A Relapsing Inflammatory Syndrome and HHV-8
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《新英格兰医药杂志》
To the Editor: The case of human herpesvirus 8 (HHV-8) reported by Dagna et al. (July 14 issue)1 is considered to be distinct from HHV-8–associated multicentric Castleman's disease owing to the absence of typical histologic findings and elevated plasma levels of interleukin-6. The histopathology of HHV-8–associated multicentric Castleman's disease is variable, as compared with the classic descriptions of HHV-8–negative Castleman's disease2,3,4 and would encompass the changes described in the report, especially in the context of cytotoxic treatment before biopsy. In HHV-8–associated multicentric Castleman's disease, the HHV-8–infected B-lineage cells can be seen either within the B-cell follicles or in the interstitium of many tissues, including bone marrow4,5 and lymph nodes, as seen in this case. Phenotypically, these cells resemble the plasmablasts in the follicles and the plasma cells in the interstitium. The infected cells secrete viral interleukin-6, which triggers an autocrine feedback loop involving human interleukin-6,3 as reflected by the elevated plasma levels of interleukin-6, particularly at the time of the biopsy.
The downstream effects of interleukin-6 are probably the cause of the clinical syndrome, which is indistinguishable from HHV-8–associated multicentric Castleman's disease. We feel that this case report represents an HHV-8–associated multicentric Castleman's disease, rather than a newly recognized HHV-8–associated inflammatory syndrome.
Ahmet Dogan, M.D., Ph.D.
Mayo Clinic
Rochester, MN 55905
dogan.ahmet@mayo.edu
Ming-Qing Du, M.B., Ph.D.
University of Cambridge
Cambridge CB2 2QQ, United Kingdom
Peter G. Isaacson, M.B., Ch.B.
University College London Hospitals
London WC1E 6JJ, United Kingdom
References
Dagna L, Broccolo F, Paties CT, at al. A relapsing inflammatory syndrome and active human herpesvirus 8 infection. N Engl J Med 2005;353:156-163.
Dupin N, Diss TL, Kellam P, et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 2000;95:1406-1412.
Du MQ, Liu H, Diss TC, et al. Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders. Blood 2001;97:2130-2136.
Bacon CM, Miller RF, Noursadeghi M, McNamara C, Du MQ, Dogan A. Pathology of bone marrow in human herpes virus-8 (HHV8)-associated multicentric Castleman disease. Br J Haematol 2004;127:585-591.
Meggetto F, Cesarman E, Mourey L, Massip P, Delsol G, Brousset P. Detection and characterization of human herpesvirus-8-infected cells in bone marrow biopsies of human immunodeficiency virus-positive patients. Hum Pathol 2001;32:288-291.
The authors reply: It seems to us that the issue raised by Dogan and colleagues is one of definition. From the clinical standpoint, severe symmetric arthrosynovitis (hardly ever observed in patients with HHV-8–associated multicentric Castleman's disease) was the referring symptom. Our patient had anemia of chronic inflammatory disease but none of the hematologic abnormalities and bone marrow features characteristically associated with HHV-8–associated multicentric Castleman's disease.1,2 On only two occasions was the level of human interleukin-6 increased; rather, it remained normal throughout the follow-up, regardless of disease activity.3 Although there is some variability in the features of Castleman's disease, some of which is apparently related to the HHV-8 infection,1,4 Castleman's disease remains primarily a morphologic diagnosis: a minimum set of criteria must be met or else the diagnosis ceases to have meaning. The microscopical appearance of the lymph nodes (including one excised before treatment) did not bear even a remote resemblance to any recognized type or variant of Castleman's disease. For these reasons, we do not believe that our patient should be given the diagnosis of Castleman's disease, but we do acknowledge the likelihood of a shared etiologic factor and pathogenesis.
Lorenzo Dagna, M.D.
Università Vita-Salute San Raffaele School of Medicine
I-20132 Milan, Italy
lorenzo.dagna@hsr.it
Juan Rosai, M.D.
Centro Diagnostico Italiano
I-20147 Milan, Italy
Paolo Lusso, M.D., Ph.D.
San Raffaele Scientific Institute
I-20132 Milan, Italy
References
Casper C. The aetiology and management of Castleman disease at 50 years: translating pathophysiology to patient care. Br J Haematol 2005;129:3-17.
Bacon CM, Miller RF, Noursadeghi M, McNamara C, Du MQ, Dogan A. Pathology of bone marrow in human herpes virus-8 (HHV8)-associated multicentric Castleman disease. Br J Haematol 2004;127:585-591.
Oksenhendler E, Carcelain G, Aoki Y, et al. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric Castleman disease in HIV-infected patients. Blood 2000;96:2069-2073.
Amin HM, Medeiros LJ, Manning JT, Jones D. Dissolution of the lymphoid follicle is a feature of the HHV8+ variant of plasma cell Castleman's disease. Am J Surg Pathol 2003;27:91-100.
The downstream effects of interleukin-6 are probably the cause of the clinical syndrome, which is indistinguishable from HHV-8–associated multicentric Castleman's disease. We feel that this case report represents an HHV-8–associated multicentric Castleman's disease, rather than a newly recognized HHV-8–associated inflammatory syndrome.
Ahmet Dogan, M.D., Ph.D.
Mayo Clinic
Rochester, MN 55905
dogan.ahmet@mayo.edu
Ming-Qing Du, M.B., Ph.D.
University of Cambridge
Cambridge CB2 2QQ, United Kingdom
Peter G. Isaacson, M.B., Ch.B.
University College London Hospitals
London WC1E 6JJ, United Kingdom
References
Dagna L, Broccolo F, Paties CT, at al. A relapsing inflammatory syndrome and active human herpesvirus 8 infection. N Engl J Med 2005;353:156-163.
Dupin N, Diss TL, Kellam P, et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 2000;95:1406-1412.
Du MQ, Liu H, Diss TC, et al. Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders. Blood 2001;97:2130-2136.
Bacon CM, Miller RF, Noursadeghi M, McNamara C, Du MQ, Dogan A. Pathology of bone marrow in human herpes virus-8 (HHV8)-associated multicentric Castleman disease. Br J Haematol 2004;127:585-591.
Meggetto F, Cesarman E, Mourey L, Massip P, Delsol G, Brousset P. Detection and characterization of human herpesvirus-8-infected cells in bone marrow biopsies of human immunodeficiency virus-positive patients. Hum Pathol 2001;32:288-291.
The authors reply: It seems to us that the issue raised by Dogan and colleagues is one of definition. From the clinical standpoint, severe symmetric arthrosynovitis (hardly ever observed in patients with HHV-8–associated multicentric Castleman's disease) was the referring symptom. Our patient had anemia of chronic inflammatory disease but none of the hematologic abnormalities and bone marrow features characteristically associated with HHV-8–associated multicentric Castleman's disease.1,2 On only two occasions was the level of human interleukin-6 increased; rather, it remained normal throughout the follow-up, regardless of disease activity.3 Although there is some variability in the features of Castleman's disease, some of which is apparently related to the HHV-8 infection,1,4 Castleman's disease remains primarily a morphologic diagnosis: a minimum set of criteria must be met or else the diagnosis ceases to have meaning. The microscopical appearance of the lymph nodes (including one excised before treatment) did not bear even a remote resemblance to any recognized type or variant of Castleman's disease. For these reasons, we do not believe that our patient should be given the diagnosis of Castleman's disease, but we do acknowledge the likelihood of a shared etiologic factor and pathogenesis.
Lorenzo Dagna, M.D.
Università Vita-Salute San Raffaele School of Medicine
I-20132 Milan, Italy
lorenzo.dagna@hsr.it
Juan Rosai, M.D.
Centro Diagnostico Italiano
I-20147 Milan, Italy
Paolo Lusso, M.D., Ph.D.
San Raffaele Scientific Institute
I-20132 Milan, Italy
References
Casper C. The aetiology and management of Castleman disease at 50 years: translating pathophysiology to patient care. Br J Haematol 2005;129:3-17.
Bacon CM, Miller RF, Noursadeghi M, McNamara C, Du MQ, Dogan A. Pathology of bone marrow in human herpes virus-8 (HHV8)-associated multicentric Castleman disease. Br J Haematol 2004;127:585-591.
Oksenhendler E, Carcelain G, Aoki Y, et al. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric Castleman disease in HIV-infected patients. Blood 2000;96:2069-2073.
Amin HM, Medeiros LJ, Manning JT, Jones D. Dissolution of the lymphoid follicle is a feature of the HHV8+ variant of plasma cell Castleman's disease. Am J Surg Pathol 2003;27:91-100.