Human herpesvirus 8+ polyclonal IgMλ B-cell lymphocytosis mimicking plasmablastic leukemia/lymphoma in HIV-infected patients

Abstract

Purpose: Multicentric Castleman disease (MCD) is a distinct lymphoproliferative disorder characterized by inflammatory symptoms, lymphadenopathy, splenomegaly, and cytopenia. Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8), is the cause of virtually all cases of MCD occurring in patients with HIV infection. MCD lesions characteristically contain HHV-8-infected polyclonal IgMλ plasmablasts. A high frequency of HHV-8-related non-Hodgkin lymphoma has been reported in these patients.

Patients and methods: We now report on three patients who presented with severe symptoms of MCD, extreme splenomegaly, and rapid expansion of B-cell lymphocytosis (44-81%) attributable to circulating HHV-8 positive plasmablasts.

Results: The circulating plasmablastic cells shared the phenotype (IgMλ, CD19+, CD20- CD138-) of HHV-8-infected cells from MCD lesions, mimicking the leukemic phase of large B-cell lymphoma occurring in HHV-8-related MCD. These patients displayed a very high HHV-8 viral load in blood (>7 logs HHV-8 DNA copies/ml) and high levels of serum vIL-6, the viral homolog of human interleukin 6. Serum IL-6 and IL-10 were also abnormally elevated. HHV-8-infected cells were demonstrated by immunoglobulin gene rearrangement analysis, to be polyclonal and likely represent an expansion of HHV-8-infected cells similar to those found in MCD lesions.

Conclusion: Thus, the spectrum of HHV-8-related plasmablastic lymphoproliferative disorders in patients with HIV infection is expanded to include HHV-8+ polyclonal IgMλ B-cell lymphocytosis. At onset, this lymphoproliferative disorder may mimic plasmablastic leukemia/lymphoma. Recognizing this unusual complication may have important implications in treatment decision avoiding unnecessary toxicity to the patients.

Keywords: HIV; human herpesvirus-8; lymphoma; multicentric Castleman disease.

Figure 1

Multicentric Castleman disease and HHV-8-positive polyclonal IgMλ B-cell lymphocytosis (patient 3). The two lymph node biopsies (before and after treatment) show typical features of multicentric Castleman disease. Immunostaining with the HHV-8 LNA-1-specific monoclonal antibody shows numerous, partly coalescent HHV-8-positive plasmablastic cells in the initial biopsy (A) and only a few HHV-8-positive cells in the second post-treatment biopsy (B). The blood smear shows numerous plasmablasts (C,D); the circulating plasmablastic cells stain positive for HHV-8 with the typical nuclear dotlike staining in brown (E). Bone marrow smear reveals the presence of large plasmablastic cells (yellow arrows) (F).

Figure 2

Flow cytometric analysis in patient 3 shows that circulating lymphocytes are mainly CD19+B cells (81%) with high expression of surface IgM and restricted lambda phenotype (99%) (A). IgH, IgLambda, and IgKappa (VkJk and Kde) clonality profiles from the diagnostic samples suspected of Bcell clonal proliferation show a clear pattern of polyclonal rearrangements. These reproducible profiles provide evidence for a polyclonal proliferation of the monotypic IgM Lambdapositive B cells (B).