Expression of Epstein-Barr Virus–Encoded Proteins in Extranodal NK/T-cell Lymphoma, Nasal Type (ENKL): Differences in Biologic and Clinical Behaviors of LMP1-Positive and -Negative ENKL

Abstract

Purpose: Extranodal NK/T-cell lymphoma, nasal type (ENKL) is closely associated with Epstein-Barr virus (EBV). To elucidate its pathogenetic role, we examined the expression profiles of EBV-encoded proteins, especially focusing on latent membrane protein 1 (LMP1).Experimental Design: Immunohistochemistry was carried out using clinical samples from ENKL cases, which were diagnosed between 1996 and 2010 at our institution. We statistically assessed the correlation between LMP1 positivity and the clinicopathologic data and further examined phosphorylation status of NF-kB RelA and Akt in ENKL cell lines.Results: Most of the 30 examined cases showed pleomorphic morphology, natural killer cell immunophenotype, and a localized disease. Immunohistochemistry detected EBERs, but not EBNA2, in all cases. LMP1 and LMP2A were positive in 22 (73.3%) and 12 cases (40.0%), respectively. LMP1-positive cases tended to show a localized disease (P ¼ 0.060, the Fisher exact test). Nuclear localization of phosphorylated RelA and detection of phosphorylated Akt were predominantly observed in LMP1-positive cases (P ¼ 0.002 and P < 0.001, respectively, the Fisher exact test). RNA silencing experiments of LMP1 in Hank1 cells suggested a positive correlation between LMP1 expression and phosphorylation of RelA and Akt. With a median follow-up period of 26.7 months (range, 0.2-142.3 months), the 2.5-year overall survival rates for LMP1-positive and -negative cases were estimated at 78.3% and 12.5%, respectively (P ¼ 0.001, log-rank test).Conclusions: LMP1 expression shows correlations with phosphorylation of RelA and Akt and possibly has a favorable impact on clinical outcome in ENKL.

Natural Killer/T Cell Lymphoma, Nasal Type: A Retrospective Clinical Analysis in North-Western China

“…Use of the IPI for predicting prognosis and selecting therapeutic options remains controversial in ENKL, [14,15,16] and has not been predictive of prognosis [28,29]. Unfavorable prognostic factors have been reported, including advanced-stage disease (stage III/IV), invasion of bone or skin, EBV DNA levels, and low absolute lymphocyte counts [20,21,30,31,32]. …”

“…5 patients (including 2 primary nasal ENKL, 1 primary lymph node ENKL, 1 primary liver ENKL, 1 primary intestines ENKL) had more than 6.1 × 10 7 copies/ml EBV DNA, with an OS of 60%. It has been demonstrated that the copy number of free EBV DNA is correlated with a negative prognosis [20,31,32,33]. …”

Gastrointestinal Lymphoma in Southwest China: Subtype Distribution of 1,010 Cases Using the WHO (2008) Classification in a Single Institution

“…Furthermore, the intestine was one of the most common extranasal sites of ENKTL-N involvement, with a relatively high frequency of metastasis and dismal follow-up outcomes. Although the pathogenesis remains unclear, EBV infection was thought to be a triggering risk factor of the tumor genesis [8,29] . Although DLBCL was also the most common histological subtype in the intestinal tract in other studies, the second most common subtype varies from region to region.…”

Nasal-type NK/T-cell lymphomas are more frequently T rather than NK lineage based on T-cell receptor gene, RNA, and protein studies: lineage does not predict clinical behavior

“…[36][37][38][39] EBV-encoded latent membrane protein expression correlated with the phosphorylation of RelA and Akt possibly had a favorable impact on clinical outcome in patients with ENKTLs. 20,40 Among pathology parameters, an adverse prognosis was correlated with a high Ki-67 labeling index and EBV DNA load but not with cellular morphology or the expression of CD56. 30,31,41 Pongpruttipan et al 8 suggested that patients with a T-cell ENKTL in the upper airway tended to have better survival although this did not reach statistical significance.…”