The Role of Epstein-Barr Virus in Pathogenesis of Hodgkin Lymphoma

• Main Authors: Kung-Chao Chang, 張孔昭
• Other Authors: Ih-Jen Su
• Format: Others
• Language: en_US
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/74949272896376841533

博士 === 國立成功大學 === 臨床醫學研究所 === 97 === Hodgkin lymphoma (HL) is one of the most important human malignancies. It has been recognized since 1832 by Dr. Thomas Hodgkin, an English pathologist, and thereafter referred to as Hodgkin “disease” for more than 150 years. In contrast to other human lymphomas, in which the tumor cells are the main populations of the tumor constituents, the tumor cells of HL, called “Hodgkin (H)/Reed-Sternberg (RS)” cells, account usually for less than 10% of tumor bulk against an inflammatory background. The enigmatic RS cells are unique in their abundant cytoplasm and characteristic bilobed nuclei with eosinophilic prominent nucleoli, imparting an “owl-eye” appearance. The viral inclusion-like morphology puzzled pathologists and led to the finding of HL association with Epstein-Barr virus (EBV). The association of HL with EBV, however, is variable in different geographic regions. My thesis is therefore designed to explore the association of HL with EBV at different time period. Furthermore, the enigmatic pathogenesis of RS cells is investigated, especially its potential association with EBV. In my first period of study, we tried to clarify the EBV association with HL in Taiwan and Vietnam, a country popular for EBV infection. By comparing pathologic features and EBV status detected by in situ hybridization in 99 HL cases diagnosed between 1996-2007 with 74 HL diagnosed from 1982-1995, we found that EBV association rate in Taiwan HL was about 50% and more frequently found in old patients with non-nodular sclerosis type. There were an increased frequency of nodular sclerosis subtype, decreased frequency of the mixed cellularity subtype, and significant decrease in EBV positivity rates among the nodular sclerosis and lymphocyte depleted subtypes in the period of 1996-2007, as compared to that of 1982-1995, that is, there were shifts in the frequency of histologic subtype and EBV association of HL in Taiwan over the last decade, with a trend closer to that seen in Western countries and Japan. Interestingly, the association rate of EBV in Vietnamese childish HL cases is nearly 100%, including nodular lymphocyte-predominant (NLP) subtype, which always shows no association with EBV in Western HL cases. The high incidence of EBV in these cases of HL is correlated with an earlier mean age of presentation of primary EBV infection, i.e. infectious mononucleosis, at 5.3 years old, in this patient population, compared to an average of 15-19 years old reported in developed countries. Our study demonstrates that in an area with an earlier mean age of onset of EBV infection, nearly all cases of pediatric HL, including all histological patterns, may be related to EBV infection. It implies an important role for environmental factors in the pathogenesis of HL. In the second stage of study, we tried to investigate the mechanism underlying the characteristic multinucleated RS cells. Since endoplasmic reticulum (ER) stress has been found to induce aberrant, cytoplasmic cyclin A expression, which will interact with Cdk2 to induce centrosome overduplication, leading to nuclear hyperdiploidy, we tested whether the aberrant expression of cyclin A is related to the RS morphology of HL cells. We found, by immunohistochemistry on 34 cases of HL, that aberrantly cytoplasmic expression of cyclin A, a cell cycle regulator, was associated with RS cell morphogenesis in both EBV-positive and -negative HL cases. In vitro, EBV-LMP1 induced cytoplasmic expression of cyclin A with an increase of multinucleated cell morphology in an EBV-negative HL cell line, L-428. Therefore, the aberrant expression of cyclin A is commonly associated with RS cell morphology in HL, probably through LMP1 signaling or other similar mechanisms in EBV-negative cases. We also demonstrate for the first time that the majority of HL cases expressed survival (GRP78 and XBP1) but not death (CHOP and ASK1) signals of endoplasmic reticulum (ER) stress in all histologic subtypes of HL and in both EBV-positive and –negative cases at a similar level. LMP1 transfection increased expression of GRP78 and XBP1 in L-428 cell line. Although, expression of ER signals did not bear prognostic significance, it may rescue HL cells from stress-induced cell death. Thus, surviving ER stress may be involved in the pathogenesis of HL. My PhD study therefore successfully finished the epidemiology of the association of EBV with HL in Taiwan and in Vietnam, and proposed a theory or mechanism to explain the characteristic RS morphology of HL.