Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue

Clinical Features

Ewing Family Tumors are rare and aggressive sarcomas predominating in children and young adults. Tumors may occasionally arise in older patients, including the elderly. These neoplasms occur at virtually any anatomic location, and may involve bone, soft tissue, or the viscera. They are reported to have a slight male predilection, and some racial groups appear to be affected more than others (e.g., European descent). Naturally, clinical presentations vary by anatomic site of disease, while symptoms tend to be non-specific such as a painful mass or a subset of bone tumors present with pathologic fracture.

Radiologic Features

In bone, routine radiographs may demonstrate permeative growth. As tumor cells readily infiltrate Haversian and Volkmann canals there may be extensive soft tissue involvement preceding radiologic evidence of cortical destruction. Repeated expansion of the periosteum can result in a multilayered periosteal reaction – a so-called “onion-skin” appearance. Imaging modalities are often complementary; for example, computed tomography and magnetic resonance imaging are helpful in assessing the extent of bone and soft tissue involvement, and the former is additionally useful in highlighting cortical destruction. In soft tissue, imaging findings tend to be rather non-specific.

Pathologic Features

Microscopic Findings

Tumors are typically infiltrative and composed of sheets of small round cells with a lobulated pattern ( Fig. 14.2 ). The cytoplasm is scant, with indistinct cell borders. It is generally pale and eosinophilic-amphophilic clear; intracytoplasmic glycogen can usually be highlighted by periodic acid–Schiff staining. The nuclei are round-ovoid and monomorphic, with evenly dispersed chromatin; mitotic activity is variable. Interspersed between cells there is usually a delicate thin-walled vasculature. Necrosis is often present; it may be geographic, and/or limited to scattered degenerating cells. A spectrum of morphologies has been reported, for example: architecturally, tumors may contain rosettes and/or pseudorosettes (“PNET”), or hyalinized stroma; the cells may be spindled, or large (“atypical”); and, particularly in the head and neck, epithelial differentiation may be present (“adamantinoma-like”) ( Fig. 14.3 ).

Ancillary Studies

Immunohistochemistry

There is no specific immunohistochemical marker for EFTs. The majority of cases contain diffuse membranous expression of CD99 (MIC2), and nuclear staining for NKX2.2. Most tumors also show strong nuclear staining for FLI1, while the subset of cases with ERG fusion partners have diffuse nuclear ERG expression. Approximately 20%–30% of cases show focal/patchy keratin expression. Synaptophysin, S100, and desmin staining is considerably less common ( Fig. 14.4 ).

Differential Diagnoses

The differential diagnosis for EFTs is broad and includes other undifferentiated round cell sarcomas (e.g., CIC -associated, BCOR -associated), poorly differentiated synovial sarcoma, mesenchymal chondrosarcoma and desmoplastic small round cell tumor, amongst many others. Identification of a disease-defining fusion product is the current gold standard for EFTs, as well as many of the entities in the differential diagnosis. This, admittedly, is not currently readily accessible in many laboratories.

CIC - and BCOR -associated sarcomas may demonstrate membranous CD99 staining; however, CIC -associated tumors generally have nuclear WT1 expression, while BCOR -associated tumors often have nuclear SATB2 expression. Poorly differentiated synovial sarcoma, while also positive for CD99, is usually positive for TLE1, a finding that is rare in EFTs; moreover, with adequate sampling, more prototypic spindle cell areas can usually be identified. Mesenchymal chondrosarcoma can express CD99 although, again with adequate sampling, this can usually be differentiated based on the presence of chondroid matrix. A number of lymphomas – notably acute lymphoblastic, acute myelogenous, and anaplastic large cell – may express CD99, but these can usually be appropriately differentiated using a broad hematolymphoid immunohistochemical panel.

Prognosis and Treatment

Treatment depends on a multidisciplinary approach. Localized disease is usually treated with a combination of chemotherapy, and surgery and/or radiation therapy. Metastasis at diagnosis is the most important prognostic indicator. The 5-year survival for localized disease is between 65% and 75%, but considerably less with metastases.

Clinical Features

CIC -associated sarcomas are rare and highly aggressive neoplasms. They predominate in young adults but have a wide distribution ranging from childhood to the elderly. These tumors predominate in deep soft tissue; however, they may be superficial, or occur in bone or the viscera. Despite initially conflicting studies, overall there appears to be a slight male predisposition.

Radiologic Features

Imaging findings tend to be non-specific. MRI T1-weighted images yield an intermediate signal, and T2-weighted images have a high signal intensity with heterogeneous contrast enhancement.