Abstract
Human Herpes virus 8 (HHV8) associated multicentric Castleman’s disease (MCD) is an unusual multifocal lymphoid hyperplasia induced by HHV8 infected B cells and associated with a characteristic systemic syndrome attributed to raised levels of IL-6. Most cases develop on a background of immunosuppression, often as a result of human immunodeficiency virus (HIV) infection. Despite the haematological problems at presentation and the difficulties in initial diagnosis, the bone marrow appearances of MCD have not been so far described. In this study we examined the pathology of bone marrow in 13 patients with MCD, 11 of whom had HIV infection, with a view to identifying features that may be helpful in early diagnosis. Patients typically presented with fever, lymphadenopathy, hepatosplenomegaly and cytopaenias. Bone marrow aspirates showed mild to moderate trilineage dysplasia, a mild plasmacytosis, and a mild eosinophilia similar to that seen in HIV infected patients without MCD. Bone marrow biopsies showed hypercellularity, architectural disorganisation, variably prominent dysplasia especially in megakaryocytes, mild eosinophilia, and a polytypic plasmacytosis representing 5–20% of all cells. Interestingly, two cases showed marked megakaryocytic and granulocytic hyperplasia with reticulin fibrosis, similar to the effects of IL-6 on the marrow in experimental systems. Importantly, in 3 cases there were small lymphoid follicles typical of MCD in diagnostic nodal specimens. Depleted germinal centres were surrounded by mantle zones containing scattered large plasmablasts which expressed HHV8 latent nuclear antigen (LNA) and showed lambda immunoglobulin light chain restriction. Furthermore, varying numbers of dispersed interstitial HHV8-LNA positive plasmablasts were present in 11/13 cases. Double immunohistochemical staining confirmed the B cell phenotype of these plasmablasts. The presence of these cells was highly specific for MCD as rare single HHV8 positive cells were identified in only 4 of 66 control bone marrow biopsies from HIV positive patients. Each of these 4 patients had Kaposi’s sarcoma and 1 also had a primary effusion lymphoma. HHV8 positive cells were not identified in bone marrow biopsies from 23 other HIV positive patients with lymphoma. These results suggest that the presence of HHV8 positive plasmablasts in bone marrow biopsies, within characteristic lymphoid follicles and/or the interstitium, is highly specific and sensitive for MCD. As the examination of bone marrow is the first diagnostic test performed in virtually all MCD patients, the features described in this study should greatly enhance the chances of early diagnosis by either providing the tissue diagnosis or prompting a lymph node biopsy and further investigations. Furthermore, the HHV8 positive cells within the bone marrow may play an important pathogenetic role in the haematological disturbances typically seen in MCD.
Early Diagnosis of Primary HIV Infection by Fourth Generation ELISA in Spouses of HIV-Positive Patients and STD Clinic Attendees
