Correspondence

Herpes-Like DNA Sequences, AIDS-Related Tumors, and Castleman's Disease

N Engl J Med 1995; 333:797-799September 21, 1995

Article

To the Editor:

An apparently new human herpesvirus, designated Kaposi's sarcoma–associated herpesvirus (KSHV) or human herpesvirus 8, has recently been identified in samples of Kaposi's sarcoma from patients infected with the human immunodeficiency virus (HIV).1 In the May 4 issue of the Journal, Moore and Chang2 reported finding KSHV DNA in samples of Kaposi's sarcoma from patients without HIV infection, and Cesarman et al.3 described finding KSHV DNA in an unusual high-grade body-cavity–based lymphoma in HIV-infected patients. The lymphoma shows a strong tendency toward primary involvement of body-cavity surfaces without local or distant spread to other viscera.4

To date, we have encountered five cases of body-cavity–based lymphoma in HIV-infected patients; in three cases DNA from fresh-frozen tumor tissue was available for analysis. We performed polymerase-chain-reaction (PCR) analysis on these three samples, using primers to amplify the 233-base-pair (bp) KS330₂₃₃ fragment of KSHV DNA, as described by Chang and coworkers.1 The results of this analysis are shown in Figure 1Figure 1PCR Amplification of KSHV DNA with KS330₂₃₃Primers.. KSHV DNA was identified in all three samples of body-cavity–based lymphoma, as well as a sample of HIV-associated Kaposi's sarcoma, but not in the other samples analyzed.

Our findings support the apparently close association of HIV-related body-cavity–based lymphoma with KSHV infection. In previous analyses of tumor tissue from two of the three patients,4 we identified clonal rearrangements of the immunoglobulin heavy-chain gene and Epstein–Barr virus (EBV) DNA sequences in both patients, but no evidence of a rearrangement of the c-myc oncogene in either. This is similar to the findings of Cesarman and colleagues3 and reinforces the idea that this unusual B-cell lymphoma has a unique genotypic character, which may be induced by an as yet undefined interaction between KSHV and EBV, without the need for c-myc activation.

Although these DNA findings shed light on the possible causation of this type of lymphoma, the reason underlying its unusual propensity to involve only body-cavity surfaces remains a mystery. One possible explanation may be deduced from our data and those of Cesarman et al.3 The detection of KSHV DNA in all 11 HIV-related body-cavity–based lymphomas analyzed thus far, but not in any of the 186 samples of nearly every other conceivable type of lymphocytic neoplasm from patients with and those without HIV infection, suggests that KSHV may reside in latent form (“hide,” to use Roizman's term5) in a rare, previously undescribed B-lymphocyte subtype that exhibits, either innately or as a result of KSHV or HIV infection (or both), a peculiar homing pattern primarily for body-cavity surfaces. This B lymphocyte, under the influence of KSHV and EBV infection, may then be a target of other factors (but not rearrangements of the c-myc oncogene) associated with HIV infection that contribute to B-cell lymphomagenesis.

Donald S. Karcher, M.D.
Serhan Alkan, M.D.
George Washington University Medical Center, Washington, DC 20037

5 References

1. 1

   Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994;266:1865-1869
   CrossRef | Web of Science | Medline

2. 2

   Moore PS, Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and those without HIV infection. N Engl J Med 1995;332:1181-1185
   Full Text | Web of Science | Medline

3. 3

   Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 1995;332:1186-1191
   Full Text | Web of Science | Medline

4. 4

   Karcher DS, Dawkins F, Garrett CT, Schulof RS. Body cavity-based nonHodgkin's lymphoma (NHL) in HIV-infected patients: B-cell lymphoma with unusual clinical, immunophenotypic, and genotypic features. Lab Invest 1992;66:Suppl:80A-80A abstract.
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5. 5

   Roizman B. New viral footprints in Kaposi's sarcoma. N Engl J Med 1995;332:1227-1228
   Full Text | Web of Science | Medline

To the Editor:

Herpesvirus-like DNA sequences have been found in association with Kaposi's sarcoma and with body-cavity–based lymphomas related to AIDS.1-4 Castleman's disease is characterized by morphologic features of angiofollicular hyperplasia and is clinically associated with fever, adenopathy, and splenomegaly. Castleman's disease has been reported in patients with AIDS. Because Castleman's disease is frequently reported in patients with Kaposi's sarcoma, we hypothesized that KSHV could be implicated in its pathogenesis. We report here the presence of DNA sequences similar to those of KSHV in peripheral-blood mononuclear cells (PBMCs) from two patients with Castleman's disease and AIDS.

Patient 1 was an HIV-1–positive 47-year-old man. He had no evidence of Kaposi's sarcoma lesions. He had a normal CD4 count (816 per cubic millimeter). He presented with cyclic fever, multifocal enlargement of peripheral lymph nodes, and splenomegaly. Castleman's disease was confirmed by histologic examination of the spleen after splenectomy. Treatment with an infusion of etoposide every three weeks was begun and was still being given at the time of this report.

Patient 2 was an HIV-1–positive 65-year-old man. He had had Kaposi's sarcoma with few cutaneous lesions that had completely disappeared after therapy with interferon alfa-2b. His CD4 count was 300 per cubic millimeter. He presented with fever and splenomegaly. Castleman's disease was diagnosed on the basis of the pathological examination of the spleen after splenectomy. Treatment consisted of an infusion of vinblastine every three weeks and 2 million units of interferon alfa-2b per day.

In both cases, treatment led to a substantial response, with remission of fever and complete regression of adenopathy. Nevertheless, the discontinuation of treatment for more than three weeks resulted in the reemergence of clinical symptoms and an inflammatory syndrome.

DNA was directly purified from uncultured PBMCs. Samples were tested for the presence of KSHV sequences by means of PCR with primers and the KS330₂₃₃ probe as described by Chang et al.1 In both samples, a DNA fragment of 233 base pairs was amplified and provided a strong positive signal after hybridization with the internal probe.

As described elsewhere, the detection of herpesvirus-like DNA sequences in PBMCs from patients with Kaposi's sarcoma seems to be uncommon.5,6 So the detection of such sequences in PBMCs from patients with Castleman's disease could be an argument for the implication of this new viral agent in the pathogenesis of this disease. In agreement is the fact that Castleman's disease is more frequently observed in patients with Kaposi's sarcoma. Our preliminary findings suggest that the same viral agent is implicated in both diseases. This hypothesis deserves to be confirmed by further studies.

Nicolas Dupin, M.D.
Isabelle Gorin, M.D.
Jean Deleuze, M.D.
Groupe Hospitalier Cochin–Port Royal, 75006 Paris, France

Henri Agut, M.D., Ph.D.
Jean-Marie Huraux, M.D.
Groupe Hospitalier Pitié–Salpêtrière, 75013 Paris, France

Jean-Paul Escande, M.D.
Groupe Hospitalier Cochin–Port Royal, 75006 Paris, France

6 References

1. 1

   Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994;266:1865-1869
   CrossRef | Web of Science | Medline

2. 2

   Huang YQ, Li JJ, Kaplan MH, et al. Human herpesvirus-like nucleic acid in various forms of Kaposi's sarcoma. Lancet 1995;345:759-761
   CrossRef | Web of Science | Medline

3. 3

   Dupin N, Grandadam M, Calvez V, et al. Herpesvirus-like DNA sequences in patients with Mediterranean Kaposi's sarcoma. Lancet 1995;345:761-762
   CrossRef | Web of Science | Medline

4. 4

   Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 1995;332:1186-1191
   Full Text | Web of Science | Medline

5. 5

   Collandre H, Ferris S, Grau O, Montagnier L, Blanchard A. Kaposi's sarcoma and new herpesvirus. Lancet 1995;345:1043-1043
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   Lebbe C, de Cremoux P, Rybojad M, Costa da Cunha C, Morel P, Calvo F. Kaposi's sarcoma and new herpesvirus. Lancet 1995;345:1180-1180
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The detection by Dupin et al. of KSHV DNA in PBMCs from patients with Castleman's disease and the confirmatory report by Karcher and Alkan of the detection of KSHV DNA in body-cavity–based lymphomas provide additional evidence that KSHV is a lymphotropic gamma herpesvirus. Kaposi's sarcoma is epidemiologically associated with lymphoproliferative disorders in both HIV-infected patients1 and those without HIV infection.2 In addition, an association with the systemic form of Castleman's disease has been reported.3 Recently, Soulier et al. demonstrated, by PCR as well as Southern hybridization, a strong association between KSHV DNA sequences and HIV-associated multicentric Castleman's disease tissues.4 They also tested PBMCs from one patient and found the DNA to be positive according to PCR only. Additional surveys are needed to determine the prevalence of KSHV infection in disorders not associated with Kaposi's sarcoma.

We disagree with Dupin and colleagues that the detection of KSHV DNA in lymphocytes from patients with kaposi's sarcoma is uncommon. In a large, blinded case–control study, we have reproducibly detected KSHV DNA by nested PCR in more than half of the PBMC samples from patients with kaposi's sarcoma (unpublished data). In contrast, only approximately 10 percent of PBMC samples from HIV-infected patients in whom kaposi's sarcoma does not develop are positive. It is unlikely that the findings of Dupin et al. are coincidental, especially in the light of the study by Soulier et al., but caution is appropriate in interpreting PCR-based studies of lymphocytes.

Patrick S. Moore, M.D., M.P.H.
Yuan Chang, M.D.
Columbia University, New York, NY 10032

4 References

1. 1

   Biggar RJ, Curtis RE, Cote TR, Rabkin CS, Melbye M. Risk of other cancers following Kaposi's sarcoma: relation to acquired immunodeficiency syndrome. Am J Epidemiol 1994;139:362-368
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2. 2

   Safai B, Mike V, Giraldo G, Beth E, Good RA. Association of Kaposi's sarcoma with second primary malignancies: possible etiopathogenic implications. Cancer 1980;45:1472-1479
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3. 3

   Frizzera G, Banks PM, Massarelli G, Rosai J. A systemic lymphoproliferative disorder with morphologic features of Castleman's disease: pathological findings in 15 patients. Am J Surg Pathol 1983;7:211-231
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4. 4

   Soulier J, Grollet L, Oksenhendler E, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 1995;86:1276-1280
   Web of Science | Medline

Author/Editor Response

We are pleased to learn that an independent laboratory has confirmed our findings that KSHV is consistently present in AIDS-related body-cavity–based lymphomas. Karcher and Alkan have also confirmed our finding that these KSHV-containing body-cavity–based lymphomas usually have clonal rearrangements of the immunoglobulin gene, contain Epstein–Barr virus, and do not have rearrangements of the c-myc gene. Unfortunately, they did not investigate other lymphoid neoplasms and thus cannot confirm our observation that among non-Hodgkin's lymphomas only body-cavity–based lymphomas contain KSHV. Karcher and Alkan suggest that the “propensity [of body-cavity–based lymphomas] to involve only body-cavity surfaces” can be explained by the existence of a rare, previously undescribed B cell latently infected with KSHV and having a “peculiar homing pattern for body-cavity surfaces” that may be a “target of other factors . . . that contribute to . . . lymphomagenesis.” We believe that this suggestion is highly speculative. Although the consistency of the association strongly suggests that KSHV has an important role in the development of AIDS-related body-cavity–based lymphomas, multiple alternative mechanisms can be postulated to explain the presence of KSHV in these lymphomas, and sufficient evidence is lacking to support a specific pathogenetic pathway at this time.

Dupin and coworkers report finding KSHV sequences in peripheral-blood mononuclear cells in two HIV-infected patients with Castleman's disease. This report is intriguing in view of the known association between Kaposi's sarcoma and Castleman's disease and the recent discovery of KSHV sequences in peripheral-blood B cells of patients with Kaposi's sarcoma.1 Unfortunately, Dupin and colleagues did not analyze DNA from tissues involved by Castleman's disease and thus failed to link KSHV directly to Castleman's disease. However, we recently discovered KSHV in DNA from such tissues that were obtained from two HIV-negative patients with multicentric Castleman's disease (unpublished data). Therefore, the spectrum of diseases containing KSHV now includes AIDS and non-AIDS–associated Kaposi's sarcoma, body-cavity–based lymphomas, and Castleman's disease. Rady and coworkers2 reported finding KSHV sequences in various cutaneous lesions in four organ-transplant recipients. However, we are not certain that KSHV is specifically associated with those lesions. The presence of KSHV in various cutaneous lesions and in uninvolved skin may reflect disseminated KSHV infection in these immunocompromised patients. KSHV sequences were identified by Chang et al.3 in uninvolved tissues obtained from patients with Kaposi's sarcoma. Therefore, it still appears that KSHV is confined to a limited number of well-defined clinical and pathological entities.

Ethel Cesarman, M.D., Ph.D.
Daniel M. Knowles, M.D.
New York Hospital–Cornell Medical Center, New York, NY 10021

3 References

1. 1

   Ambroziak JA, Blackbourn DJ, Herndier BG, et al. Herpes-like sequences in HIV-infected and uninfected Kaposi's sarcoma patients. Science 1995;268:582-583
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2. 2

   Rady PL, Yen A, Rollefson JL, et al. Herpesvirus-like DNA sequences in non-Kaposi's sarcoma skin lesions of transplant patients. Lancet 1995;345:1339-1340
   CrossRef | Web of Science | Medline

3. 3

   Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994;266:1865-1869
   CrossRef | Web of Science | Medline

Citing Articles (21)

Citing Articles

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   Suzane Ramos da Silva, Ana Paula Ferraz da Silva, Maura Moscardi Bacchi, Carlos Eduardo Bacchi, Deilson Elgui de Oliveira. (2011) KSHV genotypes A and C are more frequent in Kaposi sarcoma lesions from Brazilian patients with and without HIV infection, respectively. Cancer Letters 301:1, 85-94
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   Eiju Kanagawa, Osamu Horiike. (2009) A Case of Castleman's Disease of the Neck. Practica Oto-Rhino-Laryngologica 102:9, 761-766
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   Fangping He, Xing Wang, Bin He, Zongdi Feng, Xiaomei Lu, Yaoxin Zhang, Shujun Zhao, Renyong Lin, Yan Hui, Yongxing Bao, Zhaoxia Zhang, Hao Wen. (2007) Human herpesvirus 8: Serovprevalence and correlates in tumor patients from Xinjiang, China. Journal of Medical Virology 79:2, 161-166
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   Tom Newsom-Davis, Mark Bower, Adrian Wildfire, Christina Thirlwell, Mark Nelson, Brian Gazzard, Justin Stebbing. (2004) Resolution of AIDS-related Castleman's Disease with Anti-CD20 Monoclonal Antibodies is Associated with Declining IL-6 and TNF-α Levels. Leukemia & Lymphoma 45:9, 1939-1941
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   Daniel M Knowles. (2003) Etiology and pathogenesis of AIDS-related non-Hodgkin's lymphoma. Hematology/Oncology Clinics of North America 17:3, 785-820
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   Hal B. Jenson. (2003) Human herpesvirus 8 infection. Current Opinion in Pediatrics 15:1, 85-91
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   JEAN-LOUIS ALBERINI, PHILIPPE BLANCHE, FLORENCE TENENBAUM, ANNABELLE MERLAT-GUITARD, JEAN- YVES DEVAUX, FRANÇOIS DREYFUS, DIDIER SICARD, BRUNO RICHARD. (2003) Ga-67 in Castleman’s Disease. Clinical Nuclear Medicine 28:2, 157-159
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