Blood, 15 August 2000, Vol. 96, No. 4, pp. 1614-1616
CORRESPONDENCE
To the Editor:
Ly-1b cells and Castleman disease
We read with interest and some disappointment the paper by
Dupin et al on HHV-8 in Castleman disease (CD).1 Regarding
their observations concerning the evolution of clonal populations of HHV-8-positive B cells in this study, Dupin et al raise questions concerning the histogenesis of these cellular proliferations and fail
to recognize that these questions were previously addressed in an
article we published 4 years ago. In that paper, we
immunophenotypically and genotypically analyzed an unprecedented number
of cases of CD (n = 63) without clinical risk factors for HIV
infection and demonstrated exclusively lambda-restricted plasma cells,
immunoglobulin gene rearrangements, and non-Hodgkin
lymphoma.2 We also postulated that an immunophenotypically
distinctive B-cell subset accumulated in the mantle zone of plasma-cell
(PC) CD, which was the precursor cell of the lambda-restricted
neoplasms in these patients. The KiB-3 negative phenotype of the
mantle zone lymphocytes in CD was consistent with the phenotype of
Ly-1b lymphocytes,3 which preferentially demonstrate lambda
immunoglobulin light chain rearrangement3 and express
lambda immunoglobulin light chains.4 Ly-1b lymphocytes, although characterized as fetal (Ly-1) B lymphocytes, are found in
adult patients and are produced in bone marrow like adult (Ly-2) B
lymphocytes.5
Dupin et al's finding of latent nuclear antigen expression in
the scattered plasmablastic cells in the mantle zone of patients with
CD suggests that HHV-8 may selectively transform a subset of Ly-1b
lymphocytes that reside in mantle zones in CD and may subsequently
develop interfollicular microlymphomas in HIV infected patients with
CD. We speculate that, because Ly-1b cells are important in the control
of immune reactions involving recognition of self and non-self
antigens, they may be associated with the development of
anti-myelin-glycoprotein autoantibody formation and neuropathy in CD
patients with the POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, and skin changes) syndrome. Because
interleukin-6 (IL-6) induces plasma cell differentiation from B-cell
precursors, is produced by follicular dendritic reticulum cells and
scattered interfollicular cells in CD,6-8 and is
responsible for systemic symptoms in CD patients,9 IL-6
may also induce plasma-cell differentiation from mantle-zone Ly-1b
lymphocytic precursors in PC CD. Because only a subset of HIV-negative
CD patients are infected with HHV-8,10,11 because HHV-8
negative patients develop CD associated with the POEMS syndrome, and
because systemic symptoms in HIV/HHV-8-infected CD patients resolve
with human IL-6 neutralizing monoclonal antibodies,12 it
is likely that human IL-6 rather than viral IL-6 is the
principle pathogenic cytokine in PC CD.
The importance of Ly-1b (fetal) lymphocytes in the
pathogenesis of hyaline vascular CD is suggested by the concentric
accumulation of Ki-B3 mantle-zone lymphocytes in hyaline vascular
disease, the similarities in anatomical distribution of Ly-1b
lymphocytes, the clinical distribution of hyaline vascular
CD,13-16 and the reported series of CD in
children.17 Similarities in pathogenesis between
hyaline-vascular and plasma-cell CD are suggested by Ly-1b type of
mantle-zone immunophenotype in both, by the histologic identification
of CD showing plasma-cell and hyaline-vascular histology or a
transformation from one type of CD to another in sequential biopsies,
and by the recognition of hyaline-vascular CD that produces
IL-6 and is associated with systemic symptoms (POEMS syndrome).
Discussion of the paper by Dupin et al at the spring
2000 International Academy of Pathology meeting in New Orleans
suggested that the single transformed mantle-zone plasmablasts and the
associated plasmablastic microlymphomas lack somatic hypermutation of
immunoglobulin variable regions. Because Ly-1b cells also lack
hypermutation of immunoglobulin variable regions,18 it
would be interesting to know whether the plasmablastic lymphomas or
their transformed single-cell counterparts in the mantle zone also lack
N-region diversity or restricted V-region gene usage characteristic of Ly-1b cells.19 The lack of somatic hypermutations in the
plasmablastic lymphomas would confirm that they are not of germinal
center derivation, unlike multiple myeloma, and may offer an
explanation for the clinical differences in dissemination and behavior
of the plasmablastic lymphomas arising in CD as compared with
plasmablastic multiple myeloma. Microdissection experiments of the
lambda-restricted plasma cells in PC CD are needed to determine whether
they also lack evidence of somatic hypermutation, limited N-region
diversity, or restricted V-region usage, as do Ly-1b cells.
David M. Menke
Mayo Clinic Jacksonville, FL
References
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Dupin N, Diss T, Kellam P, et al.
HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma.
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Response:
HHV-8 positive cells in Castleman disease
Dr Menke takes us to task for not quoting his
paper1 in which he claims to have discussed the same
abnormal mantle-zone cells in Castleman disease (CD) as those that we
have described. We were, of course, aware of Dr Menke's report of
Ki-B3 negative mantle-zone cells in CD. He described these Ki-B3
negative cells in all cases of both hyaline-vascular- and
plasma-cell-variant CD. It is difficult to ascertain whether he was
referring to the entire mantle, as is suggested in figure 1A of his
paper,1 or to isolated cells, and he did not illustrate
the cytological features of the cells. By contrast, we have described
cytologically distinct HHV-8 positive, IgM
-positive plasmablasts
occurring within an otherwise normal mantle zone. These cells were
restricted to a subset of cases of plasma-cell-variant CD that were
HHV-8 positive by PCR. In this context, we saw no reason to quote Dr Menke, and nothing in his letter has caused us to change our view.
Peter G. Isaacson and Chris Boshoff
Department of Histopathology University College London
Medical School London, England
Reference
1.
Menke DM, Tiemann M, Camoriano JK, et al.
Diagnosis of Castleman's disease by identification of an immunophenotypically aberrant population of mantle zone B lymphocytes in paraffin-embedded lymph node biopsies.
Am J Clin Pathol.
1996;105:268-276.
