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Hodgkin's lymphoma is a rare hematopoietic malignancy in which the neoplastic cells constitute only a minority (1-2%) of the total tumor mass. These are large mononucleated (Hodgkin) and multinucleated (Reed-Sternberg) cells amidst a non-neoplastic inflammatory infiltrate. Malignant HRS cells exhibit strong NF-kB overexpression. They also lost the expression of typical B cell lineage genes and instead show strong expression of signaling molecules and transcription factors of other cell types. Most cases of HL carry clonal somatically mutated Ig V (Variable)-gene re-arrangement. Up to 40% of HL cases are associated with Epstein-Barr Virus (EBV), and so far, it is the only candidate for the infectious agent causing HL. Along with Nasopharyngeal carcinoma (NPC) and peripheral T cell lymphoma, HRS cells exhibit latency II program (see EBV latency and persistence) with viral antigen expression limited to EBNA-1, LMP-1, LMP-2, and EBERs.
The large majority of Hodgkin lymphoma associated with Human Immunodeficiency Virus (HIV) infection are pathogenically linked to EBV, with rates of EBV positivity ranging from 80 to 100%.
Hodgkin's disease was first described in 1832 by Thomas Hodgkin (1798-1866) who published his article "On some morbid appearances of the adsorbent glands and spleen" based on post-mortem examination of seven patients. More than 30 years later, based on some additional cases, Wilks published his article describing same type of disease naming it Hodgkin's disease. In 1994, Hodgkin's disease's currently accepted types and subtypes were listed in the Revised European-American Lymphoma classification. In 2001, the World Health Organization (WHO) lymphoma classification system renamed Hodgkin's disease to Hodgkin's lymphoma.
Types of Hodgkin's lymphoma
(cHL) Constitutes a majority of HL, has postgerminal center B lymphocyte's genotype.
Sclerosis (NSHL) Majority of cHL; 20% are EBV+.
Cellularity (MCHL) 75% are EBV+.
(LRHL) Together with LDHL comprise less than 5%of all cH cases.
(NLPHL) Represents 5% of all HL cases, has germinal center genotype and is not typically EBV-associated.
Role of Epstein-Barr virus in evolution and maintenance of HL
Evidence linking EBV to etiology of EBV+ HL
- The biological plausibility of EBV-mediated B cell transformation;
- Presence of clonal EBV genomes within HL tumor cells, which implies that infection occurred before malignant transformation;
- Epidemiologic associations with Infectious Mononucleosis (IM) (median time from IM to EBV+ HL onset is ~4 years);
- Distinctive EBV antibody titer profiles and viral loads both pre- and post-HL diagnosis (patients in remission demonstrate significant reduction in plasma viral load, whereas progressing disease is associated with rapidly increasing viral DNA levels);
- Differing demographic, clinical, and epidemiologic characteristics of EBV+ and EBV- HL (in developed countries the proportion of EBV+ HL is 20-40% cases whereas in developing counties it can reach 70-100%).
Contribution of EBV in HL development and pathogenesis
There are many potential mechanisms of EBV oncogenicity. Some of them are briefly outlined below. Much more detailed information can be found in reviews referenced listed in next section.
HRS cells are derived from preapoptotic postgerminal center B cells which escaped apoptosis. Analysis has shown that they have immunogobulin gene heavy chain rearrangements that abolish its transcription. Usually B cells that carry crippling somatic mutations are destined to die. Survival of HRS cells suggests that a transforming event such as EBV infection, has taken place.
LMP-1 expression was associated with multinuclearity in EBV- LMP-1 transfected cell line. Also, functional analysis of LMP-1 has found that EBV+ HRS-associated LMP-1 is more oncogenic than normal EBV+ B-cell-associated LMP-1. LMP-1 functions as a constitutively activated tumor necrosis factor (TNF) receptor and many of phenotyping and growth transforming effects of LMP-1 result from its ability to activate a variety of signaling pathways including, Nuclear Factor kB (NF-kB).
One EBV gene expressed at very high levels in HL, LMP-2A, carries an immunoreceptor tyrosine-based activation motif (ITAM) that resembles motif carried by immunoglobin molecules. When expressed at the cell membrane, LMP-2A provides anti-apoptotic signal.
Although no direct oncogenic activity of EBNA-1 has been observed in tissue culture assays, expression of EBNA-1 in transgenic mice induces B cell follicular lymphoma. This demonstration that EBNA-1 is oncogenic in vivo suggests that it may also play direct role in the pathogenesis of EBV-associated malignancies probably through dysregulation of JAK-STAT (Janus kinase-signal transducers and activators of transcription) pathways.
EBNA-1 also plays prominent role in evasion of immune response. It is protected from processing and presentation via the conventional major histocompatibility complex (MHC) class I pathway by virtue of its internal Glycine-Alanine repeat (GAr) domain, which acts as cis-inhibitory signal to prevent ubiquitin/proteasome dependent protein degradation. It also appears to reduce its own synthesis.Back to top
Mwakigonja AR, Kaaya EE, Mgaya EM. Malignant lymphomas (ML) and HIV infection in Tanzania. J Exp Clin Cancer Res. 2008; 27(1): 9.
Hodgkin's lymphoma tissue section. Briefly, tissue sections (5 μ thick) were stained with Hematoxylin and Eosin (H & E). Section of a Hodgkin's disease mixed cellularity (HDMC) case; note the classical Reed-Sternberg (R-S) cell [blue arrows] and eosinophil cells [black arrows] (x 400).
Massini G, Siemer D, Hohaus S. EBV in Hodgkin Lymphoma. Mediterr J Hematol Infect Dis. 2009 Nov 24;1(2):e2009013.
The role of EBV in the generation of the peculiar phenotype of HRS cells. EBV preferentially infects naïve B cells and adapt its gene expression during B cell differentiation. HRS cells originate from preapoptotic GC B cells. Expression of latency II genes in HRS cells deliver survival, proliferation and de-differentiation signals by activating various pathways.
Age-specific incidence of HL according to EBV status and countries' development based on the model by Jarrett (93) and data from Parkin DM et al; Cancer incidence in five continents; VIII, updated. IARC cancer Base No.7. Lyon, France: International Agency for Research on Cancer, 2005.
- "Hodgkin Disease"[Majr] AND "Epstein-Barr Virus Infections"[Majr]