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Blood, 15 March 2002, Vol. 99, No. 6, pp. 2259-2261
BRIEF REPORT
Regression of lymphoproliferative disorder after treatment for
hepatitis C virus infection in a patient with partial trisomy 3, Bcl-2
overexpression, and type II cryoglobulinemia
Milvia Casato,
Cristina Mecucci,
Vincent Agnello,
Massimo Fiorilli,
Glenn B. Knight,
Caterina Matteucci,
Lei Gao, and
Jonathan Kay
From the Department of Clinical Medicine, University of Rome La
Sapienza, Rome, Italy; Hematology, University of Perugia, Italy; Lahey
Clinic, Burlington, MA; Veterans Affairs Medical Center, Bedford, MA.
 |
Abstract |
A patient with type II cryoglobulinemic vasculitis and
hepatitis C virus (HCV) infection presented with a leukemiclike
proliferation of B cells bearing marginal zone B-cell phenotypic
markers. A partial trisomy 3 (bands 3q11-29) and overexpression of
Bcl-2 without t(14;18) translocation was detected in the monoclonal B
cells that were classic rheumatoid factor-producing B cells bearing
the WA cross-idiotype. Treatment with interferon- produced a
complete clinical remission and synchronous marked decreases in viremia
and monoclonal B-cell prevalence. This is the first report of partial
trisomy 3 and Bcl-2 overexpression in type II cryoglobulinemic
vasculitis associated with HCV infection. Further studies of
HCV-infected patients with and without type II cryoglobulinemia are
required to determine the prevalence and possible physiologic and/or
pathophysiologic significance of these findings.
(Blood. 2002;99:2259-2261)
© 2002 by The American Society of Hematology.
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Introduction |
Type II cryoglobulinemia, a lymphoproliferative
disorder characterized by cold-precipitable immune complexes composed
of polyclonal immunoglobulin (Ig)-G and monoclonal IgM rheumatoid
factor (mRF), predominantly occurs secondary to hepatitis C virus (HCV)
infection (HCV-type II cryogloblulinemia). The concentration of HCV in
type II cryoglobulins and the presence of a highly restricted mRF
bearing the WA cross-idiotype in approximately 80% of patients lead to the hypothesis that proliferation of the WA mRF-producing cells was
driven by HCV.1,2 Moreover, recent data demonstrated that
contrary to the premise that type II cryoglobulinemia is a low-grade
malignancy,3 the oligoclonal B-cell expansion frequently present in the bone marrow of these patients showed no evidence of
malignancy.4 In this study, we present a patient with
HCV-type II cryoglobulinemia, a leukemiclike monoclonal B-cell
proliferation bearing marginal zone B-cell (MZBC) phenotypic markers
without definitive evidence of malignancy, Bcl-2 overexpression, and
partial trisomy 3. The course of the patient's disease is
informative because this is the first report of partial trisomy 3 and
Bcl-2 overexpression in HCV-type II cryoglobulemia, and there was a synchronous decrease in B-cell proliferation and viremia with interferon- therapy.
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Study design |
Index case
A 57-year-old white male with HCV-type II
cryoglobulinemia in clinical remission for 10 years relapsed in March
1998 and presented with palpable purpura, cryoglobulinemia (4%
cryocrit), marked leukocytosis (white blood cell [WBC] count, 35.7 × 109/L), and splenomegaly. Other notable laboratory
findings were the following: positive HCV serology and HCV RNA;
anemia (hemoglobin 116 g/L); normal platelet count
(151 × 109/L); low C4 component of complement (7 mg/dL; normal range, 17-45 mg/dL); high lactate dehydrogenase (LDH)
(843 IU/mL; normal range, 325-685 IU/mL); high IgM (3.05 g/L;
normal range, 0.5-2 g/L) with a monoclonal IgM ; low IgG (3.64 g/L;
normal range, 7.5-14 g/L); but normal IgA (1.55 g/L; normal range,
0.75-3.1 g/L). There was no clinical evidence of renal or liver
disease. A chest and abdominal computed tomography (CT) scan showed a
normal liver, a 20.6 × 11.2 cm spleen, and no adenopathy. Bone
marrow examination showed multifocal clusters of small atypical
lymphocytes suspicious for lymphoproliferative disorder. Lymphocyte
phenotypes for peripheral blood and bone marrow were identical:
IgM+, +, IgD ,
CD19+, CD20+, CD22+,
CD5, CD10, CD23; villous
lymphocytes were not present. Treatment with interferon (IFN) was
initiated. Longitudinal studies from April 8, 1998, to September 24, 1999, are shown in Figure 1.
Subsequently, cryoglobulinemia remained in remission with no clinical
evidence of malignancy. CT scans performed in February and May 2001 showed no lymphadenopathy and spleen measurements of 14 × 6 cm and
13 × 6 cm, respectively. The patient expired in June 2001 from
complications of atherosclerotic peripheral vascular disease. An
autopsy was not performed. These retrospective studies were approved by
the institutional review board of the Lahey Clinic, Burlington, MA.
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| Figure 1.
An 18-month longitudinal study of the index
case demonstrating the effect of IFN therapy on viral titers and the
prevalence of IgM B cells.
Prelevalence of IgM (percentage of lymphocytes) with HCV viremia
genomic equivalents (gEs) per milliliter during treatment with IFN (3 MU given daily [qd] or 3 times weekly [tiw] as previously
described5) are demonstrated. Relapse was associated with
marked lymphocytosis (lymphocyte count of
44 × 109/L [44 000/µL]), which was due
predominantly to IgM B cells; a high level of viremia
(7.3 × 107gE/mL), and a cryocrit of 4%. WBCs
declined from 53.4 × 109/L to 5.0 × 109/L and
lymphocytosis from 82% (lymphocyte count of 44 × 109/L)
to 38% (lymphocyte count of 1.9 × 109/L) with IFN
therapy. Decreases in IFN therapy from daily to 3 times weekly
administration and interruption of therapy were accompanied by parallel
increases in viremia and monoclonal B cells. Cryoglobulinemia fell to
1% cryocrit after 1 month of therapy and remained at trace levels
(less than 1%) for the next 17 months. LDH returned to normal in May
1998 and remained within normal range throughout the remainder of the
patient's course of treatment.
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Methods
Comparative genomic hybridization (CGH) was performed on DNA
extracted from the patient's July 1,1998, peripheral blood mononuclear cells (PBMCs) as previously described with a slight
modification.6,7 Fluorescent in situ hybridization
(FISH) experiments were performed on interphase nuclei from the same
blood specimen, in routine fashion, with an alpha-satellite probe,
p3.5, for the centromeric region of chromosome (kindly
provided by M. Stul, University of Leuven, Belgium), and a mixture of
BACs for MLF1 gene at 3q25 (kindly provided by S. Morris,
Memphis, TN). The presence of t(14;18) translocation was determined by
real-time Taqman reverse-transcriptase-polymerase chain reaction
(RT-PCR) employing primers and probes specific for the major
and minor breakpoints.8 DNA samples from 2 patients with
follicular lymphoma served as the positive controls for t(14;18) translocation. The amount of DNA in each sample was normalized to the
actin DNA present in the sample. Bcl-2 and glyceraldehyde 3-phosphate
dehydrogenase (GAPDH) messenger RNA levels were determined by real-time
Taqman RT-PCR in triplicate. Standard curves were prepared using human
control RNA. Bcl-2/GAPDH ratios were calculated and normalized to
normal lymphocytes. Clonal expansion analysis and sequencing
were performed by means of routine methodology but with primers
designed to amplify VH1 region or
V 3 complementarity determining region
(CDR3) of WA mRF.
| |
Results and discussion |
An 18-month longitudinal study of the index case following relapse
of HCV infection and cryoglobulinemia is shown in Figure 1. IFN therapy
was accompanied by a marked decrease in lymphocytosis, monoclonal
IgM B cells, and viremia. The close correlation of the prevalence of
monoclonal B cells with IFN-induced decrease in viremia is consistent
with the hypothesis that the HCV infection drove the proliferation of
the monoclonal B cells but does not constitute direct evidence since
IFN has both antiviral and immunomodulatory effects.
A WA mRF was demonstrated in the cryoglobulins by detection of the WA
cross-idiotype on serologic analysis1 of the isolated mRF
(data not shown). The presence of the WA mRF was confirmed by
performing PCR B-cell clonal expansion analysis of the PBMCs and
detecting and sequencing monoclonal bands corresponding to the
VH1 region and VK3 CDR3. The sequencing
analyses (Gen-Bank accession nos. AY059634 and AY059635) demonstrated
the typical WA RF sequence.9
There was no evidence of t(14;18) translocation in the patient's
PBMCs; with the use of comparable levels of actin DNA in the test and
control samples, breakpoint amplification occurred only in the positive
control samples. There was, however, a 20-fold overexpression of Bcl-2
in the patient's PBMCs compared with normal PBMCs. The patient's
PBMCs had a Bcl-2-to-GAPDH ratio of 18:8; normal lymphocytes
had a ratio of 0:94. Overexpression of Bcl-2 in the absence of t(14;18)
translocation has been noted in PBMCs and cloned WA B cells from
patients with HCV-type II cryoglobulinemia in a preliminary
report.10
CGH and interphase FISH results confirmed a partial trisomy of
chromosome 3 (bands 3q11-29), without any involvement of the centromeric region (Figure 2). The
overrepresented region corresponds to the region commonly involved in
MZBC lymphoma.11 The existence of the partial trisomy 3 in
the monoclonal B cells was deduced from the overlapping prevalence of
monoclonal B cells determined by immunophenotyping (85%), and the
partial trisomy 3 was determined by FISH studies performed on the same
PBMC sample (80%). Unfortunately, since material was not available for
further metaphase analysis, additional structural chromosomal
abnormalities that may have been associated with the partial trisomy 3 in this patient could not be excluded although the t(14;18)
translocation was excluded by the studies described above. The marked
lymphocytosis that occurred with relapse of disease in the index case
is unusual in type II cryoglobulinemia. Our findings suggest that (1)
the duplicated genes on the third chromosome were involved in enhanced proliferation of the monoclonal B cells that resulted in the
lymphocytosis and (2) the partial trisomy 3 did not produce loss of
antigen dependence in those cells.
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| Figure 2.
Demonstration of partial trisomy 3 in the PBMCs of the index case.
(A) CGH. Partial profile of chromosome 3 showing the region of
duplication involving the long(q) arm. Chromosomal regions were
considered overrepresented when the corresponding green-to-red ratio
exceeded 1:18 and underrepresented when the ratio was below 0:83.
Thresholds were fixed on profiles obtained from hybridization of 2 differently labeled normal DNAs extracted from healthy donors.
Telomeric and centromeric regions as well as heterochromatic regions of
chromosome 1, 9, 16, and Y were excluded from analysis, because of
possibly false-positive results. Results were confirmed by means of a
99% confidence interval, with 1% error probability. (B) Interphase
FISH with probe for centromeric sequences of chromosome 3 showing only disomic nuclei. Signals were evaluated on 600 interphase
cells, of which 2.6% showed 1 spot; 97.1%, 2 spots; and 0.3%, 3 spots. (C) Interphase FISH with the locus-specific probe for MLF1 gene
(3q25) showing 3 spots in 3 of 4 nuclei. Signals were evaluated in 100 interphase cells, of which 20% showed 2 spots and 80% showed 3 spots.
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The data presented have conflicting interpretations and are
insufficient to determine whether a malignant or benign
lymphoproliferation was present in the index case. The
lymphoproliferation had characteristics common to both the B-cell
lymphocytosis associated with partial trisomy 3 and very low grade
subtypes of MZBC lymphomas.12-14 The splenomegaly
and elevated LDH that responded to IFN therapy were suggestive of
splenic lymphoma. The monoclonal B cells had MZBC markers and were
WA+; 25% or more of B-cell lymphomas associated with
HCV-type II cryoglobulinemia arise from WA+ B cells
although correlation with MZBC markers has not been
assessed.15,16 However, neither MZBCs nor splenic
lymphomas are commonly associated with HCV-type II cryoglobulinemia.
Only 5% to 10% of these patients develop overt B-cell
malignancies17,18 that are predominantly lymphoplasmacytoid
lymphoma/immunocytoma.3,19 Moreover, the correlation of
regression of the putative HCV-driven B-cell proliferation with IFN
therapy is against a malignant lypmphoproliferative process. However,
antigen-driven lymphoproliferation has been reported in some low-grade
extranodal marginal zone lymphomas.20 Since there is
evidence that the monoclonal B cells in type II cryoglobulinemia arise
predominantly in the pseudofollicle in the liver,21,22 the
lymphoproliferation in the index case could be an HCV-driven very-low-grade extranodal marginal zone lymphoma.
Overexpression of Bcl-2 has heretofore not been associated with
duplication of 3q11-29.11-13 Further studies are needed to determine the prevalance of these abnormalities in HCV infection with
and without type II cryoglobulimenia and their possible physiologic and/or pathophysiologic implications.
| |
Acknowledgments |
We thank Dr K. M. Steve Lo, Hematology Oncology,
Stamford Health System, Stamford, CT, and Dr Kristan D. Zimmermann, The
Elliot & Roslyn Jaffe Diagnostic Imaging Center, Stamford, CT, for
providing clinical data on the index case, and Dr Nicolas Chiorrazi for reviewing the manuscript.
| |
Footnotes |
Submitted July 25, 2001; accepted November 1, 2001.
Supported by grants from the Italian National Research Council (C.Me.);
the Italian National Association for Cancer Research (C. Me.); the
Italian Ministry for University and Scientific Research (MURST) (C.Me.,
M.F.); the Robert E Wise, MD, Research and Education Institute, Lahey
Clinic, Burlington, MA (V.A.); grant RO1 AI 40672-02 from the National
Institute of Allergy and Infectious Diseases (V.A.); the Veterans
Affairs Administration (V.A.); the Istituto Pasteur Fondazione Cenci
Bolognetti at the University of Roma La Sapienza (M.F.); and MURST
COFIN 2000 (M.F.).
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Presented in part at the 10th International Symposium on Viral
Hepatitis and Liver Disease, April 2000, Atlanta, GA; abstract no.
C077.
Reprints: Vincent Agnello, Lahey Clinic, 41 Mall Rd,
Burlington, MA 01805-0001; e-mail: vincent.agnello{at}lahey.org.
| |
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Top
Abstract
Introduction