Correspondence
Expression of Epstein-Barr Virus in Liver-Transplant Recipients with Lymphoproliferative Disease
N Engl J Med 1993; 329:208-209July 15, 1993
- Article
To the Editor:
I agree with the conclusions of Randhawa et al. (Dec. 10 issue)1 that liver-biopsy specimens showing evidence of the expression of the EBER-1 gene may be useful for predicting the development of post-transplantation lymphoproliferative disease and for allowing the premorbid adjustment of immunomodulators. I was surprised, however, that neither the authors nor the editorialist2 raised the issue of examining tissues other than liver as sentinel sites of latent Epstein-Barr virus (EBV). In their discussion, Randhawa et al. list oropharyngeal mucosa, lymph nodes, and circulating lymphocytes as sites of EBV latency. Indeed, only 7 of the 24 patients with post-transplantation lymphoproliferative disease presented with the liver as the initial site of involvement. Positive findings in the livers of most of the patients without clinically apparent hepatic involvement attest to the systemic nature of the EBV-related process.
Did the authors examine or have others examined lymph-node or bone marrow biopsies for either characteristic histopathological changes or EBER-I messenger RNA? The lower risk of these procedures might obviate the need for liver biopsies in some, if not all, of these patients.
2 ReferencesJ. Boyd Francis, M.D.
Roanoke Memorial Hospitals, Roanoke, VA 240331
Randhawa PS ,Jaffe R ,Demetris AJ , et al. Expression of Epstein-Barr virus-encoded small RNA (by the EBER-1 gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease. N Engl J Med 1992;327:1710-1714
Full Text | Web of Science | Medline2
Pagano JS . Epstein-Barr virus: culprit or consort? N Engl J Med 1992;327:1750-1752
Full Text | Web of Science | Medline
To the Editor:
In his editorial (Dec. 10 issue),1 Dr. Pagano discusses the role of EBV in lymphoproliferative syndromes associated with immunosuppressive therapy or immunodeficiency. He states that polyclonal lymphomas “may become monoclonal, and their growth may not be reversed by reducing immunosuppression.” We believe that this may be an inappropriate use of the word “lymphoma.” To the pathologist “lymphoma” implies a malignant monoclonal population of lymphocytes, and inherent in the word “malignant” is the idea of autonomous proliferation. The polyclonal-oligoclonal-monoclonal evolution of EBV-driven lymphocyte infiltrates is well recognized, as is the fact that EBV-driven lymphoproliferative syndromes may behave in a clinically malignant manner while still polyclonal. However, a distinction ought to be made between “clinical” and “pathological” malignancy. Since lymphoproliferative syndromes are virally driven, removal of the stimulating factor during the polyclonal or oligoclonal phase results in regression of the lesions. Thus, there is no real autonomy of proliferation. Lymphoproliferative lesions should be called lymphomas only when they have become monoclonal and are no longer dependent on extrinsic factors for proliferation.
1 ReferencesM. Ilyas, M.B., Ch.B., B.S.
N. Trendell-Smith, M.B., B.S., B.Sc.
D. Snead, M.B., B.S.
Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom1
Pagano JS . Epstein-Barr virus: culprit or consort? N Engl J Med 1992;327:1750-1752
Full Text | Web of Science | Medline
Author/Editor Response
Dr. Randhawa replies:
To the Editor: I greatly appreciate Dr. Francis' comments, but would like to reiterate that our study was based on liver-transplant recipients. Monitoring allograft function by serial liver biopsies is almost routine in these patients, whereas occasions to sample the lymph nodes, bone marrow, oropharyngeal mucosa, and salivary glands arise only infrequently in this patient population. I suspect that if these other known sites of viral latency could be serially examined in these patients, the results would be similar to those in the liver. It has been shown, for example, that lymph-node biopsies of patients with AIDS demonstrate EBV genomes before the actual development of non-Hodgkin's lymphoma.1 The most practical way of monitoring the development of EBV-associated lymphoproliferative disease in immunosuppressed persons would be to examine the expression of the EBER-1 gene serially in the circulating lymphocytes. To the best of my knowledge, such studies have not yet been performed.
1 ReferencesParmjeet Randhawa, M.D.
Presbyterian University Hospital, Pittsburgh, PA 152131
Shibata D ,Weiss LM ,Nathwani BN ,Brynes RK ,Levine AM . Epstein-Barr virus in benign lymph node biopsies from individuals infected with the human immunodeficiency virus is associated with concurrent or subsequent development of non-Hodgkin's lymphoma. Blood 1991;77:1527-1533
Web of Science | Medline
Author/Editor Response
Dr. Pagano replies:
To the Editor: I agree with the distinction made by Ilyas et al. In other words, secondary genetic charges are probably needed before such lymphoproliferative conditions become autonomous. However, it has not yet been possible to remove the “stimulating factor” -- namely, EBV -- in order to prove the point. Reducing immunosuppression does lead to the regression of early EBV lymphoproliferation. My colleagues and I are trying to block the replication of EBV episomes in EBV-driven lymphocyte lines with antisense oligomers and have retarded or stopped the growth of EBV-immortalized cell lines using this strategy.1
1 ReferencesJoseph S. Pagano, M.D.
University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC 275991
Pagano JS ,Jimenez G . Epstein-Barr viral latency and cell immortalization as targets for antisense oligomers. Ann N Y Acad Sci 1992;660:107-116
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Ronald D. Holmes, Kathy Orban-Eller, Frederick R. Karrer, David T. Rowe, Michael R. Narkewicz, Ronald J. Sokol. (2002) Response of elevated Epstein-Barr virus DNA levels to therapeutic changes in pediatric liver transplant patients: 56-month follow up and outcome. Transplantation 74:3, 367-372
CrossRef2
Ziv Ben-Ari, Peter Amlot, Surech R. Lachmanan, Ran Tur-Kaspa, Keith Rolles, Andrew K. Burroughs. (1999) Posttransplantation lymphoproliferative disorder in liver recipients: Characteristics, management, and outcome. Liver Transplantation and Surgery 5:3, 184-191
CrossRef3
Eric Raymond, Vivianne Tricottet, Didier Samuel, Michel Reynès, Henri Bismuth, Jean-Louis Misset. (1995) Epstein-Barr virus-related localized hepatic lymphoproliferative disorders after liver transplantation. Cancer 76:8, 1344-1351
CrossRef
