Anderson, Lesley

Engels, E.A.

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Hepatitis C virus infection and non-Hodgkin lymphoma:Interesting association or causal relationship?Anderson, L., & Engels, E. A. (2008). Hepatitis C virus infection and non-Hodgkin lymphoma: Interestingassociation or causal relationship? International journal of cancer. Journal international du cancer, 122(8)(8), x-xii. DOI: 10.1002/ijc.23462Published in:International journal of cancer. Journal international du cancerQueen's University Belfast - Research Portal:Link to publication record in Queen's University Belfast Research PortalGeneral rightsCopyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or othercopyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associatedwith these rights.Take down policyThe Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made toensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in theResearch Portal that you believe breaches copyright or violates any law, please contact openaccess@qub.ac.uk.Download date:15. Feb. 2017EditorialHepatitis C virus infection and non-Hodgkin lymphoma: Interesting association or causal relationship?Lesley A. Anderson1,2 and Eric A. Engels1*1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD2Ofﬁce of Preventative Oncology, Division of Cancer Prevention, National Cancer Institute, Bethesda, MDNumerous population-based studies have demonstrated an associ-ation between hepatitis C virus (HCV) infection and non-Hodgkinlymphoma (NHL),1,2 pointing to the possibility that HCV plays arole in the development of this malignancy. The Scandinavia Lym-phoma Etiology (SCALE) study, reported in this issue of the Inter-national Journal of Cancer, adds to the accumulating body of epi-demiological evidence supporting this association. The large samplesize (2,819 NHL cases and 1,856 controls), comprehensive popula-tion-based recruitment strategy, rapid case ascertainment, anddetailed classiﬁcation of NHL subtypes make SCALE one of themost comprehensive case–control studies to date. One limitation ofthe SCALE study was the very low prevalence of HCV infection(0.4% of controls, even when the investigators included individualswith intermediate serologic evidence for infection), which limitedthe power and precision of some statistical analyses. HCV seroposi-tivity was associated, although not signiﬁcantly, with overall NHLrisk (OR 2.2, 95% CI 0.9–5.3), and was signiﬁcantly associatedwith risk of B-cell lymphomas (OR 2.4, 95% CI 1.0–5.8), speciﬁ-cally lymphoplasmacytic lymphoma (OR 5.2, 95% CI 1.0–26.4).The ﬁndings of the SCALE study are consistent with the prior liter-ature, which now includes multiple case–control studies and severalcohort studies, most of which ﬁnd a positive association betweenHCV infection and NHL.1,2Given the repeated demonstration of an association, the ques-tion arises whether HCV infection is actually a cause of NHL.Bradford Hill in his landmark paper, ‘‘The Environment and Dis-ease: Association or Causation,’’ suggested 9 criteria to considerwhen assessing causation.3 In Table I, we use these criteria toreview the existing evidence for a causal relationship betweenHCV and NHL. Although Schollkopf et al. discuss some of thisevidence in relation to their ﬁndings in the accompanying article,the table organized around the Bradford Hill criteria provides auseful framework to evaluate the epidemiological and experimen-tal evidence more formally.It is useful to begin with a consideration of the biological plau-sibility of a causal relationship, based on what we know aboutHCV infection and the etiology of NHL. In most individuals,HCV manifests as chronic liver infection, which can eventuallydevelop into cirrhosis.4 This chronic infection leads to chronicstimulation of the immune system and has been associated withthe development of immune-related disorders, such as essentialmixed (Type II) cryoglobulinemia,4,5 which can itself progress toB-cell NHL.5 HCV envelope protein E2 binds to CD81 on the cellsurface of B lymphocytes, lowering their activation threshold.6,7With continued stimulation of the immune system, B lymphocytesmay develop DNA mutations, perhaps through the action of acti-vation-induced cytidine deaminase, leading to transformation.8Also, HCV-infected individuals have an elevated frequency of cir-culating lymphocytes with chromosomal translocations involvingthe bcl2 oncogene,9 implicated in essential mixed cryoglobuline-mia10,11 and many B-cell NHLs.10,12 Causality is also supportedhere by analogy, in that the proposed process of HCV-inducedlymphomagenesis (i.e. chronic immune stimulation), is similar tothe posited mechanism by which Helicobacter pylori infectioncauses gastric NHL13 and Sj€ogren syndrome causes salivary glandNHL.14 Although HCV can infect B lymphocytes,15 HCV is lesslikely to cause lymphomagenesis by a direct oncogenic mecha-nism, since the RNA virus cannot integrate its viral nucleic acidsequences into the lymphocyte genome.Strength of association and consistency are two important crite-ria for assessing causality. Two meta-analyses of 18 and 23 epide-miologic studies examined the association between HCV infectionand overall NHL risk.1,2 The ﬁrst presented a pooled odds ratio(OR) of 5.7 (95% conﬁdence interval (CI) 4.1–8.0).1 In contrast,the more recent meta-analysis by Dal Maso et al. included onlystudies with 100 patients and reported more modest pooled ORsof 2.5 (95% CI 2.1–3.1) and 2.0 (95% CI 1.8–2.2) for case–controland cohort studies, respectively.2 These associations are moder-ately strong, but still substantially weaker than other associationsbetween viruses and cancer generally accepted as causal, e.g.,human papillomavirus and cervical cancer (OR 29, 95% CI 16–53),16 or HCV and liver cancer (pooled OR 17, 95% CI 14–22).17Importantly, the associations between HCV and NHL have beeninconsistent across epidemiologic studies: while most studiesreport an association,1,2 the magnitude varies across a very widerange (ORs and relative risks 2–20). In the meta-analyses, this het-erogeneity in associations across studies has been attributed to dif-ferences in study design, including the type of control group used,differences in the measurement of HCV infection, and differencesin HCV prevalence across populations.1,2 Most recent studies havefound ORs typically in the range of 2–3, as seen in Schollkopfet al. Cohort studies that have measured HCV infection beforedevelopment of NHL have also produced rather modest estimatesof the effect of HCV on NHL risk (relative risks 1.3–2.0).Speciﬁcity of association is an area where the evidence for cau-sality is not convincing. NHL is now considered a diverse groupof separate entities that differ in their pathologic features, molecu-lar lesions, clinical outcomes and perhaps etiology.18 It has beendifﬁcult to determine from epidemiologic studies whether theHCV-NHL association is speciﬁc to particular NHL subtypes orinstead pertains to a wide range of subtypes. This limitation is atleast partly due to the relative rarity of HCV as an exposure andthe small numbers of cases for each NHL subtype within individ-ual studies. Pooled studies have suggested that both B-cell1,2,19and T-cell lymphomas1,2 are associated with HCV infection.Among B-cell NHLs, associations with HCV were seen for diffuselarge B-cell, follicular, marginal zone and chronic lymphocyticleukemia/small lymphocytic lymphoma in the meta-analyses byDal Maso et al.2 The absence of a speciﬁc association betweenHCV and one, or a few, well-deﬁned NHL subtypes (e.g., as isseen for human T lymphotropic virus I and adult T cell leukemia/*Correspondence to: Infections and Immunoepidemiology Branch,Division of Cancer Epidemiology and Genetics, National Cancer Institute,6120 Executive Blvd, EPS 7076 Rockville, MD 20892, USA. Fax: þ301-402-0817. E-mail: engelse@mail.nih.govGrant sponsor: Ireland-Northern Ireland-USA Consortium (Researchand Development Office, Northern Ireland) and the Intramural ResearchProgram of the National Cancer Institute.DOI 10.1002/ijc.23462Published online 12 February 2008 inWiley InterScience (www.interscience.wiley.com).Publication of the International Union Against Cancerlymphoma20 and for human herpesvirus 8 and primary effusionlymphoma21) is disconcerting, although given limitations in thedata, ambiguous speciﬁcity does not argue strongly against acausal role for HCV.The remaining criteria in Table 1 also deserve comment. Tem-porality (i.e., that exposure precedes the outcome) is likely to bepresent, since most HCV infections are acquired in early adult-hood, decades before development of NHL, and it is improbablethat NHL would itself increase risk for infection. Evidence fortemporality derives from a recent cohort study which showed thatHCV-infected individuals have an increased risk for NHL duringat least 6 years of subsequent follow-up.22 By ‘‘experimental evi-dence,’’ Bradford Hill meant evidence from experimental studiesin humans. While it is unethical to deliberately infect persons withHCV, indirect experimental evidence for an HCV effect comesfrom case reports of HCV treatment in NHL patients.23,24 In thesereports, clearance of HCV appears to result in remission of NHL,and reappearance of infection is associated with NHL relapse.Coherence refers to agreement of the available data with what isknown in other settings. The HCV-NHL association is generallycoherent with what is known about the development of NHL.However, we note a striking absence of association between HCVand NHL among people infected with human immunodeﬁciencyvirus25–27 and transplant patients,28 two groups with very highNHL risk. If HCV causes NHL, the absence of an association inthese immunosuppressed populations is somewhat surprising. Oneexplanation might be that an intact immune system is required forfull activation of B lymphocytes by chronic HCV infection.Finally, there is no evidence for a biological gradient of increas-ing NHL risk with increasing severity of HCV infection, althoughresearch on this aspect has been hampered by the lack of a clearlyrelevant measure of HCV severity. One possible surrogate for HCVseverity, which to our knowledge has not been investigated in thecontext of NHL, is HCV viral load, i.e., the level of virus in plasma.It may be possible to consider HCV infected subjects in three cate-gories: (i) individuals with resolved infection (i.e., seropositive butwith undetectable viral load, indicating clearance of HCV); (ii) indi-viduals with ongoing HCV infection and low viral load; and (iii)individuals with ongoing HCV infection and high viral load. Investi-gating the strength of association with NHL across these categoriescould be an intriguing approach to take with prospectively collectedspecimens. Likewise, evidence for causality would be strengthenedby data showing that treatment for HCV infection, which clears orreduces viral replication, lowers the subsequent risk of NHL.On the basis of this analysis, we would argue that, despite anextensive body of population-based and laboratory evidence onHCV infection and NHL, a causal relationship is not fully estab-lished. Several avenues might warrant further investigation. Fur-ther case–control studies, even well-conducted ones like the oneprovided by Schollkopf et al., are probably not needed unless theycan provide a unique perspective. However, conducting largerregistry-based studies, or pooling data from existing studies, willincrease the power to detect associations between HCV infectionand speciﬁc NHL subtypes. In addition, more laboratory researchis required to understand how chronic immune stimulation maylead to NHL. This research would help inform the interpretationof epidemiologic data on subtype-speciﬁc associations and possi-bly clarify why an association between HCV and NHL is not seenin immunosuppressed populations. Finally, we need additionaldata from clinicians regarding HCV treatment responses amongpatients with NHL, to conﬁrm the small case series reported thusfar. We hope that further investigation of the association betweenHCV infection and NHL will provide a better understanding of theetiology of NHL. Ultimately, this work may lead to prevention ofNHL, by allowing for the targeting and treatment of high riskHCV-infected individuals, and it could help inform treatmentstrategies for HCV-associated NHLs.References1. Matsuo K, Kusano A, Sugumar A, Nakamura S, Tajima K, MuellerNE. Effect of hepatitis C virus infection on the risk of non-Hodgkin’slymphoma: a meta-analysis of epidemiological studies. Cancer Sci2004;95:745–52.2. Dal ML, Franceschi S. Hepatitis C virus and risk of lymphoma andother lymphoid neoplasms: a meta-analysis of epidemiologic studies.Cancer Epidemiol Biomarkers Prev 2006;15:2078–85.3. Hill AB. The environment and disease: association or causation? ProcR Soc Med 1965;58:295–300.4. Kayali Z, Buckwold VE, Zimmerman B, Schmidt WN. Hepatitis C,cryoglobulinemia, and cirrhosis: a meta-analysis. Hepatology 2002;36:978–85.5. Dammacco F, Sansonno D, Piccoli C, Tucci FA, Racanelli V. Thecryoglobulins: an overview. Eur J Clin Invest 2001;31:628–38.6. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R,Weiner AJ, Houghton M, Rosa D, Grandi G, Abrignani S. Binding ofhepatitis C virus to CD81. Science 1998;282:938–41.7. Rosa D, Saletti G, De GE, Zorat F, Comar C, D’Oro U, Nuti S,Houghton M, Barnaba V, Pozzato G, Abrignani S. 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Arch Virol 1997;142:545–55.TABLE I – EVIDENCE ACCORDING TO BRADFORD HILL CRITERIA FOR THE ASSOCIATION BETWEEN HEPATITIS C VIRUS (HCV) INFECTIONAND NON-HODGKIN LYMPHOMA (NHL)Bradford Hill Criteria Evidence Strength of evidencePlausibility HCV can cause chronic antigenic stimulation of B-cells leading to DNA mutations 11Analogy Analogous to the mechanisms proposed for NHL caused by Helicobacter pylori andSj€ogren syndrome1Strength of association Case–control studies: pooled odds ratio 2.5 (95% conﬁdence interval 2.1–3.1). Cohortstudies: pooled odds ratio 2.0 (95% conﬁdence interval 1.8–2.2)11Consistency Substantial heterogeneity among studies 1Speciﬁcity Associations reported between HCV and several NHL subtypes 0Temporality Cohort studies demonstrate that HCV infection precedes development of NHL 11Experiment Antiviral treatment causes NHL regression 11Coherence The data are mostly coherent with outside considerations. 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Franceschi S, Polesel J, Rickenbach M, Dal ML, Probst-Hensch NM,Fux C, Cavassini M, Hasse B, Koﬂer A, Ledergerber B, Erb P, Clif-ford GM. Hepatitis C virus and non-Hodgkin’s lymphoma: ﬁndingsfrom the Swiss HIV cohort study. Br J Cancer 2006;95:1598–602.28. Morton LM, Landgren O, Chatterjee N, Castenson D, Parsons R, Hoo-ver RN, Engels EA. Hepatitis C virus infection and risk of post-trans-plant lymphoproliferative disorder among solid organ transplantrecipients. Blood 2007;110:4599–605.xii ANDERSON AND ENGELS

Hepatitis C virus infection and non-Hodgkin lymphoma: Interesting association or causal relationship?

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