Purpose: Nasopharyngeal cancer (NPC) is a malignant epithelial carcinoma which is intimately associated with EBV. The latent presence of EBV affects the function of p53, Bcl-2, and survivin. We thus investigated the relationship between EBV status, p53, Bcl-2, and survivin in biopsy specimens from patients with primary NPC. Experimental Design: Archival formalin-fixed, paraffin-embedded NPC biopsies were evaluated in 80 patients treated with curative radiation from a single institution. The presence of EBV was determined using EBER in situ hybridization, whereas p53, Bcl-2, and survivin were assessed using immunohistochemistry. Results: The majority of NPC specimens in this patient cohort were EBER-positive (64 of 78, or 82%), which in turn, was significantly associated with ethnicity (P = 0.0007), and WHO subtype 2A/2B (P = 0.04). EBER-positive tumors were also associated with p53 (P = 0.002), Bcl-2 (P = 0.04), and nuclear survivin (P = 0.03) expression. Patients with EBER-positive NPC fared better, with a 10-year overall survival of 68% versus 48% for EBER-negative patients (P = 0.03). For nuclear survivin, patients with either low or high nuclear survivin fared worse than patients with intermediate survivin expression (P = 0.05), suggesting that there is an optimal proportion of survivin-expressing cells for best function and clinical outcome. Conclusions: With an extended median follow-up time of 11.4 years, EBV status remains a strong predictor for overall survival in NPC. EBV-positive NPC has strong molecular associations with p53, Bcl-2, and survivin expression. Furthermore, we provide clinical data revealing the potentially dual nature of survivin in predicting clinical outcome.Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the head and neck site, with incidences of 20 to 30 per 100,000 people in areas such as Southeast Asia (a region of >100 million people) and the Mediterranean basin (a region of >300 million people) (1). NPC is anatomically located in close proximity to the base of the skull, rendering it a significant challenge for conventional and experimental treatments. In fact, inadequate tumor volume coverage may be partially responsible for the modest 5-year overall survival (OS) rate of f70% when patients are treated with conventional radiotherapy alone (2 -4). Although intensity-modulated radiotherapy does improve local control, the risk of distant metastases remains high at f40% (2). A predilection for developing distant metastases, a young median age of presentation (at f50 years), and the intimate association with EBV are features that render NPC a unique head and neck epithelial malignancy (5).The latent presence of EBV is unique to malignancies such as NPC, Burkitt's lymphoma, Hodgkin's lymphoma, peripheral T cell lymphomas, natural killer cell lymphomas, and gastric carcinomas (1). Approximately 75% to 81% of patients with NPC worldwide harbor the EBV genome, which is present in the type II latency. This form of latency is characterized by the expression ...

BACKGROUND To derive a better understanding of the biologic behavior of nasopharyngeal carcinoma (NPC), the authors evaluated a number of molecular variables to address the hypothesis that p53 dysfunction in NPC is associated with Epstein‐Barr virus (EBV), increased tumor angiogenesis, lower likelihood of apoptosis, and poorer clinical outcome. MATERIALS The biopsy samples from 87 NPC patients were obtained and sections were made to detect EBV, using in‐situ hybridization; the authors used immunohistochemistry to assess p53, p21WAF1/CIP1 expression, and microvessel density count (MVD). In situ end labelling was used to evaluate apoptosis and necrosis. Analyses were conducted on the association between each of these variables as well as clinical outcome, including survival and local control. RESULTS There was a highly significant association between EBV‐encoded RNA (EBER) positivity with p53 over‐expression in that only 1 out of 32 p53 over‐expressing tumors was EBER negative, as opposed to 19 out of 48 p53 negative tumors being EBER negative (P = 0.001). In addition, EBER positivity was highly associated with World Health Organization (WHO) type 3 NPC, Asian/Chinese ethnicity, a lower apoptotic index, and p21 over‐expression. p53 over‐expression was associated with a higher MVD count. Controlling for age and nodal status, EBER positivity was associated with both improved overall survival (P = 0.02), and disease‐free survival (P = 0.04). In contrast, the presence of tumor necrosis was associated with an inferior local control (P = 0.03). CONCLUSION p53 protein was over‐expressed in approximately one third of NPC samples in the current study, and this correlated significantly with the presence of EBER. Epstein‐Barr virus status was also associated with WHO type 3 NPC, Asian/Chinese ethnicity, and induction of p21. The presence of EBV appeared to predict for improved survival, the mechanism of which remains to be elucidated in this biologically complex disease. Cancer 2002;94:1997–2006. © 2002 American Cancer Society. DOI 10.1002/cncr.10440