v
Search
Advanced

Publications > Journals > Journal of Clinical and Translational Hepatology > Article Full Text

  • Review Article
  • OPEN ACCESS

Hepatitis Virus-associated Non-hodgkin Lymphoma: Pathogenesis and Treatment Strategies

  • Wenjing Zhang1,#,
  • Fan Du2,#,
  • Li Wang1,#,
  • Tao Bai2,
  • Xiang Zhou3,*  and
  • Heng Mei4
 Author information  Cite
Journal of Clinical and Translational Hepatology   2023;11(5):1256-1266

doi: 10.14218/JCTH.2022.00079S

Abstract

Over the last decade, epidemiological studies have discovered a link between hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). The regression of HCV-associated NHL after HCV eradication is the most compelling proof supporting HCV infection’s role in lymphoproliferative diseases. HBV infection was found to significantly enhance the incidence of NHL, according to the epidemiological data. The exact mechanism of HCV leading to NHL has not been fully clarified, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HCV and cytokines; (2) Direct mechanisms: oncogenic effects mediated by intracellular HCV proteins; (3) hit-and-run mechanism: permanent genetic B lymphocytes damage by the transitional entry of HCV. The specific role of HBV in the occurrence of NHL is still unclear, and the research on its mechanism is less extensively explored than HCV, and there are mainly the following possible mechanisms: (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HBV; (2) Direct mechanisms: oncogenic effects mediated by intracellular HBV DNA. In fact, it is reasonable to consider direct-acting antivirals (DAAs) as first-line therapy for indolent HCV-associated B-NHL patients who do not require immediate chemotherapy. Chemotherapy for NHL is affected by HBV infection and replication. At the same time, chemotherapy can also activate HBV replication. Following recent guidelines, all patients with HBsAg positive/HBV DNA≥2,000 IU/mL should be treated for HBV. The data on epidemiology, interventional studies, and molecular mechanisms of HCV and HBV-associated B-NHL are systematically summarized in this review.

Graphical Abstract

Keywords

Hepatitis C virus, Hepatitis B virus, Non-hodgkin lymphoma, B cell

Introduction

Currently, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection affects hundreds of millions of individuals worldwide, which can result in hepatic complications such as liver cirrhosis and hepatocellular carcinoma (HCC) as well as extrahepatic complications including B-cell lymphatic neoplasms. Therefore, this issue may bring a significant burden to the health system and is of clinical relevance, especially in countries with high HBV and HCV prevalence. This review presents an overview of epidemiology, possible mechanisms of pathogenesis, and treatment options.

Non-hodgkin lymphoma (NHL), HBV and HCV: an overview

NHL is one of the most common hematologic malignancies in humans. In the USA, about 81,560 people are diagnosed with NHL, and 20,720 die of the disease, accounting for 4.3% of malignant tumors and 3.3% of cancer mortality in 2021. The etiology of NHL is still largely unknown, and 15–20% of NHL relate to a particular virus infection, including HIV, Epstein-Barr virus (EBV), HPV8, human T lymphocyte virus type I (HTLV-I), HCV, or HBV.1

HCV belongs to genus Hepacivirus of Flaviviridae, is a single-stranded positive RNA virus with no reverse transcriptional activity. It has a diameter of 30–60 nm and consists of about 9.6×103 nucleotides. It is hepatotropic and lymphotropic and can infect peripheral blood mononuclear cells (PBMCs) and replicate in them. The length of the HCV genome is 9.5 KB, which is composed of highly conserved 5′-terminal, 3′- terminal, and a single open reading frame between the two ends.2 The open coding region can encode a polyprotein precursor, spliced into three structural proteins (core protein, E1, E2) and seven nonstructural proteins (NS1, NS2, NS3, NS4A, NS4B, NS5A, NS5B) by host and virus signaling enzymes. The HCV gene is easy to mutate and can be divided into at least six genotypes and multiple subtypes.3 In 2019, the World Health Organization reported that 58 million individuals worldwide suffered from hepatitis C infection, with 290,000 people dying from the disease.

HBV is a hepatotropic DNA virus of family Viroviridae consisting of incomplete circular double-stranded DNA. The negative strand contains about 3,200 base pairs, and the length of the positive strand is variable, equivalent to 50–80% of the negative strand. The four open reading frames in the HBV genome, i.e., S, C, P, and X regions, are all located in the negative strand. S region mainly encodes HBsAg, the C region mainly encodes HBeAg and HBcAg, the P region encodes a macromolecule alkaline polyskin that participates in HBV replication, and the X region encodes X protein that has a transactivation effect and activates various regulatory genes of HBV itself.4 Currently, Hepatitis B is a serious public health problem. According to the World Health Organization, around 296 million individuals worldwide have chronic HBV infection and approximately 820,000 people died from HBV-related liver illnesses in 2019.

Association between HCV and NHL: epidemiological data

An extensive investigation of this correlation between the hepatitis C virus and NHL initially found that patients with mixed cryoglobulinemia (MC) had a high HCV seroprevalence of nearly 100%.5,6 MC is a chronic lymphoproliferative disease, usually presented as small vessel vasculitis due to immune complex accumulation in the vascular wall and complement activation. The clinical manifestations include weakness, Raynaud’s phenomenon, rash, membranous proliferative glomerulonephritis, etc. The prominent feature is the presence of cryoglobulins, a kind of globulin that precipitate at temperatures below 37°C. Cryoglobulins are usually categorized into three types by their structure. Type I is made up of a single monoclonal immunoglobulin, whereas types II and III are mixed cryoglobulins.6 According to epidemiological research, 8–10% of MC patients are vulnerable to NHL, with a 35-fold increased risk of HCV-associated NHL than the general population.7

Clinical practice proves the causal connection between HCV and B-NHL. HCV infection was found in 53 (2.9%) of lymphoma patients and 41 (2.3%) healthy controls in a large, multicenter, case-control study involving five European countries [OR 1.42; (95% CI: 0.93–2.15)].8 The link between HCV and B-NHL has been verified in large-scale epidemiological investigations. Gisbert et al.9 published a systematic review of 48 studies (5,542 patients) with a mean HCV infection rate of 13%. HCV prevalence was much higher in B-NHL patients than in healthy controls (17% vs. 1.5%) in 10 studies. In subtype-specific studies, HCV was mainly linked to lymphoplasmacytic lymphoma (Morbus Waldenström), diffuse large B-cell lymphoma (DLBCL), and marginal zone lymphoma (MZL). Notably, the risk estimations for follicular lymphoma were not increased.10 A large prospective French ANRS-Lympho-C study reported similar results in that MZL (39%) and DLBCL (39%) were the most prevalent NHL subtypes linked to HCV infection.11 HCV infection was shown to lead to inferior survival of patients with DLBCL.12 Successful anti-HCV therapy greatly reduces the risk of NHL among HCV patients, but only noted in patients <65 years of age but not those >65 years of age, suggesting HCV patients should be treated with antivirals as early as possible.13

Several investigations have shown that HCV has an etiological role in lymphoma development. Similar to the degradation of gastric mucosa-related lymphoid tissue lymphoma after Helicobacter pylori extinction,14 many studies have demonstrated that patients suffering from HCV-associated lymphoma can obtain remission of lymphoma after antiviral therapy. This was first found in nine individuals with splenic lymphoma treated with interferon and Ribavirin as first-line therapy.15 All individuals who achieved HCV clearance (undetectable HCV RNA) acquired a lymphoma response. None of the six other patients in the study who did not have HCV infection and received antiviral medication experienced lymphoma regression. In HCV-infected patients, immunoglobulin heavy chain gene (IgH) rearrangement and t (14;18) translocation in PBMCs disappeared after antiviral treatment.16 In t (14;18) translocation, BCL-2 is translocated from its normal site 18q21 to co-located with the IgH seat at 14q32, which results in the initiation of transcription of the gene in lymphoma cells, resulting in overexpression of the BCL-2 protein or activation by the NF-κB anti-apoptotic pathway. The BCL-2 gene is considered closely related to the genesis and development of DLBCL.

For NHL patients with HCV infection, the antiviral regimen based on an interferon and Ribavirin combination can completely or partially relieve some indolent lymphoma.15,17 And recurrence of the virus after the initial virological response leads to lymphoma progression.18 Antiviral therapy reduces extrahepatic manifestations (e.g., cryoglobulinemia vasculitis, malignant B-cell lymphoproliferative diseases) related to HCV when a sustained virological response (SVR) is achieved. In patients with cryoglobulinemia vasculitis, SVR was associated with higher complete response (CR) [OR 20.76, (95% CI: 6.73–64.05)], while in patients with malignant B-cell lymphoproliferative disease, SVR was related to higher objective response [OR 6.49, (95% CI: 2.02–20.85)]. According to the results of four HCV study populations including over 7,000 patients, SVR reduced extrahepatic mortality [OR 2.29, (95% CI: 1.49–3.52); p<0.001].19

Association between HBV and NHL: epidemiological data

Studies in China, South Korea, Japan, and other HBV-endemic areas have shown that the HBV infection rate in NHL is much higher than in the general population.20–23 In a prospective cohort study of 603,585 enrolled Korean population, Engels et al.24 found 53,045 HBsAg positive (8.8%), suggesting that South Korea is a high epidemic area of HBV. After over 10 years of follow-up, the risk of NHL in the HBsAg positive group was considerably higher than in the negative group [OR 1.74, (95% CI: 1.45–2.09)]. In NHL subtypes, positive HBsAg was linked to a higher risk of DLBCL (OR 2.01, 95% CI: 1.48–2.75) than negative HBsAg. Li et al.25 analyzed a large-scale retrospective cohort study of Chinese patients. They found that the risk of B-cell NHL, multiple myeloma, and acute lymphoblastic leukemia in the HBV infection group was more significant than in the non-HBV infection group. The HBV infection rate was higher, especially in aggressive B-NHL (including DLBCL, MCL, primary mediastinal large B-cell lymphoma, and Burkitt lymphoma). The aggressive B-NHL group had a considerably higher HBsAg-positive rate than the indolent B-NHL group. Meanwhile, the prevalence of positive HBeAg status, positive anti-HBe status, and antiHBc status in the aggressive B-NHL group was significantly higher than in the indolent B-NHL group, respectively.26 In addition, three meta-analyses showed that the risk of NHL in HBV-positive individuals was 2–3 times greater than in the general population.27–29 According to a study using the Taiwan health insurance research database from 1997 to 2013, hepatitis B vaccination, being the most effective method of preventing hepatitis B infection, can significantly reduce the prevalence of HBV-associated NHL in adolescents and young adults <20 years of age.30 HBV infection was found to significantly enhance the incidence of NHL, particularly B-NHL, in all of the studies mentioned above.

In addition, populations in HBV-endemic areas have high rates of occult HBV infection.23,31 Occult HBV infection is defined as HBV DNA being continuously expressed in serum or tissues or both, but HBsAg is negative in patients.32 In contrast with normal subjects and other patients with non-liver solid tumors, NHL patients are more likely to have an occult HBV infection. This may indicate a link between occult HBV infection and the occurrence and progression of NHL.23,33 The stable existence of HBV covalently closed circular DNA (cccDNA) in cells, which may be employed as a template for gene transcription, causes occult infection. Extrasomal HBV cccDNA exists in staining virus microchromosomes, which are very stable and persistent. Additionally, HBV infection can persist for life once initiated, even after successful immune control, due to the long half-life of hepatocytes.34 It means that HBV can reactivate even after the infection has been resolved.35

Pathogenesis of HCV-associated NHL

The exact mechanism of HCV leading to NHL has not been fully clarified, and there are mainly the following possible mechanisms. (1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HCV and cytokines; (2) Direct mechanisms: oncogenic effects mediated by intracellular HCV proteins; (3) hit-and-run mechanism: permanent genetic B lymphocyte damage by the transitional entry of HCV (Fig. 1).

Pathogenesis of HCV-associated NHL.
Fig. 1  Pathogenesis of HCV-associated NHL.

(1) Indirect mechanisms: Stimulation of B lymphocytes by extracellular HCV and cytokines; Chronic antigenic stimulation of a B cell that interacts with the cognate HCV antigen via its surface Igs; HCV-E2 protein binds to the high-affinity receptor CD81 on B cells; Viral antigens stimulate lymphocyte receptors on a continuous basis, resulting in proliferation; Evidence of oncogenic signal upregulation (IL10, IL6, BAFF, BLyS). (2) Direct mechanisms: Oncogenic effects mediated by intracellular HCV proteins; Oncogenic effects of HCV replication in B cells mediated by intracellular viral proteins; Induction of oncogenic signals (BCL2, IL10, sIL2R) and reduced sensitivity to Fas-induced apoptosis (decreased levels of caspases 3/7); In vitro expression of HCV core protein and NS3 proteins induce NOS and ROS generation; These cause DNA repair damage and mitochondrial injury that may precede cellular transformation. (3) Hit-and-run mechanism: Permanent genetic B lymphocytes damage by the transitional entry of HCV; The hit-and-run theory proposes that a transiently intracellular virus causes permanent genetic B-cell damage. HCV, hepatitis C virus; NHL, non-Hodgkin lymphoma; IL, interleukin; BAFF, B-cell activating factor; BLyS, B lymphocyte stimulator; BCR, B-cell receptor; NOS, nitric oxide synthase; ROS, reactive oxygen species; AID, activity-induced cytosine deaminase.

Indirect mechanisms: stimulation of B lymphocytes by extracellular HCV and cytokines

Increasing evidence shows that HCV-associated antigens can induce nonmalignant clonal expansion of B cells by chronic stimulation of B cells, leading to malignant lymphoproliferative diseases by a gene mutation. Antibody responses against HCV are mainly directed toward the HCV-E2 protein. Quinn et al.36 found that HCV-E2 protein can activate B lymphocytes in patients with HCV-associated lymphoma, which confirmed that HCV as a chronic antigen could stimulate B-cell proliferation. It was shown that in most patients with HCV-associated lymphoma, the monoclonal IgM was encoded by a limited set of variable (V) region genes, notably the germline genes VH1-69 (also named 51p1) and VkA27 (also named kv325). Interestingly, MC patients expressed the same set of genes (VH1-69 and VkA27).37 Chan et al.38 explored 10 human B-cell hybridomas from the peripheral blood B cells from a patient with an asymptomatic HCV infection. They demonstrated that the VH1-69 gene found in HCV-related lymphoma and MC is involved in the anti-E2 immune response. These outcomes link the HCV-associated lymphoproliferative diseases with the immune response to HCV antigens.

Marasca et al.39 studied five HCV-positive nodal marginal zone B-cell lymphoma cases and found that the VH1-69 gene was used expressed in three cases, and the CDR 3s of the three cases were highly similar. This suggests that the selection of B cells involves a common antigen, which may be HCV antigen epitope. This indicates that B-cell selection involves a common antigen, possibly an HCV epitope. Correspondingly, MC (especially MC II) can transform into malignant lymphocytic diseases, and about 8–10% of MC II patients can transform into B-NHL.7 In a case series,40 20 of 231 MC patients developed B-NHL within a median time of 8.8 years. Sequential variable-diversity-joining pattern exploration in one patient during both MC and B-cell small lymphocytic lymphoma revealed that the lymphoma was caused by a clone of overstimulation during MC,41 confirming the effect of chronic antigenic stimulation on the growth of HCV-related lymphoma.

CD81 is a cell surface adhesion molecule expressed in various tissue cells, including B, T, and natural killer cells. The role of CD81 on B cells is to form activated co-receptors with CD19, CD21, and Leul 3 and cooperate with B-cell receptor (BCR) to transmit antigen and complement recognition signals to B cells to reduce the activation threshold of B cells.37,42 CD81 is thought to be an HCV-E2 protein receptor, and the interactions between CD81 and HCV-E2 protein can cause genomic instability in the host. Purified E2 protein binding to B cells can lead to a double-strand DNA break in the variable region of the IGVH gene resulting in hypermutation.38,43 Somatic cells need to activate the activity-induced cytosine deaminase (AID) during hypermutation, and CD81/E2 can increase AID expression. Overexpression of AID can lead to DNA base mismatch and mutation of Ig and non-Ig genes. AID activation by HCV has been correlated with the induction of mutations in the beta-catenin, BCL6, and p53 genes in B cells.44 HCV in conjunction with CD81 and BCR may cause gene mutation, such as high expression of Bcl-2, the double-strand break of DNA, and eventually lead to malignant clonal proliferation of cells.39,40,45,46 HCV has been shown to protect human B cells against Fas-mediated apoptosis even in the absence of viral entrance into the human B-cell through E2-CD81 interaction.47

Cytokines are also involved in the progression of HCV-associated lymphoma. B-cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, is involved in B-cell proliferation.48 In chronic HCV infection, upregulation of BAFF has been observed.49 HCV patients without MC have lower BAFF levels, while those with cryoglobulinemia have intermediate levels and those with NHL have higher levels.50 BAFF expression was upregulated by HCV-induced GU-enriched miRNAs via exosome transmission and TLR7 activation. The mechanisms of miRNA action are important in the development of extrahepatic manifestations in HCV-infected hepatocyte-immune system communication.51 In addition, dysregulated microRNAs (miRNAs), particularly miR-26b downregulation, may contribute to the deterioration of tumor suppression.52 Cytokines including interleukin (IL)-6 and IL-10 have also been linked to the proliferation of hepatitis C virus-infected B cells.53,54

Direct mechanisms: oncogenic effects mediated by intracellular HCV proteins

Virological lymphotropic has been assumed to play a critical role in the pathogenesis of HCV-related lymphoproliferative disease (LPD) since the first evidence of HCV potential to infect peripheral mononuclear cells.55 It has been demonstrated that HCV causes lymphotropic infection.56–58 Studies have shown that HCV replicates in B cells, T cells, macrophages, monocytes, Kupffer cells, and dendrocytes.57,59 HCV RNA-negative strands (i.e., the viral replicative intermediates) were found in neutrophils,60 peripheral mononuclear cells,61 and CD34+ stem cells62 by some investigators. A negative-strand strand of HCV RNA cannot be attributed solely to passive absorption by HCV circulation in peripheral blood, as evidenced by the expression of HCV-encoding proteins NS3 and NS5 in PBMCs,63–65 suggesting that HCV replicates and generates HCV proteins.

Other studies have shown that HCV persists in PBMCs from immune-deficient mice with severe combined immunodeficiency. They injected intraperitoneally PBMCs taken from HCV patients suffering from LPDs into severe combined immune deficiency (SCID) mice and discovered viral RNA (such as negative-strand HCV RNA) at various times following the injection.66 It was found that, based on results from injecting lymphoid cells from HCV-positive patients in SCID mice, the samples derived from HCV patients with malignant LPD had a high number of HCV replicative intermediates, more significant signals when DNA sequences of the viral genome were analyzed. Serial passage of these infected cells took place successfully in various mice. Transgenic mice with malignant lymphoma expressed HCV core mRNA in enlarged lymph nodes. According to these results, HCV core proteins may significantly affect the growth of malignant lymphomas.67

In addition, Sung et al.68 established B-cell lines that consistently produced infectious viruses from an HCV-positive lymphoma. By detecting both HCV negative-strand RNA by reverse transcription-polymerase chain reaction, as well as the NS5A protein, Nakai discovered that the recombinant strain of HCV J6JFH1 was capable of infecting human B cells separated from human peripheral blood. Despite HCV replication being less efficient in B lymphocytes than in hepatocyte line (Huh7) cells, their outcomes show that human B lymphocytes without other non-B cells can be infected with HCV.69

Intracellular viral proteins have been demonstrated to potentially contribute to direct oncogenic transformation in several mouse models. For instance, following a latency period of between 180 and 600 days, mice with the combination of interferon regulatory factor-1 inactivation and persistent expression of HCV structural proteins, such as CN2, develop lymphoproliferative diseases.70 The main events that were discovered to cause lymphoproliferation in this model included increased levels of IL2, IL10, and Bcl-2 as well as increased Bcl-2 expression.

It has been demonstrated that the HCV core protein and NS3 proteins increase the production of nitric oxide synthase (NOS) and reactive oxygen species (ROS), which lead to DNA repair damage and mitochondrial injury and may precede cellular transformation,71 which might be one of the factors causing DNA mutations and double-strand breaks. Overall, the decreased ability of HCV-infected cells to effectively repair DNA damage combined with HCV’s capacity to cause DNA damage would cause random rearrangements to occur in the genome, increasing the risk of developing cancer.

Permanent B-cell damage, the hit-and-run theory

The basic idea in hit-and-run mechanisms is that they lead to permanent genetic mutations even after viral clearance due to transient intracellular reproduction and proliferation of viral proteins. In B-cell lines and PBMCs in vitro, HCV has been discovered to produce a high mutation frequency of cellular genes (p53, Bcl-6, immunoglobulin heavy chain, and beta-catenin genes) by causing double-strand breaks and motivating AID and error-prone polymerases, stimulating tumor necrosis factor α (TNF-α) generation. The amplification of HCV-induced mutations in tumor suppressor genes and protooncogenes is realized in HCV-related B-NHL in vivo, indicating that they may transform the B cells into oncogenes. It may be regarded as a hit-and-run mode of cell change to induce the mutator phenotype in B cells by HCV infection, neither acute nor chronic.44,45 Green et al.72 proposed that in human ABC-like DLBCL, genetic changes of BCL6 may work in a hit-and-run fashion in early precursors. At the same time, dependence on alternative oncogenic mechanisms, including nuclear-factor kB and BCR signaling pathways, are developed by evolved tumor cells. The overexpression of AID in B cells of HCV-infected individuals may exert a critical effect on lymphomagenesis. As a result, the CD19+ cell subset of B cells from PBMCs overexpress many lymphomagenesis genes, including AID.73 However, similar results have not been repeated in vivo,74 and more research shall confirm these findings.

Pathogenesis of HBV-associated NHL

The presence of HBV DNA in B cells, plasma, and tumor tissues of DLBCL patients has recently been discovered using next-generation sequencing, confirming HBV’s lymphoid and carcinogenic potential.75 The specific role of HBV in the occurrence of NHL is still unclear, and the research on its mechanism is less extensively explored than HCV,76 and there are mainly the following possible mechanisms.1) Indirect mechanisms: stimulation of B lymphocytes by extracellular HBV; 2) Direct mechanisms: oncogenic effects mediated by intracellular HBV DNA (Fig. 2).

Pathogenesis of HBV-associated NHL.
Fig. 2  Pathogenesis of HBV-associated NHL.

(1) Indirect mechanisms: Stimulation of B lymphocytes by extracellular HBV; Antigens of HBV can also trigger chronic antigenic stimulation that causes immune response, genetic damage, and lymphocyte proliferation. B-cell antigen stimulation-related genes (e.g., CD83, NFKBIZ, etc.) were upregulated. Among them, mutations in NFKBIZ gene were associated with abnormal NF-κB pathway and dysregulation of pro-oncogenes, which could lead to the development of ABC subtype DLBCL. (2) Direct mechanisms: Oncogenic effects mediated by intracellular HBV DNA; HBV infects B cells directly, causing genetic mutations (MYD88, GRB2, BCL2, TP53, NFKBIA, FAS, MYC, STAT3, PRKCB) and signaling pathway altered (p53, FOXO, BCR, JAK-STAT, NF-κB) that lead to the development of cancerous tumors; HBV DNA can repeatedly target and integrate protein-coding genes (ANKS1B, CAPZB, CTNNA3, EGFLAM, FHOD3, HDAC4, OPCML), which have significantly altered expression levels in NHL and may be potential candidate oncogenes for DLBCL. HBV, hepatitis C virus; NHL, non-Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma.

Indirect mechanisms: stimulation of B lymphocytes by extracellular HBV

One mechanism may be the long-term stimulation of HBV antigen in patients with hepatitis B, which induces an immune response and promotes abnormal proliferation of lymphocytes. Gene expression analysis revealed that B-cell antigen stimulation-related genes (e.g., CD83, NFKBIZ, etc.) were upregulated. Among them, mutations in the NFKBIZ gene were associated with abnormal NF-κB pathway and dysregulation of pro-oncogenes, which could lead to the development of ABC subtype DLBCL.77 By studying HBV immunoglobulin variable region gene fragments in the DLBCL tissues of patients with positive HBsAg, Deng et al.78 found that HBsAg-positive DLBCL patients tended to use the heavy chain gene IGHV4-34 (42.1%) and light chain gene IgKV4-1 (65.5%), which were higher than normal peripheral blood B cells. IGHV4-34 gene fragment mainly encodes antibodies to recognize viral antigens and autoantigens. Therefore, it is suggested that specific antigens are involved in the pathogenesis of DLBCL. It was also found that almost all HCDR3, KCDR3, and LCDR3 showed high homology with specific antibody sequences of HBV-associated antigens (mainly HBsAg), confirming that HBV antigenic stimulation is one of the pathogenetic mechanisms. However, Ren et al.79 found by gene sequencing comparison that there was no biased usage of the IGVH gene in HBsAg-positive DLBCL patients, and that the CDR3 region in HBsAg-positive DLBCL patients did not have a fixed type, nor was there any sequence identity with hepatitis B virus surface antibody (anti-HBs). They propose that HBV infection of B cells may lead to an overactive state, resulting in enhanced mutations mediated in part by APOBEC and AID. Finally, it increases the overall mutation burden in HBsAg-positive DLBCLs.

In conclusion, the evidence and literature related to the chronic antigen stimulation theory are still scarce and the findings are not yet uniform, so further studies are still needed to validate it. However, in general, more findings support the idea that HBV infection of lymphocytes leads to DLBCL.

Direct mechanisms: oncogenic effects mediated by intracellular HBV DNA

Another possible mechanism is that, similar to EBV-driven lymphoma, HBV infects B cells directly, causing genetic alterations in the formation of malignant tumors.80 HBV has the characteristics of the hepatotropic virus, which can cause chronic hepatitis and may lead to HCC; simultaneously, it can survive in extrahepatic sites such as lymph nodes, lymphoblastoid cells, vascular elements, and bile ducts in the liver.81 The main area of HBV replication is in the liver, but the lymphatic system is a virtual repository for the virus. Some studies have isolated HBV DNA from PBMCs.82–84In vitro, HBV can infect B lymphocytes directly, and HBV nucleic acid and antigen have been found in the lymphoma tissues of HBV-positive patients. In tissues from DLBCL patients who were serum HBsAg positive, HBx protein, a transcription factor that plays an important role in tumorigenesis, was highly expressed.85 Analysis by whole genome sequencing/whole exome sequencing , transcriptome sequencing, and targeted sequencing techniques revealed significantly enhanced gene mutations with unique mutation features in HBsAg-positive DLBCL patients.79 Mutation tag analysis identified tags associated with APOBEC, suggesting that the frequency of gene mutations is increased in patients with HBV-positive DLBCL and is partially due to APOBEC/AID. The most critical mutational pathways in patients with HBV-positive DLBCL are consistent with those involved in HBV-associated pathways, and these genes include MYD88, GRB2, BCL2, TP53, NFKBIA, FAS, MYC, STAT3, and PRKCB. In addition, high-frequency mutations identified in patients with HBV-positive DLBCL involve other important signaling pathways, including p53, FOXO, BCR, JAK-STAT, NF-κB, and related signaling pathways such as epigenetic modifications, immune escape, and cell migration.

HBV DNA may integrate into the B-cell genome and directly destroy tumor suppressors or activate tumor genes, as in HBV-induced HCC.86 It has been shown that HBV DNA can be integrated into PBMCs.82 Using a high-throughput virus integration assay (HIVID), HBV DNA was also discovered to be integrated into the NHL cell genome.87 Combining HIVID and immunohistochemical analysis, HBV DNA was found to repeatedly target and integrate seven protein-coding genes, namely ANKS1B, CAPZB, CTNNA3, EGFLAM, FHOD3, HDAC4, and OPCML, in lymphoma tissues, which have significantly altered expression levels in NHL and may be potential candidate oncogenes for DLBCL. Thus, it provides strong evidence for the connection between NHL and HBV infection.

According to Zhou et al.,76 serum HBV activity may not significantly impact the pathogenesis of aggressive B-NHL. Like HCV-associated B-NHL, transient intracellular virus-induced permanent genetic cell damage may be more related to the pathogenesis of invasive B-NHL than to viral activity in the serum. They discovered that patients with indolent B-NHL and HBV infection had higher HBV DNA levels when they were first diagnosed with B-NHL than those with aggressive B-NHL. Patients with both indolent B-NHL and HBV infection showed considerably higher serological HBV activity than those with aggressive B-NHL.

Treatment for HCV-associated NHL

Because of its antiviral and immunostimulatory properties, interferon (IFN) has been used to treat chronic HCV for more than 20 years.88 Its pegylation (PEG-IFN) made it possible to administer subcutaneous injections weekly rather than at least triweekly, and the combination with Ribavirin significantly increased the effectiveness of the treatment.89,90 Clinical tolerability (flu-like syndrome, acute dysimmunological pathologies, neurocognitive disorders) and biological toxicity (neutropenia and thrombocytopenia for IFN, hemolytic anemia for Ribavirin) were the main limitations of this combination. Hematological toxicity is the main obstacle to concurrent chemotherapy and antiviral therapy. In recent years, IFN-free direct antiviral agents (DAAs) have been introduced to treat HCV infection, and these drugs demonstrated high efficacy in promoting (SVR), ranging from 90–100%.91,92

The regression of HCV-associated NHLs after HCV eradication is the most compelling proof supporting HCV infection’s role in LPDs. As an additional benefit, eradicating HCV after cytotoxic chemotherapy may prevent HCV exacerbations. The treatment of HCV-associated B-NHL still needs to be optimized. There are three different approaches to timing HCV treatment: first-line (DAAs) for hematological conditions, second-line DAAs after chemotherapy, and DAAs concurrently with chemotherapy. Table 1 shows the main studies of DAAs conducted in HCV patients with associated NHL.93–98

Table 1

Current evidence from DAA-based antiviral therapy for the treatment of HCV-positive NHLs

ReferenceStudy designPatients, nLymphoma subtype, n (%)HCV RNA (genotype), n (%)Cirrhosis, n (%)MC, n (%)DAAs therapy, n (%)Chemotherapy, n (%)Sustained virologic response, n (%)MC response, n (%)NHL response, n (%)Follow-up, m
Alric et al., 201693Prospective cohort10MZL: 6 (60); DLBCL: 3 (30); Other: 1 (10)Genotype 1: 6 (60); Genotype 2: 1 (10); Genotype 3: 1 (10); Genotype 5: 1 (10); Genotype 6: 1 (10)1 (10)7 (70)SOF-based regimenConcomitant: 9 (90)9 (90)–CR: 9 (90); PR: 1 (10)12
Arcaini et al., 201694Retrospective cohort46MZL: 37 (80); LPL: 2 (4); FL: 2 (4); CLL/SLL: 4 (9); NHL NOS: 1 (2)Genotype 1: 29 (63); Genotype 2: 12 (26); Genotype 3: 3 (7); Genotype 4: 2 (4)7 (15)15 (33)SOF-based regimen: 39 (85); Other regimen: 7 (11)No.45 (98)CR: 7 (15)CR: 12 (26); PR: 19 (41); SD: 11 (24); PD or NR: 4 (9)8
Persico et al., 201895Prospective cohort20DLBCLGenotype 1b: 20 (100)4 (20)–SOF-based regimen: 20 (100)Concomitant: 20 (100)20 (100)–CR: 19 (95); PD: 1 (5)12
Merli et al., 201996Retrospective cohort47DLBCL: 45 (96); FL: 2 (4)Genotype 1: 26 (56); Genotype 2: 16 (34); Other 3: 5 (10)12 (25)5 (11)SOF-based regimen: 47 (100)Before DAA: 38 (81); Concomitant: 9 (19)45 (96)–CR: 46 (98); PD: 1 (2)33.6
Frigeni et al., 202097Retrospective cohort66MZL: 53 (80); Non-MZL: 13 (20)Genotype 1: 38 (59); Genotype 2: 19 (29); Other 3: 8 (12)7 (11)27 (41)SOF-based regimen: 66 (100)No.65 (98)CR: 14 (21); PR: 31 (47); SD: 15 (23); PD: 5 (8)17
Merli et al., 202298Prospective cohort40MZL: 27; Non-MZL: 131: 16 (40); 2: 21 (53); 3: 2 (5); 4: 1 (2)014 (35)SOF-based regimen: 40 (100)No.40 (100)CR:8 (57); PR: 1 (7)CR: 8 (20); PR: 10 (25); SD: 16 (40); PD: 6 (15)37

CLL, chronic lymphocytic leukemia; DAA, direct antiviral agent; DLBCL, diffuse large B-cell lymphoma; HCV, hepatitis C virus; LPD, lymphoproliferative disease; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma.

It is reasonable to consider DAAs administration as first-line therapy for indolent lymphoma patients who would not need instant chemotherapy. As found with (IFN), the HCV-associated lymphoma might be regressed after HCV eradication.99 There are few case reports of DAAs all-oral treatment of the hematological disease being completely response. Arcaini et al.94 explored the virological and lymphoproliferative disease response (LDR) of 46 patients who had chronic HCV infection and indolent B-cell NHLs, or chronic lymphocytic leukemia (CLL) treated with DAAs. The DAAs therapy lasted 12 weeks on average (6–24 weeks). At week 12 after completing DAAs, 45 patients (98%) had an SVR; the total LDR rate was 67%. The 1-year progression-free and total survival rates were 75% and 98%, respectively, following a median follow-up of 8 months. A recent prospective study treated patients with HCV-associated indolent lymphomas with genotype-appropriate DAAs. 100% of patients experienced a persistent virologic response. The overall response rate for lymphoma was 45%, with eight patients (20%) obtaining a CR and 10 patients (25%) having a partial response. Six patients advanced and 16 had stable disease.98 These results suggest that DAAs based antiviral therapy is beneficial for patients with indolent B-NHL, particularly those with marginal zone type, and reveal the etiological role of HCV in B-NHL.

Conversely, antiviral therapy alone is unlikely to be sufficient in treating aggressive NHL, and therefore immediate chemotherapy is necessary. This is often in conjunction with the CD20 antibody rituximab (chemo-immunotherapy, as CIT, is known). Despite limited data,100 revised international hematology (National Comprehensive Cancer Network) and hepatology (European Association for the Study of the Liver) guidelines recommend patients with HCV-related DLBCL achieve a CR after first-line immunochemotherapy (I-CT) before undergoing HCV eradication with DAAs.101–102 Moreover, recent studies have shown that concurrent DAAs and R-CHOP management for the prevention of hepatic toxicity could be feasible, efficient, and ideally preferable to deferred management of DAAs.95,96 An international retrospective analysis96 of 47 HCV-related DLBCL patients treated concurrently (coincident cohort: n=9) or sequentially (sequential cohort: n=38) in 23 Italian and French centers examined the hematological and virological outcomes and survival. This cohort of HCV-related DLBCL patients had an excellent outcome, with a high SVR rate, well tolerance, and high progression-free survival, indicating that DAAs are beneficial to eradicating HCV both after and during I-CT. This group of HCV-positive DLBCL patients had an excellent result, with a high SVR rate, well tolerance, and prolonged progression-free survival, indicating that DAAs are beneficial to eradicating HCV both after and during I-CT. Future research should evaluate the ideal time for HCV treatment with DAAs in patients with aggressive lymphomas. As a result, HCV testing at the time of NHL diagnosis and HCV load detection along the course of the disease are required.103,104 A retrospective study showed that the cumulative incidence rate of lymphoma in HCV-infected patients after antiviral therapy was lower than that in untreated HCV-infected patients, indicating the preventive effect of antiviral treatment on B-NHL,105,106 and early initiation of antiviral treatment is recommended.

Treatment of HBV-associated NHL

HBV increases the risk of NHL and further affects the chemotherapy effect and prognosis of NHL patients.107,108 According to a meta-analysis,108 DLBCL patients with chronic HBV infection had significantly poorer progression-free survival (PFS) at 2- and 5-years and overall survival (OS). Patients who were seronegative for HBsAg had a lower CR rate, higher progressive disease (PD) rate, and more advanced clinical features.109 Chemotherapy for NHL is affected by HBV infection and replication. At the same time, chemotherapy can also activate HBV replication.110 According to studies, HBV reactivation is a risk for HBsAg-positive NHL patients who receive rituximab-containing immunochemotherapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) and the rate of HBV reactivation can be as high as 70%. Compared to the CHOP group, abnormal liver function is significantly higher, and fulminant hepatitis can occur in severe cases in the R-CHOP group.111,112 Wei et al.113 conducted a multicenter large-sample data analysis that showed HBV infection status had no significant effect on prognosis in patients with DLBCL receiving CHOP chemotherapy. Compared to HBsAg-negative patients, OS in R-CHOP chemotherapy was worse in HBsAg-positive patients, and prognostic factor analysis revealed that HBsAg constituted an independent negative prognostic factor.

Following recent guidelines, all patients with HBsAg positive/HBV DNA≥2,000 IU/mL should be treated for HBV. In most patients, anti-HBV treatment should be continued indefinitely.112 Although immunocompetent patients with HBsAg positive/HBV DNA<2,000 IU/mL do not need HBV treatment, those undergoing immune-inhibitive therapy are at a high risk of progressing to the immune-reactive stage and should begin antiviral therapy as soon as possible before starting chemotherapy.114–116 In patients with a hematological disease in remission, ECIL recommendations indicate 12-month continuing prophylaxis after stopping immunosuppressive treatment,115 whereas other authors advocate continuing for 12–24 months after stopping Chemotherapy.116

Using cohort studies on B-cell lymphomas and concomitant HBV infection, Wang et al.117 found CAR-T-cell therapy to be safe and efficient for patients with advanced B-cell malignancies and chronic or resolved HBV infection. Antiviral treatment with tenofovir disoproxil, entecavir, or lamivudine was sustained with a good compliance rate in patients with chronic HBV infection. Patients with resolved HBV infection were supervised for HBsAg, ALT, and HBV DNA and given antiviral drugs if HBV reactivation was examined. In two patients with chronic HBV infection and one with resolved HBV infection, HBV was reactivated. No HBV-associated hepatitis flare occurred. The three cohorts’ responses to CAR-T cell treatment were not significantly different. No great diversity was found between the cohorts in neurologic toxicity and cytokine release syndrome. The cohorts were similar in PFS and OS (HBV-Chronic, HBV Resolved, and No HBV infection).

Hepatitis B vaccines have been found to reduce the incidence of NHL. For example, Huang and colleagues30 found that anti-HBV treatment significantly reduced the risk of HBV-associated NHL in a cohort study with 16 years of follow-up. Hepatitis B vaccination, being the most effective method of preventing hepatitis B infection, can significantly reduce the prevalence of HBV-associated NHL in adolescents. It was also reported that some HBsAg-positive B-NHL patients achieved CR of lymphoma for many years after anti-HBV therapy.118,119 These results suggest that HBV is related to B-NHL, and antiviral therapy can reduce the activation of chemotherapy-related hepatitis B and have a therapeutic effect on some types of NHL. The above evidence from case reports or small studies, which need further investigation in the future.

Conclusions and further considerations

Current evidence on the link between HCV or HBV and NHL has been summarized in this review. The mechanism of hepatitis virus-related lymphoma is not fully understood and needs further research. The results of antiviral therapy in HCV-associated indolent NHL are encouraging. DAAs are recommended for their high SVR rate, short-term treatment and are generally well tolerated; this will further improve the remission rate of HCV-NHL. In addition, some studies have demonstrated that early anti-HCV treatment has a preventive effect on B-NHL, which has to be verified in further large-scale prospective epidemiological studies. Hepatitis B vaccines have been found to reduce the incidence of NHL. Investigations have demonstrated poor overall treatment outcomes and prognosis in HBV-NHL, and current studies have confirmed that CAR-T-cell therapy is safe and effective in HBV-NHL.

Abbreviations

AID: 

activity-induced cytosine deaminase

BAFF: 

B-cell activating factor

BCR: 

B-cell receptor

cccDNA: 

closed circular DNA

CLL: 

chronic lymphocytic leukemia

CR: 

complete response

DAAs: 

direct antiviral agents

DLBCL: 

diffuse large B-cell lymphoma

EBV: 

Epstein-Barr virus

HBV: 

hepatitis B virus

HCV: 

hepatitis C virus

HIVID: 

high-throughput virus integration assay

HTLV-I: 

human T lymphocyte virus type I

I-CT: 

immunochemotherapy

IFN: 

interferon

IgH: 

immunoglobulin heavy -chain gene

IL: 

interleukin

LDR: 

lymphoproliferative disease response

LPD: 

lymphoproliferative disease

MC: 

mixed cryoglobulinemia

miRNAs: 

microRNAs

MZL: 

marginal zone lymphoma

NHL: 

non-Hodgkin lymphoma

NOS: 

nitric oxide synthase

OS: 

overall survival

PBMCs: 

peripheral blood mononuclear cells

PD: 

progressive disease

PFS: 

progression-free survival

ROS: 

reactive oxygen species

SCID: 

severe combined immune deficiency

SVR: 

sustained virological response

TNF: 

tumor necrosis factor

TNF-α: 

tumor necrosis factor α

Declarations

Funding

This research was funded by the Wuhan Municipal Health Commission (grant number WX17Q06).

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Writing of the manuscript (WZ), revision of the manuscript (LW, FD, TB and HM), and developing the idea for the article and critically reviewing it (XZ). All authors read and approved the final version of the manuscript.

References

  1. Lyons SF, Liebowitz DN. The roles of human viruses in the pathogenesis of lymphoma. Semin Oncol 1998;25(4):461-475 PubMed/NCBI
  2. Clarke B. Molecular virology of hepatitis C virus. J Gen Virol 1997;78(Pt 10):2397-2410 View Article PubMed/NCBI
  3. Simmonds P, Bukh J, Combet C, Deléage G, Enomoto N, Feinstone S, et al. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 2005;42(4):962-973 View Article PubMed/NCBI
  4. Tiollais P, Pourcel C, Dejean A. The hepatitis B virus. Nature 1985;317(6037):489-495 View Article PubMed/NCBI
  5. Pascual M, Perrin L, Giostra E, Schifferli JA. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 1990;162(2):569-570 View Article PubMed/NCBI
  6. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992;327(21):1490-1495 View Article PubMed/NCBI
  7. Monti G, Pioltelli P, Saccardo F, Campanini M, Candela M, Cavallero G, et al. Incidence and characteristics of non-Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Arch Intern Med 2005;165(1):101-105 View Article PubMed/NCBI
  8. Nieters A, Kallinowski B, Brennan P, Ott M, Maynadié M, Benavente Y, et al. Hepatitis C and risk of lymphoma: results of the European multicenter case-control study EPILYMPH. Gastroenterology 2006;131(6):1879-1886 View Article PubMed/NCBI
  9. Gisbert JP, García-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in B-cell non-Hodgkin’s lymphoma: systematic review and meta-analysis. Gastroenterology 2003;125(6):1723-1732 View Article PubMed/NCBI
  10. de Sanjose S, Benavente Y, Vajdic CM, Engels EA, Morton LM, Bracci PM, et al. Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium. Clin Gastroenterol Hepatol 2008;6(4):451-458 View Article PubMed/NCBI
  11. Michot JM, Canioni D, Driss H, Alric L, Cacoub P, Suarez F, et al. Antiviral therapy is associated with a better survival in patients with hepatitis C virus and B-cell non-Hodgkin lymphomas, ANRS HC-13 lympho-C study. Am J Hematol 2015;90(3):197-203 View Article PubMed/NCBI
  12. Tsai YF, Liu YC, Yang CI, Chuang TM, Ke YL, Yeh TJ, et al. Poor Prognosis of Diffuse Large B-Cell Lymphoma with Hepatitis C Infection. J Pers Med 2021;11(9):844 View Article PubMed/NCBI
  13. Huang CF, Lai HC, Chen CY, Tseng KC, Kuo HT, Hung CH, et al. Extrahepatic Malignancy Among Patients With Chronic Hepatitis C After Antiviral Therapy: A Real-World Nationwide Study on Taiwanese Chronic Hepatitis C Cohort (T-COACH). Am J Gastroenterol 2020;115(8):1226-1235 View Article PubMed/NCBI
  14. Roggero E, Zucca E, Pinotti G, Pascarella A, Capella C, Savio A, et al. Eradication of Helicobacter pylori infection in primary low-grade gastric lymphoma of mucosa-associated lymphoid tissue. Ann Intern Med 1995;122(10):767-769 View Article PubMed/NCBI
  15. Hermine O, Lefrère F, Bronowicki JP, Mariette X, Jondeau K, Eclache-Saudreau V, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002;347(2):89-94 View Article PubMed/NCBI
  16. Zuckerman E, Zuckerman T, Sahar D, Streichman S, Attias D, Sabo E, et al. The effect of antiviral therapy on t(14;18) translocation and immunoglobulin gene rearrangement in patients with chronic hepatitis C virus infection. Blood 2001;97(6):1555-1559 View Article PubMed/NCBI
  17. Vallisa D, Bernuzzi P, Arcaini L, Sacchi S, Callea V, Marasca R, et al. Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin’s lymphoma: a multicenter Italian experience. J Clin Oncol 2005;23(3):468-473 View Article PubMed/NCBI
  18. Arcaini L, Bruno R. Hepatitis C virus infection and antiviral treatment in marginal zone lymphomas. Curr Clin Pharmacol 2010;5(2):74-81 View Article PubMed/NCBI
  19. Cacoub P, Desbois AC, Comarmond C, Saadoun D. Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis. Gut 2018;67(11):2025-2034 View Article PubMed/NCBI
  20. Chen J, Wang J, Yang J, Zhang W, Song X, Chen L. Concurrent infection of hepatitis B virus negatively affects the clinical outcome and prognosis of patients with non-Hodgkin’s lymphoma after chemotherapy. PLoS One 2013;8(7):e69400 View Article PubMed/NCBI
  21. Kim JH, Bang YJ, Park BJ, Yoo T, Kim CW, Kim TY, et al. Hepatitis B virus infection and B-cell non-Hodgkin’s lymphoma in a hepatitis B endemic area: a case-control study. Jpn J Cancer Res 2002;93(5):471-477 View Article PubMed/NCBI
  22. Takai S, Tsurumi H, Ando K, Kasahara S, Sawada M, Yamada T, et al. Prevalence of hepatitis B and C virus infection in haematological malignancies and liver injury following chemotherapy. Eur J Haematol 2005;74(2):158-165 View Article PubMed/NCBI
  23. Chen MH, Hsiao LT, Chiou TJ, Liu JH, Gau JP, Teng HW, et al. High prevalence of occult hepatitis B virus infection in patients with B cell non-Hodgkin’s lymphoma. Ann Hematol 2008;87(6):475-480 View Article PubMed/NCBI
  24. Engels EA, Cho ER, Jee SH. Hepatitis B virus infection and risk of non-Hodgkin lymphoma in South Korea: a cohort study. Lancet Oncol 2010;11(9):827-834 View Article PubMed/NCBI
  25. Li X, Zheng Y, Zhu H, Lin X, Zhang Y, Zhao Y, et al. Risk of Onset of Hematological Malignancies in Patients Infected with the Hepatitis B Virus: Results from a Large-Scale Retrospective Cohort Study in China. Acta Haematol 2017;137(4):209-213 View Article PubMed/NCBI
  26. Wang C, Xia B, Ning Q, Zhao H, Yang H, Zhao Z, et al. High prevalence of hepatitis B virus infection in patients with aggressive B cell non-Hodgkin’s lymphoma in China. Ann Hematol 2018;97(3):453-457 View Article PubMed/NCBI
  27. Nath A, Agarwal R, Malhotra P, Varma S. Prevalence of hepatitis B virus infection in non-Hodgkin lymphoma: a systematic review and meta-analysis. Intern Med J 2010;40(9):633-641 View Article PubMed/NCBI
  28. Yi HZ, Chen JJ, Cen H, Yan W, Tan XH. Association between infection of hepatitis B virus and onset risk of B-cell non-Hodgkin’s lymphoma: a systematic review and a meta-analysis. Med Oncol 2014;31(8):84 View Article PubMed/NCBI
  29. Dalia S, Chavez J, Castillo JJ, Sokol L. Hepatitis B infection increases the risk of non-Hodgkin lymphoma: a meta-analysis of observational studies. Leuk Res 2013;37(9):1107-1115 View Article PubMed/NCBI
  30. Huang CE, Yang YH, Chen YY, Chang JJ, Chen KJ, Lu CH, et al. The impact of hepatitis B virus infection and vaccination on the development of non-Hodgkin lymphoma. J Viral Hepat 2017;24(10):885-894 View Article PubMed/NCBI
  31. Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol 2007;46(1):160-170 View Article PubMed/NCBI
  32. Bréchot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, Paterlini-Bréchot P. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely “occult”?. Hepatology 2001;34(1):194-203 View Article PubMed/NCBI
  33. Wang F, Xu RH, Han B, Shi YX, Luo HY, Jiang WQ, et al. High incidence of hepatitis B virus infection in B-cell subtype non-Hodgkin lymphoma compared with other cancers. Cancer 2007;109(7):1360-1364 View Article PubMed/NCBI
  34. Pollicino T, Squadrito G, Cerenzia G, Cacciola I, Raffa G, Craxi A, et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 2004;126(1):102-110 View Article PubMed/NCBI
  35. Lenci I, Marcuccilli F, Tisone G, Di Paolo D, Tariciotti L, Ciotti M, et al. Total and covalently closed circular DNA detection in liver tissue of long-term survivors transplanted for HBV-related cirrhosis. Dig Liver Dis 2010;42(8):578-584 View Article PubMed/NCBI
  36. Quinn ER, Chan CH, Hadlock KG, Foung SK, Flint M, Levy S. The B-cell receptor of a hepatitis C virus (HCV)-associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis. Blood 2001;98(13):3745-3749 View Article PubMed/NCBI
  37. Ivanovski M, Silvestri F, Pozzato G, Anand S, Mazzaro C, Burrone OR, et al. Somatic hypermutation, clonal diversity, and preferential expression of the VH 51p1/VL kv325 immunoglobulin gene combination in hepatitis C virus-associated immunocytomas. Blood 1998;91(7):2433-2442 PubMed/NCBI
  38. Chan CH, Hadlock KG, Foung SK, Levy S. V(H)1-69 gene is preferentially used by hepatitis C virus-associated B cell lymphomas and by normal B cells responding to the E2 viral antigen. Blood 2001;97(4):1023-1026 View Article PubMed/NCBI
  39. Marasca R, Vaccari P, Luppi M, Zucchini P, Castelli I, Barozzi P, et al. Immunoglobulin gene mutations and frequent use of VH1-69 and VH4-34 segments in hepatitis C virus-positive and hepatitis C virus-negative nodal marginal zone B-cell lymphoma. Am J Pathol 2001;159(1):253-261 View Article PubMed/NCBI
  40. Ferri C, Sebastiani M, Giuggioli D, Cazzato M, Longombardo G, Antonelli A, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum 2004;33(6):355-374 View Article PubMed/NCBI
  41. De Re V, De Vita S, Marzotto A, Gloghini A, Pivetta B, Gasparotto D, et al. Pre-malignant and malignant lymphoproliferations in an HCV-infected type II mixed cryoglobulinemic patient are sequential phases of an antigen-driven pathological process. Int J Cancer 2000;87(2):211-216 View Article PubMed/NCBI
  42. Rosa D, Saletti G, De Gregorio E, Zorat F, Comar C, D’Oro U, et al. Activation of naïve B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders. Proc Natl Acad Sci U S A 2005;102(51):18544-18549 View Article PubMed/NCBI
  43. Machida K, Cheng KT, Sung VM, Lee KJ, Levine AM, Lai MM. Hepatitis C virus infection activates the immunologic (type II) isoform of nitric oxide synthase and thereby enhances DNA damage and mutations of cellular genes. J Virol 2004;78(16):8835-8843 View Article PubMed/NCBI
  44. Machida K, Cheng KT, Sung VM, Shimodaira S, Lindsay KL, Levine AM, et al. Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci U S A 2004;101(12):4262-4267 View Article PubMed/NCBI
  45. Machida K, Cheng KT, Pavio N, Sung VM, Lai MM. Hepatitis C virus E2-CD81 interaction induces hypermutation of the immunoglobulin gene in B cells. J Virol 2005;79(13):8079-8089 View Article PubMed/NCBI
  46. Zuckerman E, Zuckerman T, Sahar D, Streichman S, Attias D, Sabo E, et al. bcl-2 and immunoglobulin gene rearrangement in patients with hepatitis C virus infection. Br J Haematol 2001;112(2):364-369 View Article PubMed/NCBI
  47. Chen Z, Zhu Y, Ren Y, Tong Y, Hua X, Zhu F, et al. Hepatitis C virus protects human B lymphocytes from Fas-mediated apoptosis via E2-CD81 engagement. PLoS One 2011;6(4):e18933 View Article PubMed/NCBI
  48. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 1999;189(11):1747-1756 View Article PubMed/NCBI
  49. Sène D, Limal N, Ghillani-Dalbin P, Saadoun D, Piette JC, Cacoub P. Hepatitis C virus-associated B-cell proliferation—the role of serum B lymphocyte stimulator (BLyS/BAFF). Rheumatology (Oxford) 2007;46(1):65-69 View Article PubMed/NCBI
  50. Landau DA, Rosenzwajg M, Saadoun D, Klatzmann D, Cacoub P. The B lymphocyte stimulator receptor-ligand system in hepatitis C virus-induced B cell clonal disorders. Ann Rheum Dis 2009;68(3):337-344 View Article PubMed/NCBI
  51. Liao TL, Chen YM, Hsieh SL, Tang KT, Chen DY, Yang YY, et al. Hepatitis C Virus-Induced Exosomal MicroRNAs and Toll-Like Receptor 7 Polymorphism Regulate B-Cell Activating Factor. mBio 2021;12(6):e0276421 View Article PubMed/NCBI
  52. Peveling-Oberhag J, Crisman G, Schmidt A, Döring C, Lucioni M, Arcaini L, et al. Dysregulation of global microRNA expression in splenic marginal zone lymphoma and influence of chronic hepatitis C virus infection. Leukemia 2012;26(7):1654-1662 View Article PubMed/NCBI
  53. Feldmann G, Nischalke HD, Nattermann J, Banas B, Berg T, Teschendorf C, et al. Induction of interleukin-6 by hepatitis C virus core protein in hepatitis C-associated mixed cryoglobulinemia and B-cell non-Hodgkin’s lymphoma. Clin Cancer Res 2006;12(15):4491-4498 View Article PubMed/NCBI
  54. Persico M, Capasso M, Persico E, Masarone M, Renzo Ad, Spano D, et al. Interleukin-10 - 1082 GG polymorphism influences the occurrence and the clinical characteristics of hepatitis C virus infection. J Hepatol 2006;45(6):779-785 View Article PubMed/NCBI
  55. Zignego AL, Macchia D, Monti M, Thiers V, Mazzetti M, Foschi M, et al. Infection of peripheral mononuclear blood cells by hepatitis C virus. J Hepatol 1992;15(3):382-386 View Article PubMed/NCBI
  56. Wang JT, Sheu JC, Lin JT, Wang TH, Chen DS. Detection of replicative form of hepatitis C virus RNA in peripheral blood mononuclear cells. J Infect Dis 1992;166(5):1167-1169 View Article PubMed/NCBI
  57. Revie D, Salahuddin SZ. Human cell types important for hepatitis C virus replication in vivo and in vitro: old assertions and current evidence. Virol J 2011;8:346 View Article PubMed/NCBI
  58. Vannata B, Arcaini L, Zucca E. Hepatitis C virus-associated B-cell non-Hodgkin’s lymphomas: what do we know?. Ther Adv Hematol 2016;7(2):94-107 View Article PubMed/NCBI
  59. Navas MC, Fuchs A, Schvoerer E, Bohbot A, Aubertin AM, Stoll-Keller F. Dendritic cell susceptibility to hepatitis C virus genotype 1 infection. J Med Virol 2002;67(2):152-161 View Article PubMed/NCBI
  60. Crovatto M, Pozzato G, Zorat F, Pussini E, Nascimben F, Baracetti S, et al. Peripheral blood neutrophils from hepatitis C virus-infected patients are replication sites of the virus. Haematologica 2000;85(4):356-361 PubMed/NCBI
  61. Ferri C, Monti M, La Civita L, Longombardo G, Greco F, Pasero G, et al. Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood 1993;82(12):3701-3704 PubMed/NCBI
  62. Sansonno D, Lotesoriere C, Cornacchiulo V, Fanelli M, Gatti P, Iodice G, et al. Hepatitis C virus infection involves CD34(+) hematopoietic progenitor cells in hepatitis C virus chronic carriers. Blood 1998;92(9):3328-3337 PubMed/NCBI
  63. Jabłońska J, Ząbek J, Pawełczyk A, Kubisa N, Fic M, Laskus T, et al. Hepatitis C virus (HCV) infection of peripheral blood mononuclear cells in patients with type II cryoglobulinemia. Hum Immunol 2013;74(12):1559-1562 View Article PubMed/NCBI
  64. Pawełczyk A, Kubisa N, Jabłońska J, Bukowska-Ośko I, Caraballo Cortes K, Fic M, et al. Detection of hepatitis C virus (HCV) negative strand RNA and NS3 protein in peripheral blood mononuclear cells (PBMC): CD3+, CD14+ and CD19+. Virol J 2013;10:346 View Article PubMed/NCBI
  65. Dai B, Chen AY, Corkum CP, Peroutka RJ, Landon A, Houng S, et al. Hepatitis C virus upregulates B-cell receptor signaling: a novel mechanism for HCV-associated B-cell lymphoproliferative disorders. Oncogene 2016;35(23):2979-2990 View Article PubMed/NCBI
  66. Bronowicki JP, Loriot MA, Thiers V, Grignon Y, Zignego AL, Bréchot C. Hepatitis C virus persistence in human hematopoietic cells injected into SCID mice. Hepatology 1998;28(1):211-218 View Article PubMed/NCBI
  67. Ishikawa T, Shibuya K, Yasui K, Mitamura K, Ueda S. Expression of hepatitis C virus core protein associated with malignant lymphoma in transgenic mice. Comp Immunol Microbiol Infect Dis 2003;26(2):115-124 View Article PubMed/NCBI
  68. Sung VM, Shimodaira S, Doughty AL, Picchio GR, Can H, Yen TS, et al. Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: the apoptotic effects of virus infection. J Virol 2003;77(3):2134-2146 View Article PubMed/NCBI
  69. Nakai M, Seya T, Matsumoto M, Shimotohno K, Sakamoto N, Aly HH. The J6JFH1 strain of hepatitis C virus infects human B-cells with low replication efficacy. Viral Immunol 2014;27(6):285-294 View Article PubMed/NCBI
  70. Machida K, Tsukiyama-Kohara K, Sekiguch S, Seike E, Tóne S, Hayashi Y, et al. Hepatitis C virus and disrupted interferon signaling promote lymphoproliferation via type II CD95 and interleukins. Gastroenterology 2009;137(1):285-296.E11 View Article PubMed/NCBI
  71. Machida K, McNamara G, Cheng KT, Huang J, Wang CH, Comai L, et al. Hepatitis C virus inhibits DNA damage repair through reactive oxygen and nitrogen species and by interfering with the ATM-NBS1/Mre11/Rad50 DNA repair pathway in monocytes and hepatocytes. J Immunol 2010;185(11):6985-6998 View Article PubMed/NCBI
  72. Green MR, Vicente-Dueñas C, Romero-Camarero I, Long Liu C, Dai B, González-Herrero I, et al. Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma. Nat Commun 2014;5:3904 View Article PubMed/NCBI
  73. Ito M, Murakami K, Suzuki T, Mochida K, Suzuki M, Ikebuchi K, et al. Enhanced expression of lymphomagenesis-related genes in peripheral blood B cells of chronic hepatitis C patients. Clin Immunol 2010;135(3):459-465 View Article PubMed/NCBI
  74. Tucci FA, Broering R, Johansson P, Schlaak JF, Küppers R. B cells in chronically hepatitis C virus-infected individuals lack a virus-induced mutation signature in the TP53, CTNNB1, and BCL6 genes. J Virol 2013;87(5):2956-2962 View Article PubMed/NCBI
  75. Sinha M, Sundar K, Premalata CS, Asati V, Murali A, Bajpai AK, et al. Pro-oncogenic, intra host viral quasispecies in Diffuse large B cell lymphoma patients with occult Hepatitis B Virus infection. Sci Rep 2019;9(1):14516 View Article PubMed/NCBI
  76. Zhou X, Wuchter P, Egerer G, Kriegsmann M, Kommoss FKF, Witzens-Harig M, et al. Serological hepatitis B virus (HBV) activity in patients with HBV infection and B-cell non-Hodgkin’s lymphoma. Eur J Haematol 2020;104(5):469-475 View Article PubMed/NCBI
  77. Arthur SE, Jiang A, Grande BM, Alcaide M, Cojocaru R, Rushton CK, et al. Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. Nat Commun 2018;9(1):4001 View Article PubMed/NCBI
  78. Deng L, Song Y, Young KH, Hu S, Ding N, Song W, et al. Hepatitis B virus-associated diffuse large B-cell lymphoma: unique clinical features, poor outcome, and hepatitis B surface antigen-driven origin. Oncotarget 2015;6(28):25061-25073 View Article PubMed/NCBI
  79. Ren W, Ye X, Su H, Li W, Liu D, Pirmoradian M, et al. Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma. Blood 2018;131(24):2670-2681 View Article PubMed/NCBI
  80. Marcucci F, Mele A. Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood 2011;117(6):1792-1798 View Article PubMed/NCBI
  81. Galun E, Ilan Y, Livni N, Ketzinel M, Nahor O, Pizov G, et al. Hepatitis B virus infection associated with hematopoietic tumors. Am J Pathol 1994;145(5):1001-1007 PubMed/NCBI
  82. Umeda M, Marusawa H, Seno H, Katsurada A, Nabeshima M, Egawa H, et al. Hepatitis B virus infection in lymphatic tissues in inactive hepatitis B carriers. J Hepatol 2005;42(6):806-812 View Article PubMed/NCBI
  83. Mason A, Wick M, White H, Perrillo R. Hepatitis B virus replication in diverse cell types during chronic hepatitis B virus infection. Hepatology 1993;18(4):781-789 View Article PubMed/NCBI
  84. Pontisso P, Vidalino L, Quarta S, Gatta A. Biological and clinical implications of HBV infection in peripheral blood mononuclear cells. Autoimmun Rev 2008;8(1):13-17 View Article PubMed/NCBI
  85. Wang Y, Wang H, Pan S, Hu T, Shen J, Zheng H, et al. Capable Infection of Hepatitis B Virus in Diffuse Large B-cell Lymphoma. J Cancer 2018;9(9):1575-1581 View Article PubMed/NCBI
  86. Sung WK, Zheng H, Li S, Chen R, Liu X, Li Y, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet 2012;44(7):765-769 View Article PubMed/NCBI
  87. Li M, Shen Y, Chen Y, Gao H, Zhou J, Wang Q, et al. Characterization of hepatitis B virus infection and viral DNA integration in non-Hodgkin lymphoma. Int J Cancer 2020;147(8):2199-2209 View Article PubMed/NCBI
  88. Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Bisceglie A, Peters M, et al. Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med 1986;315(25):1575-1578 View Article PubMed/NCBI
  89. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361(6):580-593 View Article PubMed/NCBI
  90. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358(9286):958-965 View Article PubMed/NCBI
  91. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, Corregidor A, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014;384(9956):1756-1765 View Article PubMed/NCBI
  92. Webster DP, Klenerman P, Dusheiko GM. Hepatitis C. Lancet 2015;385(9973):1124-1135 View Article PubMed/NCBI
  93. Alric L, Besson C, Lapidus N, Jeannel J, Michot JM, Cacoub P, et al. Antiviral Treatment of HCV-Infected Patients with B-Cell Non-Hodgkin Lymphoma: ANRS HC-13 Lympho-C Study. PLoS One 2016;11(10):e0162965 View Article PubMed/NCBI
  94. Arcaini L, Besson C, Frigeni M, Fontaine H, Goldaniga M, Casato M, et al. Interferon-free antiviral treatment in B-cell lymphoproliferative disorders associated with hepatitis C virus infection. Blood 2016;128(21):2527-2532 View Article PubMed/NCBI
  95. Persico M, Aglitti A, Caruso R, De Renzo A, Selleri C, Califano C, et al. Efficacy and safety of new direct antiviral agents in hepatitis C virus-infected patients with diffuse large B-cell non-Hodgkin’s lymphoma. Hepatology 2018;67(1):48-55 View Article PubMed/NCBI
  96. Merli M, Frigeni M, Alric L, Visco C, Besson C, Mannelli L, et al. Direct-Acting Antivirals in Hepatitis C Virus-Associated Diffuse Large B-cell Lymphomas. Oncologist 2019;24(8):e720-e729 View Article PubMed/NCBI
  97. Frigeni M, Besson C, Visco C, Fontaine H, Goldaniga M, Visentini M, et al. Interferon-free compared to interferon-based antiviral regimens as first-line therapy for B-cell lymphoproliferative disorders associated with hepatitis C virus infection. Leukemia 2020;34(5):1462-1466 View Article PubMed/NCBI
  98. Merli M, Rattotti S, Spina M, Re F, Motta M, Piazza F, et al. Direct-Acting Antivirals as Primary Treatment for Hepatitis C Virus-Associated Indolent Non-Hodgkin Lymphomas: The BArT Study of the Fondazione Italiana Linfomi. J Clin Oncol 2022;40(35):4060-4070 View Article PubMed/NCBI
  99. Arcaini L, Vallisa D, Rattotti S, Ferretti VV, Ferreri AJM, Bernuzzi P, et al. Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi. Ann Oncol 2014;25(7):1404-1410 View Article PubMed/NCBI
  100. European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol 2017;66(1):153-194 View Article PubMed/NCBI
  101. Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB, et al. Diffuse Large B-Cell Lymphoma Version 1.2016. J Natl Compr Canc Netw 2016;14(2):196-231 View Article PubMed/NCBI
  102. Carrier P, Jaccard A, Jacques J, Tabouret T, Debette-Gratien M, Abraham J, et al. HCV-associated B-cell non-Hodgkin lymphomas and new direct antiviral agents. Liver Int 2015;35(10):2222-2227 View Article PubMed/NCBI
  103. Merli M, Visco C, Spina M, Luminari S, Ferretti VV, Gotti M, et al. Outcome prediction of diffuse large B-cell lymphomas associated with hepatitis C virus infection: a study on behalf of the Fondazione Italiana Linfomi. Haematologica 2014;99(3):489-496 View Article PubMed/NCBI
  104. Zhou X, Lisenko K, Lehners N, Egerer G, Ho AD, Witzens-Harig M. The influence of rituximab-containing chemotherapy on HCV load in patients with HCV-associated non-Hodgkin’s lymphomas. Ann Hematol 2017;96(9):1501-1507 View Article PubMed/NCBI
  105. Torres HA, Mahale P. Most patients with HCV-associated lymphoma present with mild liver disease: a call to revise antiviral treatment prioritization. Liver Int 2015;35(6):1661-1664 View Article PubMed/NCBI
  106. Taborelli M, Polesel J, Montella M, Libra M, Tedeschi R, Battiston M, et al. Hepatitis B and C viruses and risk of non-Hodgkin lymphoma: a case-control study in Italy. Infect Agent Cancer 2016;11:27 View Article PubMed/NCBI
  107. Hu S, Chen N, Lu K, Zhen C, Sui X, Fang X, et al. The prognostic roles of hepatitis B virus antibody in diffuse large B-cell lymphoma patients. Leuk Lymphoma 2021;62(6):1335-1343 View Article PubMed/NCBI
  108. Rong X, Wang H, Ma J, Pan S, Wang H, Jing S, et al. Chronic hepatitis B virus infection is associated with a poorer prognosis in diffuse large B-cell lymphoma: a meta-analysis and systemic review. J Cancer 2019;10(15):3450-3458 View Article PubMed/NCBI
  109. Zhou X, Wuchter P, Egerer G, Kriegsmann M, Mataityte A, Koelsche C, et al. Role of virological serum markers in patients with both hepatitis B virus infection and diffuse large B-cell lymphoma. Eur J Haematol 2019;103(4):410-416 View Article PubMed/NCBI
  110. Pei SN, Chen CH. Risk and prophylaxis strategy of hepatitis B virus reactivation in patients with lymphoma undergoing chemotherapy with or without rituximab. Leuk Lymphoma 2015;56(6):1611-1618 View Article PubMed/NCBI
  111. Pei SN, Chen CH, Lee CM, Wang MC, Ma MC, Hu TH, et al. Reactivation of hepatitis B virus following rituximab-based regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients. Ann Hematol 2010;89(3):255-262 View Article PubMed/NCBI
  112. Kim SJ, Hsu C, Song YQ, Tay K, Hong XN, Cao J, et al. Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia Lymphoma Study Group. Eur J Cancer 2013;49(16):3486-3496 View Article PubMed/NCBI
  113. Wei Z, Zou S, Li F, Cheng Z, Li J, Wang J, et al. HBsAg is an independent prognostic factor in diffuse large B cell lymphoma patients in rituximab era: result from a multicenter retrospective analysis in China. Med Oncol 2014;31(3):845 View Article PubMed/NCBI
  114. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67(2):370-398 View Article PubMed/NCBI
  115. Mallet V, van Bömmel F, Doerig C, Pischke S, Hermine O, Locasciulli A, et al. Management of viral hepatitis in patients with haematological malignancy and in patients undergoing haemopoietic stem cell transplantation: recommendations of the 5th European Conference on Infections in Leukaemia (ECIL-5). Lancet Infect Dis 2016;16(5):606-617 View Article PubMed/NCBI
  116. Sarmati L, Andreoni M, Antonelli G, Arcese W, Bruno R, Coppola N, et al. Recommendations for screening, monitoring, prevention, prophylaxis and therapy of hepatitis B virus reactivation in patients with haematologic malignancies and patients who underwent haematologic stem cell transplantation-a position paper. Clin Microbiol Infect 2017;23(12):935-940 View Article PubMed/NCBI
  117. Wang Y, Liu Y, Tan X, Pan B, Ge J, Qi K, et al. Safety and efficacy of chimeric antigen receptor (CAR)-T-cell therapy in persons with advanced B-cell cancers and hepatitis B virus-infection. Leukemia 2020;34(10):2704-2707 View Article PubMed/NCBI
  118. Koot AW, Visscher AP, Huits RM. Remission of splenic marginal zone lymphoma in a patient treated for hepatitis B: a case of HBV-associated lymphoma. Acta Clin Belg 2015;70(4):301-303 View Article PubMed/NCBI
  119. Mansoor MS, Wolfsohn DM. Resolution of Small Bowel Follicular Lymphoma With Treatment of Concomitant Hepatitis B. J Clin Gastroenterol 2015;49(10):885-887 View Article PubMed/NCBI
Copyright © 2023 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2751366
  • Visits today : 2659
Back to Top

Hepatitis Virus-associated Non-hodgkin Lymphoma: Pathogenesis and Treatment Strategies

Wenjing Zhang, Fan Du, Li Wang, Tao Bai, Xiang Zhou, Heng Mei
  • Reset Zoom
  • Download TIFF