Lymphadenitis and lymphoproliferative lesions associated with the human herpes virus-6 (HHV-6)

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Abstract
A newly described herpes virus, human herpes virus 6, (HHV-6), has been linked to exanthema subitum but beyond this its pathogenetic impact remains to be determined. A large body of evidence links it to various lymphoproliferative disorders and this study was conducted to identify forms of lymphoproliferation linked to HHV-6. We studied biopsy samples from 32 patients with disorders of the lymphatic system for the presence of HHV-6, both by polymerase chain reaction (PCR) and in-situ hybridization (ISH) methods, as well as Epstein-Barr virus (EBV) viral DNA, clonal rearrangements of the antigen receptor genes and bcl-2 genes. All the specimens were studied morphologically and a clinical follow-up of up to 4 years was obtained. Seven of the 32 patients were positive for HHV-6 DNA and the remainder were negative. Two of these HHV-6 positive specimens, both from elderly persons, showed a similar distinct histological pattern diagnosed as malignant B-cell lymphoma of high grade malignancy. Two other HHV-6-positive specimens were reactive lymphadenopathies occuring in younger adults. In addition, one further specimen with evidence of EBV-involvement was from a patient who died 3 months after biopsy with fatal infectious mononucleosis (IM). These five samples had HHV-6 DNA by PCR and ISH. Two specimens without specific histologic abnormalities showed evidence of HHV-6 only by PCR but not by ISH. Both high grade malignant lymphomas showed clonal proliferations, one of monoclonal B-cells and the other of clonal T-cells. All the other HHV-6-positive samples presented a polyclonal pattern. The malignant lymphomas positive for HHV-6 had a supprising clinical course. After the initiation of anti-tumor therapy, both showed complete remission, one with a follow-up of 3 years and the other of 1 year. These data suggest that there are well defined lymphoproliferative lesions linked to HHV-6. These include a reactive polyclonal lymphadenitis in which, under certain, as yet undefined conditions, a monoclonal lymphoma may arise. The latter has a typical morphology and clinical behavior, which in the patients studied, showed rapid regression after therapy.