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

Abstract

IntroductionType 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. Study design Index caseA 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 ϫ 10 9 /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 ϫ 10 9 /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 ϫ 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 ϩ , ϩ , IgD Ϫ , CD19 ϩ , CD20 ϩ , CD22 ϩ , CD5 Ϫ , CD10 Ϫ , CD23 Ϫ ; 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 ϫ 6 cm and 13 ϫ 6 cm, respectively. The patient expired in June 2001 from complications of atherosclerotic peripheral vascular disease. An autopsy was...

Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity?

“…18 Antiviral therapy may also induce complete remission of lymphoplasmatic lymphoma or immunocytoma 16 and marginal zone lymphoproliferation. 13,19,20 Taken together, these data support a mechanistic role for HCV the pathogenesis of a subset of SLVL. Moreover, HCV plus SLVL appears to be part of the spectrum of HCV-driven cryoglobulinassociated lymphoproliferative disorders.…”

Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas

“…Our results reveal multiple patterns of response and extend the use of antiviral treatment of HCV-associated lymphomas to the MZL group, beyond the splenic lymphoma with villous lymphocytes (SLVLs) group already described. 18,31,32,34 Therapeutic studies in HCV-associated lymphomas have begun with the effect of interferon alpha on surrogate markers of clonal B lymphoid expansion in HCV infection, that is, type II cryoglobulinemia and clonal IgH and Bcl-2 rearrangement, in the absence of overt lymphoma. Mazzaro et al 39 In all three studies, molecular response was strongly correlated with virologic response, but the latter also emphasized the occurrence of t(14;18) negativation in some cases of partial or even null virologic response.…”

“…The first case of interferon treatment of an overt HCVassociated lymphoma was reported by Casato et al 31 This lymphoma was of MZL type. Hermine et al 32 reported the first series of HCV-associated SLVLs treated by interferon with or without ribavirin: complete remission was achieved in eight of nine patients.…”

“…Only a few therapeutic studies on 15 patients in total are published so far. 18,[31][32][33][34] In this study, we have examined the responses to antiviral treatment of eight additional patients with HCVassociated MZL.…”

Toxicity and Outcome of Intensive Chemotherapy for Acute Lymphoblastic Leukemia Complicated with Turner's Syndrome

“…Furthermore, in this case study, the patient had karyotypical abnormalities including t(3;9)(q11;p13). Although abnormalities at 3q11 have been observed in lymphoid neoplasms (17), this specific translocation has not been reported previously. It is also not yet clear whether this translocation is associated with leukemogenesis in patients with Turner's syndrome.…”