Over the past decades, evidences have emerged to indicate the involvement of EBV in various malignancies, such as Burkitt's lymphoma, Hodgkin's disease and nasopharyngeal carcinomas. EBV is also present in tumors of similar morphology (lymphoepithelioma-like carcinomas) arising in a variety of organs, predominantly in stomach, salivary gland and thymus. As reports of EBV-positive TETs have been divergent and as different methods have been used to detect EBV, the role of EBV in the oncogenesis of thymoma is controversial.
In 1985, Leyvraz found that thymic carcinoma was associated with EBV infection, which was probably the earliest case report[12]. Thereafter, more and more cases were reported. Niehues T et al reported a 14-year-old boy with EBV-associated thymic carcinoma [13]. Stéphan JL Epstein-Barr virus–positive undifferentiated thymic carcinoma in a 12-year-old white girl[14]. MatsunoY reported Epstein-Barr virus DNA in a Japanese case of lymphoepithelioma-like thymic carcinoma[15]. Giordano S hypothesize that EBV infection could have caused thymoma [16]. Fujii, T also reported in three previous cases of EBV-associated thymic carcinoma, lymphoepithelioma-like thymic carcinoma was shown to be closely associated with EBV in their series[17]. Takeuchi H described the first case of EBV-associated thymic carcinoid tumor found by in situ hybridization (ISH) on paraffin-embedded sections[18].
The researches above almost employed ISH to detect the EBV infection, and they reached an agreement that EBV was associated thymic carcinoma but not thymoma. In our study, 72 thymomas and 15 thymic carcinomas were used to detect the viral genome at both DNA and RNA levels. We employed nested polymerase chain reaction (PCR) to test the EBV DNA. The RNA levels were detected by Epstein–Barr-encoded RNA (EBER) ISH. The nested PCR results showed detectable EBV genome in none of type A thymoma, eight (29.6%) type AB, one(16.7%) type B1, fifteen(57.7%)type B2, four(40.0%)type B3 and fourteen(93.3%) thymic carcinomas, respectively. As the malignancy of TETs increases, EBV infection became higher gradually. In 2004 WHO pulmonary, pleural and mediastinal tumors, type A, AB were classed into benign tumors, which also had low EBV infection rate in our study. A close relationship between EBV infection and thymic carcinomas was found, which is consistent with the previous studies. However, only one type B2 thymoma showed discernible in situ signals by EBER ISH. And three cases of thymic carcinomas showed weak signals by EBER ISH. These results show that nested PCR is a sensitive method for screening the EBV genome in thymic epithelial tumors and thymic carcinomas are more often associated with the virus as previously reported.
There also existed some opposite opinions. Engel et al analyzed 157 cases of TETs of Danish patients for EBV by applying in situ hybridization for EBER. All investigated cases were EBER negative. Therefore, they supposed that EBV does not seem to be implicated in the pathogenesis of TETs[19]. 16 western thymomas were investigated for the presence of Epstein-Barr virus (EBV) DNA sequences. The result showed none of the 16 thymomas contained evidence of the EBV genome. These results fail to demonstrate EBV genome in western thymomas and stand in contrast to those of McGuire who previously reported that the EBV genome is present in thymomas occurring in southern Chinese patients[20].
Recently, it is reported that EBV involved in thymoma-associated myasthenia gravis [21, 22]. Here, we also analyzed the relationship between EBV infection and thymoma-associated myasthenia gravis.
Generally speaking, several factors influences the judge about the roles EBV played in TETs. Firstly, EBV is a widespread infection in the population, with an infection rate of more than 90% in children aged 3 to 5 years. And the infected person would carry the virus for life. Secondly, the EBV infection rate is different due to different regions and environments. This explained why EBV associated TETs was different from different parts of the world. Thirdly, EBV positive rates were inconsistent due to different sensitivity and specificity of the detection methods. More researches still need to be done to figure out the relationship between TETs and EBV.