Posted October 06, 2010

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A 19-year-old Caucasian man presented with a rapidly growing, painful, firm mass of the left buttock. Imaging revealed a heterogeneously enhancing 8.0 cm mass in the sacrococcygeal area without bony involvement. An excisional biopsy revealed an ill-defined heterogeneous mass with a grey-tan, somewhat friable cut surface, and gross areas of hemorrhage and necrosis. Immunohistochemistry showed strong membranous staining for CD99, with negative reactivity for multiple cytokeratins, CD45, desmin, smooth muscle actin, S100 protein, synaptophysin, chromogranin, and MyoD-1. Fluorescence in-situ hybridization performed on touch preparations of the tumor showed the presence of a t(11;22) translocation in all examined tumor cells.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 15 and is an Ewing sarcoma/primitive neuroectodermal tumor.

Criteria for Diagnosis and Comments: In combination with the histologic findings, the above data are consistent with the diagnosis of EWS/PNET. Ewing sarcoma (EWS) and primitive neuroectodermal tumor (PNET) represent a spectrum of primitive malignancies that were previously separated based on the presence of neuroectodermal differentiation. Those tumors that showed histologic and/or ultrastructural evidence of neuroectodermal differentiation, including rosette formation and the presence of dense-core granules, were categorized as PNET. Those lesions with no evidence of neuroectodermal differentiation using any modality were classified as EWS. In recent decades, however, it was recognized that this separation is artificial in terms of clinical behavior and molecular pathogenesis. Thus, the current preferred terminology for this family of tumors is EWS/PNET.

EWS/PNET typically occurs in adolescents and young adults with a peak incidence between 10 to 15 years. Men are more frequently affected than women with a ratio of 1.4 to 1. The most common bony sites are the diaphysis or metaphyseal-diaphyseal portion of long bones. Flat bones are also common locations, particularly the pelvis and ribs. Characteristic radiographic findings include a permeative and poorly marginated lesion with reactive periosteal new bone formation (“onion skinning”) and an associated soft tissue mass. Other frequent radiographic findings include a lytic appearance or a ‘moth eaten’ pattern of bone destruction. Common soft tissue locations include the paravertebral soft tissues and the extremities, including upper thigh, buttock and proximal arm.

Macroscopically, EWS/PNET is a soft, somewhat friable tumor mass which has a gray-yellow to gray-tan cut surface. Frequently, these tumors show extensive areas of hemorrhage and necrosis. The histopathology of these tumors shows some variability; however, most tumors are composed of monotonous appearing round cells with distinct nuclear borders, scant clear to eosinophilic cytoplasm, and indistinct cytoplasmic borders, growing in sheets or large clusters. A smaller percentage of Ewing sarcomas have cells which are larger, with slightly irregular cell contours and conspicuous nucleoli. Tumor cells have varying amounts of cytoplasmic glycogen which is highlighted with PAS staining. Despite the immature appearance of the tumor, mitotic figures are infrequent. Ewing sarcoma can be richly vascular with thin-walled vessels that are often obscured by the densely packed tumor cells. Vessels are frequently highlighted in necrotic tumors, with viable cells present in a perivascular distribution.

Immunohistochemistry for CD99 (MIC2) is extremely sensitive for EWS/PNET. However, it is important to note that CD99 can stain other lesions in the differential diagnosis, including lymphoblastic lymphoma and small cell osteosarcoma. Additionally, Ewing sarcoma shows reactivity for vimentin, with more variable staining for synaptophysin, cytokeratins, CD57, and neuron specific enolase. Ewing sarcoma does not stain for actins or CD45.

Approximately 85% of EWS/PNET cases show a reciprocal translocation of t(11;22)(q24;q12) which creates a fusion protein between the EWS gene on chromosome 22 and the FLI1 gene on chromosome 11. The remaining 15% of cases show a number of alternative translocation partners with the EWS protein, including ERG on chromosome 21 and ETS gene which is also on chromosome 21. These functional fusion proteins disrupt the normal function of many genes associated with cell proliferation, differentiation, signaling and apoptosis.

As noted in the master list, the differential diagnosis includes other small round blue cell tumors such as alveolar rhabdomyosarcoma, metastatic small cell carcinoma, desmoplastic small round cell tumor, neuroblastoma, and lymphoblastic lymphoma. Because these tumors show significant cytologic and architectural overlap, immunohistochemical studies are crucial in separating these entities. Lymphoblastic lymphoma shows positive immunohistochemical staining for CD43, CD34, CD10, CD79a and TdT. Alveolar rhabdomyosarcomas show a solid architecture and positive staining for myogenin, desmin, myo-D1, and muscle-specific actin; cytogenetic analysis often shows a translocation between chromosomes 2 and 13 [t(2;13)(q35;q14)]. Desmoplastic small round cell tumor occurs predominantly within the abdomen of children and young adults, with a strong male predilection. Desmoplastic small round cell tumors have small round cells arranged in nests with prominent stromal desmoplasia, and show positive staining for cytokeratins, EMA, vimentin, desmin, and WT-1. Neuroblastomas show variable amounts of neuropil, rosette formation, and schwannian stroma. In addition, neuroblastomas show positive staining for NSE, synaptophysin, chromogranin, CD57 and CD56. Small cell carcinomas show a dot-like staining pattern with keratins, and also show positive staining for TTF-1, chromogranin, and synaptophysin.

With advancements in neoadjuvant chemotherapy and radiation, the five-year survival of EWS/PNET is between 36 to 56 percent with long-term survival rates of 70 to 80 percent in patients with non-metastatic disease.