Epstein-barr virus serology in the management of recurrent nasopharyngeal carcinoma

Abstract

Hong Kong, situated in the Southern part of China, is an endemic area where the incidence of nasopharyngeal carcinoma (NPC) is among the highest in the world. The cancer, which is located at the deepest part of the human skull, represents one of the most difficult tumours to treat in the head and neck region. The management of tumour recurrence after radiotherapy is even more challenging.

Epstein-Barr virus (EBV) is a human herpes virus and it is the first virus that is discovered to be associated with human malignancy. Over the past few decades, the role of EBV serology in the management of NPC has been extensively investigated. More recently, a series of EBV encoded microRNAs, which are short, non-coding RNAs, are found to be commonly expressed in NPC.

In our studies, we have investigated the role of EBV DNA and EBV miRNA BART7 in the management of recurrent NPC. Plasma EBV DNA is accepted as a tumour marker for NPC. We found that in patients with recurrent NPC, the pre-operative level of plasma EBV DNA reflects the tumour load and correlates with the T-stage of the tumour. It also predicts the chance of resection margins that are histologically positive for malignancy. When measured serially after surgery, it is useful to detect tumour recurrence. However, we found that up to 15.5% of our patients, who had tumour recurrence in the nasopharynx, were seronegative for EBV DNA. In such circumstances, plasma EBV miRNA BART7, which is expressed independently of EBV DNA, may be used for such purpose. Moreover, using the in-vitro model, we demonstrated that the expression of EBV miRNA BART7 in the HONE1 cell line increases the rate of proliferation, migration and invasion of tumour cells.

By using the same in-vitro model, we found that the EBV miRNA BART7 increases the sensitivity of the HONE1 cells to ionizing radiation in a dose-dependent manner. This is confirmed with the in-vivo experiments using the zebra fish model.

In our previous study on the multivariate analysis of prognostic factors in salvage nasopharyngectomy for recurrent NPC, we found that the resection margin status is one of the most important independent factors influencing the local tumour control and overall survival. In order to improve the chance of obtaining clear margins after surgery, we have to depend on the intra-operative frozen section analysis and the post-operative histological examination of the resection margin specimen. In our current study, we showed that contrast MRI is accurate in assessing the local extent of recurrent nasopharyngeal carcinoma. During nasopharyngectomy, a radial resection margin of 15mm should be taken with the underlying medial pterygoid muscle. For tumours with parapharyngeal extension, the pharyngobasilar fascia should be resected enbloc with the specimen. The chance of local recurrence after salvage nasopharyngectomy in patients with histologically uninvolved margins was 20.0%. Tissue EBV miRNA BART7 is useful to identify a subgroup of patients with histologically close margins who are at increased risk of subsequent local tumour recurrence. Post-operative adjuvant treatment is warranted for these patients.