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Role of Viruses in Leukemia and Lymphoma

Dr Sampurna Roy MD

 

                                                                                                                      

 

Several new lymphotropic viruses have been identified and new associations between known viruses and disease have emerged.

There are two families of viruses that contribute to lymphomagenesis in humans: herpesviruses and retroviruses.

The two herpesviruses are the Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8).

Human T-cell leukemia virus-1 (HTLV-1) is a retrovirus which is the causative agent of adult T-cell leukemia/lymphoma (ATL).

Infection with human immunodeficiency virus (HIV) is also associated with a greatly increased risk of lymphoma development although here the role of the virus appears to be indirect.

Related post: AIDS related malignant tumours

Lymphotropic Herpesviruses:

Related post: Epstein-Barr Virus Related Malignant Tumours

EBV was first identified because of its involvement in Burkitt’s lymphoma (BL) and was later shown to be associated with infectious mononucleosis and nasopharyngeal carcinoma.

The virus is almost invariably found in endemic BL which occurs in areas of malaria such as equatorial Africa and Papua New Guinea.

It is also associated with the majority of Burkitt’s lymphoma cases in South America but is less often found in sporadic and AIDS-associated BL.

In EBV-associated cases, all of the tumour cells are infected by virus and the viral infection is clonal suggesting that the virus is likely to play a role in disease pathogenesis.

Viral gene expression, however, is tightly restricted with  only one nuclear protein, EBNA1, and the small EBER RNA molecules being expressed.

EBV is also associated with lymphomas occurring in immunosuppressed persons, notably transplant recipients and AIDS patients.

The B-cell lymphoproliferative disease (BLPD) lesions seen in transplant patients in many ways resemble lymphoblastoid cell lines generated by infection of  peripheral blood in vitro.

Lesions may regress following reduction or withdrawal of immuno-suppressive therapy, even at a stage when they appear monoclonal. This suggests that these tumours are purely virally driven, at least in the early stage.

In the last decade EBV has been firmly linked to a proportion of cases of Hodgkin’s disease.

In EBV-associated cases the virus is present in all Reed-Sternberg cells, the viral infection is clonal and EBV gene products are expressed.

In addition to the EBNA1 protein and EBER RNAs, Reed-Sternberg cells express the LMP-1 protein which is known  to have oncogenic potential in experimental systems, thus it would appear likely that the virus is contributing to disease pathogenesis.

In developed countries EBV-associated cases account for about a third of all cases.

Mixed cellularity cases are much more likely to be EBV-positive than nodular sclerosis cases and paediatric and older adult cases are more likely to be positive than cases on the young adult age incidence peak.

EBV is also invariably associated with several other rarer tumors including pyothorax-associated lymphomas and nasal NK/T-cell lymphomas (lethal midline granuloma).

The virus is also frequently found is association with HHV-8 or Kaposi’s sarcoma-associated herpes virus (KSHV) is the most recently identified human herpes virus.

Viral genomes were first detected in Kaposi's Sarcoma (KS) using molecular techniques and it was only later viral particles were visualized by electron microscopy.

HHV-8 is associated with all forms of KS although whether  it is causal remains to be determined.

The virus is also associated with primary effusion lymphomas and multicentric Castleman’s disease and here, particularly in the former condition, a role in the pathogenesis appears more certain.

Recently it has been suggested HHV-8 may have an indirect role in multiple myeloma  (virus encodes a homologue of the interleukin 6 protein).

Retrovirus:

HTLV-1 was the first human retrovirus to be identified and is causally associated  with adult  T-cell leukaemia, an aggressive malignancy of mature T-cells.

Unlike EBV, HTLV-1 has a restricted geographical distribution and incidence follows the occurrence of the virus.

Retroviruses have much smaller genomes than herpesviruses, however HTLV-1 encodes several proteins,in addition to the viral structural proteins, which are believed to be involved in transformation.

The most well characterized of these is the Tax protein which has the ability to up-regulate viral and  cellular genes including the interleukin-2 receptor gene.

In 1997 the identification of a fifth human retrovirus  (HRV5) was reported.

Little is known about this virus at present as  it has not been possible to grow it in vitro and the virus has only been found at very low levels in clinical samples.

Any association with leukaemia and lymphoma remains to be determined.

There is now very clear evidence for an association between several human viruses and a diverse range of lymphoid diseases. 

It is likely that with the availability of more sophisticated techniques additional viruses will be identified in the future and more disease associations will emerge.

Further reading:

Molecular characterization of human T-cell lymphotropic virus type 1 full and partial genomes by illumina massively parallel sequencing technology.

Inhibition of Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by HIV-1 Nef and Cellular MicroRNA Hsa-miR-1258.

Virus-associated lymphomas.

Virus-associated lymphomagenesis.

The roles of human viruses in the pathogenesis of lymphoma.

Human lymphotropic viruses associated with lymphoid malignancy: Epstein-Barr and HTLV-1.

Immunologic markers, uveitis, and kerato conjunctivitis  sicca associated with human T-cell lymphotropic virus type 1.

 

 

Dr Sampurna Roy  MD

Consultant  Histopathologist (Kolkata - India)


 

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