Page 1492 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 83 Virus-Associated Lymphoma 1327

in mediating mutations thought to play a role in DLBCL
Autologous Bone Marrow Transplant in an HIV-Seropositive Patient 102
With Hodgkin Lymphoma lymphomagenesis.
A 38-year-old human immunodeficiency virus (HIV)–positive patient Epidemiology of Viral Infection and
+
3
with a CD4 count of 485 cells/mm is diagnosed with classic Hodgkin
lymphoma (HL) and treated with doxorubicin (Adriamycin), bleomycin, Associated Lymphoma
vinblastine, and dacarbazine (ABVD), achieving a complete remission.
Two years later he presents with retroperitoneal lymphadenopathy and The association between HCV and lymphoma was first recognized
is found on biopsy to have relapsed HL. He is treated with salvage in patients with HCV-associated type II mixed cryoglobulinemia, an
chemotherapy and has a complete response, as well as good perfor- autoimmune extrahepatic manifestation of HCV infection, although
mance status and no active infections. His HIV remains well controlled it is now recognized that patients with HCV but without type II
on antiretroviral therapy. He is deemed an excellent candidate for 105
high-dose therapy and undergoes consolidation with autologous bone mixed cryoglobulinemia also show a predisposition to B-NHL. In
marrow transplant. systematic reviews, approximately 13%–18% of B-cell lymphomas
are associated with HCV infection. 106,107 Most commonly, these
lymphomas are histologically indolent subtypes, with splenic mar-
ginal zone lymphoma (MZL), nongastric MALT, and lymphoplasma-
Bone Marrow Transplant in Patients With HIV cytic lymphoma more often seen in association with HCV than
aggressive histologies such as DLBCL. 108–111 In cases of HCV-
Autologous bone marrow transplant has been successful in HIV- associated DLBCL, histologic transformation should be considered
seropositive patients with NHL, with these patients having adequate because studies have demonstrated that DLBCL in this setting more
stem cell mobilization, nonrelapse mortality rates comparable to frequently has evolved out of low-grade lymphoma as compared with
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those for HIV-negative patients, count recovery within 2 weeks of HCV-negative patients with DLBCL. For example, in Taiwan, the
+
stem cell rescue, and maintained control of HIV viral loads and CD4 rate of chronic HCV infection in patients with NHL was 11%,
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counts after high-dose chemotherapy. 95,96 There have also been suc- 10-fold higher than in the general Taiwanese population. Among
cessful reduced-intensity allogeneic bone marrow transplants in HCV-infected patients with lymphoma, nodal and splenic MZL, but
HIV-seropositive patients, making the possibilities for treating HIV not MALT lymphomas, were increased. The HCV–lymphoma
patients with NHL even more vast, even in those patients with association is more apparent in some countries than in others, with
chemotherapy-resistant disease (see box on Autologous Bone Marrow the association being established most clearly in Italy and Japan.
Transplant in an HIV-Seropositive Hodgkin Lymphoma Patient). 97,98 Several studies in regions or countries where HCV infection is less
Outcomes of patients with HIV undergoing allogeneic bone marrow prevalent have failed to identify any association with lymphoma. 114–116
transplant have improved in the post-HAART era. 99,100 The first In the United States, data from the National Cancer Institute Surveil-
national trial of allogeneic bone marrow transplant for patients with lance, Epidemiology, and End Results registry and the Department
HIV and hematologic malignancy is ongoing. The role of transplant of Veterans Affairs have demonstrated a small but significant increase
in curing HIV is an area of active investigation, including cell engi- in B-NHL risk with HCV infection. 109,117
neering strategies to render cells resistant to HIV. Further evidence in support of an etiologic relationship comes
from studies in which successful treatment of HCV was followed by
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lymphoma regression. The most dramatic illustration comes from
HEPATITIS C VIRUS patients with splenic lymphoma with villous lymphocytes treated
with ribavirin and IFN. Furthermore, clearance of HCV infection
Viral Biology and B-Lymphocyte Proliferation has been shown to reduce the incidence of B-NHL, with cumulative
incidence of lymphoma among patients with a sustained virologic
HCV is an enveloped, positive-stranded RNA virus. 101,102 Infection response of 0% at 15 years, as compared with 2.6% at 15 years among
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involves interactions between E2, a viral structural protein with two both nonresponders and untreated patients. However, the mecha-
hypervariable regions, and a cellular protein CD81 present on hepa- nisms by which chronic HCV infection contributes to lymphoma-
tocytes and B lymphocytes. A polyprotein is translated from viral genesis remain largely undefined, although hypotheses include an
RNA and is cleaved by cellular and viral proteases, including NS3, indirect role related to B-cell activation and proliferation in the
to yield proteins required for viral replication. The RNA-dependent setting of chronic antigenic stimulation. 120
RNA polymerase that replicates the viral genome lacks proofreading Certain HCV genotypes may confer increased risk for NHL, with
capacity, thus generating genetic heterogeneity among viral progeny. genotypes 2a/III and 2b/IV seen more frequently in the HCV-
Viral replication occurs predominantly in hepatocytes, but viral RNA seropositive patients who develop NHL. However, there is no clear
and NS3 have also been detected in B cells, although HCV replica- association between genotype and NHL risk, and varying responses
tion in B cells remains controversial. 103 to antiviral therapy by genotype further complicate these analyses.
Chronic infection can be associated with mixed cryoglobulinemia,
a systemic immune disease that results from clonal expansion of B
cells producing an IgM autoantibody against IgG, leading to deposi- Diagnostic and Prognostic Considerations
tion of immune complexes on endothelial surfaces and resulting in
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inflammation. In this setting of B-cell proliferation, some patients In contrast to EBV-, KSHV-, or HTLV-1–associated tumors, there is
develop B-cell NHL, which is classically of low-grade histology. no established role for studies demonstrating HCV nucleic acid or
Several hypotheses have been advanced with regard to how HCV protein in tumor cells. Thus serologic study and measurement of
might drive B-cell proliferation. There is controversy as to whether HCV copy number are the only tools available for inferring an
infection of B cells plays any role in this process. A lymphoma cell association. We recommend checking HCV serologic characteristics
line that produces infectious HCV has been reported. Even in the in all patients with B-cell lymphomas most commonly associated
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absence of infection of B cells, interaction of the HCV E2 protein with chronic HCV infection. In addition, screening patients with
with CD81 on B cells may drive B-cell proliferation or lower the chronic HCV for a monoclonal gammopathy and cryoglobulinemia
threshold for other B-cell stimuli to drive proliferation. Immuno- may be of benefit to identify patients at highest risk for malignant
globulin signaling may be activated by immunoglobulin–virus transformation. Elevated serum γ-globulin levels have been found to
complexes, and Toll-like receptor 7 signaling may be activated by viral be a predictor of NHL among patients with type II mixed cryoglobu-
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RNA. Finally, it is noted that E2 binding triggers expression of linemia. In patients who are HCV seropositive, HCV RNA is
activation-induced deaminase, an enzyme that is important in gen- evaluated in plasma. There seems to be a predilection of HCV-
erating somatic hypermutation and that has also been implicated associated lymphomas to involve extranodal sites, particularly the