Proposed Modifications and Incorporation of Plasma Epstein-Barr Virus DNA Improve the TNM Staging System for Epstein-Barr Virus-Related Nasopharyngeal Carcinoma

Cancer. 2019 Jan 1;125(1):79-89. doi: 10.1002/cncr.31741. Epub 2018 Oct 23.


Background: The prognosis of patients who have Epstein-Barr virus (EBV)-related nasopharyngeal carcinoma (NPC) in which the tumor tissues harbor EBV have a better prognosis than those without EBV-related NPC. Therefore, the eighth edition of the TNM staging system could be modified for EBV-related NPC by incorporating the measurement of plasma EBV DNA.

Methods: In total, 979 patients with NPC who received intensity-modulated radiotherapy (IMRT) were retrospectively reviewed. Recursive partitioning analysis was conducted based on tumor (T) classification, lymph node (N) classification, and EBV DNA measurement to derive objectively the proposed stage groupings. The validity of the proposed stage groupings was confirmed in a prospective cohort of 550 consecutive patients who also received with IMRT.

Results: The pretreatment plasma EBV DNA level was identified as a significant, negative prognostic factor for progression-free survival and overall survival in univariate analysis (all P < .001) and multivariate analysis (all P < .05). Recursive partitioning analysis of the primary cohort to incorporate EBV DNA generated the following proposed stage groupings: stage RI (T1N0), RIIA (T2-T3N0 or T1-T3N1, EBV DNA ≤2000 copies/mL), stage RIIB (T2-T3N0 or T1-T3N1, EBV DNA >2000 copies/mL; T1-T3N2, EBV DNA ≤2000 copies/mL), stage RIII (T1-T3N2, EBV DNA >2000 copies/mL; T4N0-N2), and stage RIVA (any T and N3). In the validation cohort, the 5-year progression-free survival rate was 100%, 87.9%, 76.7%, 68.7%, and 50.4% for proposed stage RI, RIIA, RIIB, RIII, and RIV NPC, respectively (P < .001). Compared with the eighth edition TNM stage groupings, the proposed stage groupings incorporating EBV DNA provided better hazard consistency, hazard discrimination, outcome prediction, and sample size balance.

Conclusions: The proposed stage groupings have better prognostic performance than the eighth edition of the TNM staging system. EBV DNA titers should be included in the TNM staging system to assess patients who have EBV-related NPC.

Keywords: TNM staging system; nasopharyngeal carcinoma; plasma Epstein-Barr virus DNA; proposed stage groupings; recursive partitioning analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA, Viral / blood*
  • DNA, Viral / radiation effects
  • Epstein-Barr Virus Infections / pathology*
  • Epstein-Barr Virus Infections / radiotherapy
  • Female
  • Herpesvirus 4, Human / genetics*
  • Herpesvirus 4, Human / radiation effects
  • Humans
  • Male
  • Nasopharyngeal Carcinoma / pathology*
  • Nasopharyngeal Carcinoma / radiotherapy
  • Nasopharyngeal Carcinoma / virology
  • Nasopharyngeal Neoplasms / pathology*
  • Nasopharyngeal Neoplasms / radiotherapy
  • Nasopharyngeal Neoplasms / virology
  • Neoplasm Staging
  • Prognosis
  • Prospective Studies
  • Radiotherapy, Intensity-Modulated
  • Retrospective Studies
  • Survival Analysis
  • Treatment Outcome


  • DNA, Viral