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HHV-6 Positive Reed-Sternberg Cells in Nodular Sclerosis Hodgkin Lymphoma

Alexa J. Siddon, MD1, Larissa Lozovatsky1, Ayman Mohamed2, and S. David Hudnall, MD1

Department of 1Pathology, Yale School of Medicine, and 2 Precipio Diagnostics, New Haven, CT, USA


Classical Hodgkin lymphoma (HL) is comprised of malignant Reed-Sternberg (RS) cells scattered within a mixed inflammatory background. The unusual bimodal age distribution of HL suggests that infectious agents may play a role in etiology. The presence of Epstein-Barr virus (EBV) within the RS cells in a proportion of HL cases supports this idea.  However, the most common subtype of HL, nodular sclerosis HL (NSHL), is the subtype least often EBV-associated.
HHV-6 is a near-ubiquitous herpesvirus first acquired in childhood characterized most often by asymptomatic life-long persistence. Since  a few reports have suggested a role for HHV-6 in HL, we have analyzed a cohort of NSHL cases for both EBV and HHV-6, and sought to specifically localize these viruses to the malignant RS cells.
Formalin-fixed paraffin-embedded lymph nodes from 20 primary cases of NSHL were examined by EBER ISH, HHV-6 IHC, and HHV-6 PCR followed by Southern blot. In cases with HHV-6 positive RS cells by IHC, laser capture microdissection (LCM) was performed to collect purified RS cells. DNA from LCM-captured RS cells was extracted, amplified by whole genome amplication, and subjected to HHV-6 PCR to confirm that the RS cells were HHV-6 positive.
Of 17 cases of NSHL, 13 were HHV-6 PCR positive (76%). Five of 20 cases (25%) contained numerous EBV positive RS cells and 10 of 21 cases (48%) contained numerous HHV-6 positive RS cells by IHC (in 3 cases RS cells were positive for both HHV-6 and EBV). The presence of HHV-6 specifically within RS cells was confirmed both by HHV-6 PCR on LCM-captured RS cells and by HHV-6 FISH.
We have demonstrated that HHV-6 genome is present within the neoplastic RS cells of a significant proportion of NSHL cases, most of which were EBER ISH negative. These findings support that in some cases, HHV-6 may play a role in the etiology of NSHL. Further studies to examine the contribution of HHV-6 to the etiology of HL are ongoing.  


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