Chronic/relapsing lymphadenopathy associated with HHV-6B infection: a new benign clinico-pathologic entity occurring in immunocompetent individuals

Background. HHV-6 DNA sequences were disclosed in lymph node (LN) tis- sues of several patients with lymphoid malignancies, but a direct major role of HHV-6 in lymphoid malignant transformation has so far not been confirmed. In contrast, active HHV-6 infection has been associated to either infectious mononucleosis-like syndrome or acute lymphadenitis occurring in febrilepatients with systemic symptoms, or to Rosai-Dorfman disease in which viral antigens have been detected by immunohistochimical (IHC) analyses in both histiocytes and follicular dendritic cells (FDCs). Methods. We have retrospec- tively analyzed clinical and pathological data of 365 adult patients, consecutive- ly observed at our Institution over a period of 5 years (2006-2010), because of enlarged superficial lymph nodes and subsequently undergoing lymphadenec- tomy. In the benign/reactive cases in which well-recognized etiologies have been excluded, an involvement of HHV-6 active infection or reactivation was investigated by molecular and immunohistochemical examinations. Results. Malignant disorders, namely malignant lymphoproliferative disorders or solid cancer metastases, were found in 227 cases (62%), whereas in 138 cases (38%) benign/reactive pictures were documented on lymph node examination. Among these latter cases, a well-recognized etiology was demonstrated in 84 patients (61%), while in 54 cases (39%), a well-defined non-malignant reactive/infectious cause could not be documented. Immunohistochemical analyses resulted negative for both HHV-6A and HHV-6B in 38 of these latter lymph nodes (70%). In 7 patients (13%), a scattered, scanty and aspecific pos- itivity for HHV-6B late protein was documented in rare interfollicular plasma cells and histiocytes. Surprisingly, in 9 patients (17%), immunohistochemical analyses showed HHV-6B positive staining of FDCs, together with scattered positivity of interfollicular cells. These 9 HIV-negative adult patients (median age 42 years, range 18-76 years), with either localized or generalized LAP, were observed for a median follow-up of 38 months (range 28-166). Of note, six of them presented with recurrent LAP (one to 3 recurrences), without evolving into lymphoma. A common LN histological pattern at presentation showed florid fol- licular hyperplasia with concurrent mild paracortical expansion. Three cases also showed features consistent with PTGC. Constitutional symptoms were absent in all patients. The IHC reactions for both HHV-6A and HHV-6B, per- formed on further control cases, represented by 131 LN tissues from patients with either benign LAP induced by other known etiologies or lymphoma, were invariably negative. Serology was positive for both IgM and IgG with high avid- ity suggesting viral reactivation/reinfection. However, the molecular analyses failed to detect HHV-6 viremias in cell-free-serum samples of all the 9 patients with positive HHV-6B IHC staining, while positivity for HHV-6B DNA was dis- closed by PCR analyses in 7 out of the 7 LN tissues studied. Conclusions. We show for the first time that local reactivation/infection of HHV-6B should be con- sidered among the possible causes of chronic/relapsing benign LAP in immuno- competent individuals. IHC is the method of choice for investigating the pres- ence of HHV-6 infection in such cases. HHV-6B may indirectly modulate and trigger the proliferation of lymphocytes, by locally affecting FDCs and LN microenvironment. FDCs may indeed be involved in presenting HHV-6B anti- gens to other immune cells, mainly cortical B lymphocytes.