By Nita Sharma Das, PhD, ND
The accurate diagnosis of Ewing's Sarcoma (ES) is essential for early therapeutic intervention. There is no specific hematological or urine analysis that can indicate ES, which makes the diagnosis a clinical challenge. There are certain non-specific inflammatory clinical signs which are common to both ES and osteomyelitis.
Biochemical reports show the existence of anemia, leukocytosis, and an elevated erythrocyte sedimentation rate and lactate dehydrogenase levels in blood, but these are nonspecific. Differential diagnostic tests are therefore necessary to detect ES. The diagnostic pathway described here is important in making an early diagnosis of the condition.
Children are most vulnerable to ES. However, it is uncommon in children below 5 years of age. A thorough physical examination may indicate a bone disorder, but in the majority of cases, it fails to provide any definite result because ES shares similar physical findings with other bone-related disorders.
Some findings may be:
- Tendinitis along with pelvic girdle inflammation in growing children and adolescents, suggesting ES or osteomyelitis
- Similar to patients with septicemia, patients with ES may complain of bone pain, malaise, and fever
- The symptoms of anorexia, and unexplained weight loss are present in children under 5 years of age with ES or disseminated neuroblastoma
Therefore, finding a suspected bony lesion on physical examination requires further specific diagnostic tests to diagnose ES.
The type of tumor is confirmed by biopsy. Core biopsy methods are preferable to provide a histological diagnosis of the tumor cell. In case repeated core biopsy attempts fail to provide a definite result, an open biopsy is done. The most commonly used method for tumor biopsy, namely, fine needle aspiration method (FNAC), is usually not applicable to Ewing's Sarcoma, because the sample is insufficient for adequate histological examination and molecular analysis.
The microscopic examination of tumor cells shows the presence of sheets of tiny round cells, with round nuclei showing finely discrete chromatin and small nucleoli. The clear or pale cytoplasm is scanty with unclear edges. The ultramicroscopic examination of the tumor cells reveals that the organelles are dispersed into an aggregated cytoplasmic glycogen. In ES, cytoplasmic glycogen is usually present as periodic acid-Schiff-positive diastase-digestible granules.
CD99 is a cell surface glycoprotein which presents with “chain-mail” pattern of staining of the cell membrane in over 90% of ES cases. It is a product of the MIC2 gene and is considered as a crucial biomarker for ES. Immunohistochemical biomarkers such as S-100 protein and PGP 9.5 are detected in some cases, indicating neural differentiation. Positivity for vimentin is also common in ES. However, this biomarker is also present in synovial sarcoma, lymphoma, lymphoblastic leukemia and other tumors. Other variants like large spindle-shaped cells and adamantinoma-like cells are characteristically present in ES.
The standard radiological finding of Ewing's Sarcoma involves a diffuse infiltration with destruction of the affected bone. This lesion often has an outer covering composed of onion skin-like membrane, and spiculae, indicating the occurrence of periosteal reaction to the bone destruction. The pelvic bone is one of the most common sites for tumor formation but it may be difficult to detect such tumors with plain radiography.
Computed tomography (CT) scan and MRI are usually recommended for detecting soft tissue affected by ES, bone destruction and lung metastases.
Other imaging diagnostic technology, such as bone scan is also preferred to detect ES. A high 99mTc-MDP uptake indicates ES.
Gene analysis is one of the most advanced molecular techniques used to diagnose ES. Specific chromosomal translocations present in ES are detected using molecular genetic testing techniques. Reverse transcriptase polymerase chain reactions (rt-PCR) and fluorescent based in situ hybridization (FISH) assays are the two techniques that are used to detect fusion genes.
Among different probable chromosomal translocations, the most common is the EWS-FLI1 fusion gene which is formed by the t(11;22)(q24;q12) translocation. In ES, 85% of tumors that exhibited a rearrangement of the EWS gene showed this type. However, several other fusion genes are also known to occur.