Extraosseous Ewing sarcoma with foci of neuroblastoma-like differentiation associated with EWSR1(Ewing sarcoma breakpoint region 1)/FLI1 translocation without prior chemotherapy

Summary

Peripheral primitive neuroectodermal tumor/Ewing sarcoma and neuroblastoma are distinct malignant tumors belonging to the group of undifferentiated solid pediatric tumors. We report a case of a 14-year-old adolescent girl who presented with a right lower quadrant mass. At surgery, a mobile retroperitoneal mass was entirely removed. Histologic evaluation revealed 2 distinct components; the first, consisting of sheets of undifferentiated cells, was CD99+ and CD56−, whereas the second, consisting of multiple foci of neuropil and maturing neuroblasts, was CD99− and CD56+. Fluorescence in situ hybridization analysis revealed the presence of EWSR1/FLI1 translocation in both histologic distinct components. MYCN (myelocytomatosis viral related oncogene, neuroblastoma derived) was not amplified. The tests for t(11;22) and t(21;22) performed by reverse transcription–polymerase chain reaction were negative. The final diagnosis corresponds to an extraosseous Ewing sarcoma with foci of neuroblastoma-like differentiation. This is the first case, documented by molecular studies, in which neuroblastoma-like differentiation has been noted in primitive neuroectodermal tumor/Ewing sarcoma without prior chemotherapy.

Introduction

Peripheral primitive neuroectodermal tumor/Ewing sarcoma (PNET/ES) and neuroblastomas (NBs) belong to the group of pediatric small round cell tumors and are 2 clearly distinct malignant tumors [1]. However, the presence of morphological and immunophenotypic neural differentiation suggests a link between the two. Clinically, ES is a frequent highly malignant tumor that usually affects children and young adults. In the same age group, extraskeletal PNET/ES is most frequently developed in extremities, paravertebral regions, and the retroperitoneum. Conversely, NB occurs in early childhood and is distributed along sympathetic ganglia in addition to the adrenal medulla. Approximately 80% to 90% of patients with NB have elevated levels of catecholamine metabolites (vanillylmandelic acid and homovanillic acid) in their urine [1]. PNET/ES are nonsecreting tumors. Pathologically, the gross appearance of both tumors varies, but in general, they are multilobulated, soft, fleshy, gray, and partially hemorrhagic tumors. Microcalcifications are rare in PNET/ES but are frequent in NB. Microscopically, NB tumors have a broad spectrum of differentiation varying between undifferentiated tumors composed only of small rounded blue cells and ganglioneuroma composed uniquely of ganglia and Schwann stromal cells [1]. NB with varying degrees of differentiation containing Schwann and ganglion cells and/or neuropil is easily distinguished from PNET/ES. In contrast, undifferentiated NB tumors and ES have overlapping histopathologic morphology. Moreover, Homer-Wright rosettes, containing a central solid core of neurofibrillary material surrounded by neuroblasts, can be found in both NB and in PNET. Immunohistochemically, the MIC2 (CD99) antigen demonstrates a membranous expression in a large majority of PNET/ES [2]. NB cells are characterized by an intense expression of the 140-kd neural cell adhesion molecule, neural cell adhesion molecule (N-CAM) (CD56) [3]. Both tumors stain positive for neural markers, including neuron-specific enolase, Leu-7, and synaptophysin.

Cytogenetic and molecular analyses have revealed that 90% to 95% of PNET/ES are characterized by rearrangement of the EWSR1 (Ewing sarcoma breakpoint region 1) gene on 22q12 [4]. The most frequent translocation is t(11;22)(q24;q12), resulting in fusion of the FLI gene on 11q24. The fusion gene encodes an oncoprotein (EWS-FLI fusion protein) domain of FLI1 that generates aberrantly active transcription factors capable of DNA binding and malignant transformation [4]. Many cytogenetic markers have been described in NB: MYCN amplification is the most important prognostic factor in this tumor, whereas 11q23 deletion is associated with aggressive tumors and a poor prognosis [5]. The treatment varies greatly between the localized stages of these 2 distinct tumors. The treatment of low-risk nonmetastatic NB is uniquely surgical removal of the primary tumor. In contrast, patients with localized PNET/ES systematically receive chemotherapy before or after surgery. The chemotherapy consists of a combination of several drugs including anthracyclines and, frequently, doxorubicin. We present the first case documented with molecular studies of an extraosseous ES with foci of NB-like differentiation without prior chemotherapy, discovered in a 14-year-old adolescent girl who presented with a retroperitoneal mass.