Lymph node metastases of Ewing sarcoma/peripheral neuroectodermal tumor (ES/PNET).

James Ewing described the bone neoplasm subsequently named after him in a case report of a 14-year-old girl who had the tumor within the radius (1). Arthur Purdy Stout is thought to have described PNET for the first time in a 42-year-old man who had a neoplasm involving the ulnar nerve (2). More recently, Askin and colleagues described a malignant small-cell neoplasm occurring in the soft tissues of the thoracopulmonary region in a series of 20 children and adolescents; this lesion subsequently acquired the designation “Askin tumor” (3). On the basis of molecular findings, all three of these neoplasms are now recognized to be part of a single neoplastic process with varying degrees of neuroepithelial differentiation, the ES/PNET family of tumors (4).

In general, there remains a substantial correlation between the histologic features and the site of origin, with classical ES (as described by Ewing) being situated in bones and classical PNET being based in soft tissues. However, substantial overlap has been reported in the literature. Neoplasms with the classical features of ES can arise at extramedullary sites (5), and cases of PNET have been described in bones (6).

ES/PNET is the second most frequent bone tumor in children, occurring in three children per million each year. Approximately 80% of ES/PNET occur between the ages of 5 and 20 years old, with a median age of 14 years (4). A predilection for boys with a male-to-female of 1.5:1, and a marked predilection for whites over African-Americans has been observed. There is no evidence of familial predisposition or environmental risk factors (4,7).

The cell of origin of ES/PNET is unknown, but data derived from gene expression profiling studies have shown an ES/PNET transcriptional signature similar to that of mesenchymal stem cells (8). Translocations involving the ews gene, most commonly t(11;22)(q24;q12)/ews-fli1, occur in most cases of ES/PNET and may be an initiating event in pathogenesis.

Patients with ES/PNET often present with local pain, swelling, or a mass, and can also exhibit fever and weight loss (4,9,10). Laboratory abnormalities can include leukocytosis and an elevated erythrocyte sedimentation rate. ES/PNET most often occurs in bones and, for patients with a bone neoplasm, the clinical picture can resemble patients with osteomyelitis. The bones most frequently involved by ES/PNET are the long bones of the appendages, mandible, clavicle, rib, and pelvis (11). ES/PNET most often arises in the medullary canal of the diaphysis. Fractures can be associated with ES/PNET in long bones. In 10% of patients, multiple bones are involved.

ES/PNET has a high propensity to metastasize. The most frequent sites of metastases are the lungs, other bones, and the central nervous system (12). Regional lymph nodes metastases are not common at time of initial diagnosis.

Lymph node metastases of ES/PNET resemble the primary neoplasm (Figs. 97.1,97.2,97.3,97.4). Primary neoplasms with classical features of ES are composed of small, uniform cells with round to ovoid nuclei, scanty cytoplasm, and indistinct cell borders resulting in a sheet-like or syncytial appearance (4,7,9,10,13). The nucleoli are small and inconspicuous, and mitoses are present but often not numerous. In many cases, fibrous septae separate the neoplasm, imparting a lobular pattern (Figs. 97.1,97.2,97.3). Necrosis is very common and can be extensive. Neoplasms with classic features of PNET, usually arising in soft tissue, have some evidence of neuroepithelial differentiation. The neoplastic cells are larger and less uniform, often with prominent nucleoli; pseudorosettes of neoplastic cells surrounding blood vessels or true Homer-Wright rosettes can be identified. A number of uncommon variants of ES/PNET have described, including an adamantinoma-like variant, atypical ES/PNET, in which the neoplastic cells are larger with prominent nucleoli, and cases with abundant sclerosis or cell spindling (13).

Glycogen in the cytoplasm of the cells of ES/PNET is a characteristic feature. In over 75% of cases, glycogen is readily identified by the periodic acid–Schiff (PAS) reaction with diastase treatment (14). Although still helpful, there are many exceptions to this rule. Some cases of ES/PNET have relatively little cytoplasmic glycogen, and other tumors in the differential diagnosis (e.g., neuroblastoma and lymphomas)
can have abundant glycogen in a small subset of cases (7).