Ewing sarcoma represents a rare form of cancer that develops in bones or soft tissues, primarily affecting children and young adults. The study of histology involves examining tissue samples under a microscope to identify and characterize diseases. For Ewing sarcoma, this microscopic analysis of tissue is central to definitive diagnosis. It provides initial observations that guide further specialized testing to confirm this malignancy.
Classic Microscopic Appearance
Under a microscope, a pathologist observing a standard hematoxylin and eosin (H&E) stained slide of Ewing sarcoma reveals a proliferation of cells known as a “small, round, blue cell tumor.” These small cells possess large, darkly stained, round or oval nuclei that absorb the blue/purple dye from hematoxylin, giving them their “blue” appearance. The cytoplasm surrounding the nucleus is notably scant, with very little visible around each nucleus.
The arrangement of these cells is often uniform, presenting a monotonous field with little variation in cell size or shape. This uniformity can make distinguishing individual cell boundaries challenging, as they often pack closely together. A distinctive feature is the presence of glycogen within the cytoplasm of these tumor cells. This carbohydrate can be visualized using a specialized stain called Periodic acid-Schiff (PAS), which causes the glycogen deposits to appear magenta.
Sometimes, the tumor cells may organize into structures known as Homer-Wright rosettes. These are clusters of tumor cells arranged concentrically around a central, empty space, representing a tangle of neural processes. The presence of Homer-Wright rosettes suggests some degree of neuroectodermal differentiation within the tumor, reflecting its potential origin from primitive nerve tissue. While not universally present, their observation can provide a helpful clue in microscopic assessment.
Ancillary Diagnostic Studies
Beyond H&E staining, pathologists employ additional tests on the tissue sample to confirm Ewing sarcoma. These ancillary studies provide molecular and protein markers that distinguish Ewing sarcoma from similar-appearing cancers. These techniques ensure diagnostic accuracy for appropriate treatment planning.
Immunohistochemistry (IHC) uses antibodies to detect specific proteins within tumor cells. For Ewing sarcoma, the most consistently expressed protein is CD99, appearing as a strong, diffuse membrane staining pattern, often described as “ring-like” around the cell’s periphery. While CD99 is highly sensitive, its presence is not entirely specific, meaning other tumors can also express it. Therefore, additional IHC markers like NKX2.2, a nuclear transcription factor, are frequently used to support the diagnosis, as its expression is common in Ewing sarcoma.
Molecular and genetic testing provides definitive confirmation for Ewing sarcoma. This cancer is characterized by specific chromosomal translocations, involving the swapping of genetic material between chromosomes. The most common translocation, found in approximately 85-90% of cases, is t(11;22)(q24;q12), which leads to the fusion of the EWSR1 gene on chromosome 22 with the FLI1 gene on chromosome 11, forming an EWSR1-FLI1 fusion gene. Detecting this fusion gene, often through FISH or RT-PCR, provides conclusive molecular evidence for Ewing sarcoma. Other less common fusion partners for EWSR1 exist, but the presence of any EWSR1 fusion gene is highly characteristic.
Distinguishing From Other Cancers
Ewing sarcoma’s “small, round, blue cell tumor” appearance presents a diagnostic challenge, as several other cancers can share a similar look under the microscope. This necessitates a differential diagnosis, where pathologists consider and rule out other possibilities using the ancillary tests. This approach ensures that patients receive the correct diagnosis and targeted therapy.
Cancers that can mimic Ewing sarcoma include lymphoma, a malignancy of the lymphatic system. While both can present as small blue cell tumors, lymphoma cells express different immunohistochemical markers (e.g., CD45, CD20, or CD3), which are absent in Ewing sarcoma. Neuroblastoma, a cancer originating from nerve cells, also appears as a small blue cell tumor and may form rosettes. However, neuroblastoma cells stain positive for neural markers (e.g., synaptophysin or chromogranin), and lack the characteristic EWSR1 gene fusions found in Ewing sarcoma.
Rhabdomyosarcoma, particularly the embryonal subtype, can also resemble Ewing sarcoma. This muscle cancer is distinguished by its expression of muscle-specific markers like desmin and myogenin, which are not present in Ewing sarcoma. Small cell carcinoma, an aggressive lung cancer, can also appear as small blue cells. However, small cell carcinoma often shows neuroendocrine differentiation markers, originates in different anatomical locations, and lacks the specific genetic translocations seen in Ewing sarcoma. IHC profiles and molecular signatures become the decisive factors in accurately differentiating these tumors, guiding pathologists to the correct diagnosis.
Prognostic Information From Histology
Beyond diagnosis, histological examination of Ewing sarcoma tissue provides valuable information regarding a patient’s likely outcome or the cancer’s anticipated behavior. Pathologists assess specific features within the tumor sample that correlate with prognosis. This information, combined with clinical factors, guides treatment intensity and predicts response.
A significant prognostic indicator derived from histology is the extent of tumor necrosis after chemotherapy. Necrosis refers to areas of dead tumor cells within the tissue sample. Pathologists quantify the percentage of tumor necrosis in the resected specimen following neoadjuvant chemotherapy. A high percentage of tumor necrosis (generally 90% or greater) indicates a good response to treatment and is consistently associated with a more favorable prognosis and improved survival rates.
The pathologist’s report confirms the overall tumor size and its anatomical location, both significant prognostic factors. Larger tumors (typically exceeding 8 centimeters) and tumors located in axial sites (spine, pelvis, ribs) or proximal extremities (close to the body’s trunk) are often associated with a less favorable prognosis compared to smaller tumors in distal extremities. Some rare cases of Ewing sarcoma exhibit atypical histological features, such as cells that are larger or show more variation in size and shape. These “large-cell” or “atypical” variants may be associated with a different clinical course, though their exact prognostic impact is a complex area of ongoing research.