Surgery is preferable if the tumor is located in a limb, otherwise, chemotherapy and radiation followed by surgery is the usual mode of treatment.

Stem cell transplantation, immune checkpoint inhibitors, chimeric antigen receptors are showing promise and renewed hope of a long term disease free state and even cure. Other treatment modalities like small molecule therapy and anti-sense oligonucleotide therapy are in developmental stages.

 

edited Sept.2020.

 

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