Evaluation of Epstein-Barr virus infection in sinonasal small round cell tumors

Sinonasal undifferentiated carcinoma, olfactory neuroblastoma and malignant melanoma of the sinonasal regions are included within the category of small round cell tumors of the sinonasal region. It is difficult to diagnose these tumors on the basis of light-microscopic features alone, but, in some instances, immunohistochemical staining evaluating cytokeratin and S-100 protein, for example, is of value. On the other hand, the sinonasal region is a significant site for Epstein-Barr-virus (EBV)-related tumors, including sinonasal undifferentiated carcinoma or malignant lymphoma. Twenty-three sinonasal small round cell tumors (SSRCT) comprising 5 sinonasal undifferentiated carcinomas, 9 olfactory neuroblastomas and 9 malignant melanomas were evaluated for the presence of EBV infection by in situ hybridization for EBV-encoded RNA, combined with immunostaining for EBV-related proteins (LMP-1 and EBNA2). Furthermore, 55 SSRCT comprising 37 sinonasal undifferentiated carcinomas, 9 olfactory neuroblastomas, and 9 malignant melanomas were examined for the presence of cytokeratins (AE1/ AE3 and CAM5.2), S-100 protein and p53 protein using immunohistochemical staining. According to in situ hybridization for detecting EBV-encoded RNA 1 (EBER1), all of the sinonasal undifferentiated carcinomas showed clear, intense hybridization signals localized over the nuclei of the tumor cells and, in 3 out of 9 (33.3%) malignant melanomas, hybridization signals were also recognized. However, none of the olfactory neuroblastomas revealed hybridization signals. Immunohistochemically, 4 out of 5 (80%) sinonasal undifferentiated carcinomas were positive for LMP-1, whereas only 2 out 9 (22.2%) malignant melanomas and no olfactory neuroblastomas were positive. With regard to EBNA2, sinonasal undifferentiated carcinomas, malignant melanomas and olfactory neuroblastomas were all negative. Out of 37 sinonasal undifferentiated carcinomas 35 (94.6%) showed a diffuse positive immunoreaction for AE1/AE3, whereas neither olfactory neuroblastoma nor malignant melanoma revealed a positive reaction. All 9 malignant melanomas and 6 out of 9 olfactory neuroblastomas (75%) were positive for S-100 protein, whereas only 6 cases of sinonasal undifferentiated carcinomas (19.4%) were positive. As for p53 protein, 16 of 37 sinonasal undifferentiated carcinomas (43.2%) were positive, whereas neither olfactory neuroblastoma nor malignant melanoma revealed any positive reaction. The above results suggest that EBV infection is closely associated with sinonasal undifferentiated carcinomas, and that some malignant melanomas may also have a relationship with its infection. For the differential diagnosis of SSRCT, it is important to evaluate EBV infection along with immunohistochemical staining for cytokeratins and S-100 protein. The overexpression of p53 protein was found to be related to the oncogenesis of sinonasal undifferentiated carcinoma; however, there was no association between its overexpression and malignant melanoma or olfactory neuroblastoma.