Archives of Medical Research 45 (2014) 417e431

ORIGINAL ARTICLE

Prevalence and Prognostic Significance of EpsteineBarr Virus Infection in Classical Hodgkin’s Lymphoma: A Meta-analysis Ju-Han Lee, Younghye Kim, Jung-Woo Choi, and Young-Sik Kim Department of Pathology, Korea University Ansan Hospital, Ansan, Republic of Korea Received for publication December 2, 2013; accepted June 4, 2014 (ARCMED-D-14-00684).

Background and Aims. The prevalence and prognostic significance of Epstein-Barr virus (EBV) infection in classical Hodgkin’s lymphomas (cHLs) remain elusive. To examine the epidemiological and prognostic differences between EBV-positive and -negative cHLs, we conducted a meta-analysis of 119 published studies including 13,045 cases. Methods. We pooled the results of relevant published studies identified using the PubMed and Embase. The effect sizes of outcome parameters were calculated by prevalence, odds ratio (OR), or hazard ratio using a random-effects model. Results. The pooled prevalence of EBV infection in cHL was 47.9%, which was significantly higher in Africa and Central and South America than other regions. EBV-positive cHL showed higher incidence in children than in adults (69.7 vs. 41.1%). EBV-positive cHL was significantly related to male (OR 5 1.8, 95% CI: 1.510e2.038; p !0.001), mixed cellularity subtype (OR 5 3.8, 95% CI: 3.243e4.451; p !0.001), and advanced clinical stages (OR 5 1.2, 95% CI: 1.072e1.369; p 5 0.002). However, the presence of EBV in cHL was not associated with overall or event-free survival. Conclusions. The prevalence of EBV differs according to age, sex, region, histologic subtype, and clinical stage of cHL. However, the presence of EBV has little effects on cHL patient’s survival. Ó 2014 IMSS. Published by Elsevier Inc. Key Words: Hodgkin’s lymphoma, Epstein-Barr virus, Meta-analysis.

Introduction Classical Hodgkin’s lymphoma (cHL) is largely a monoclonal B cell neoplasm and consists of Hodgkin and Reed-Sternberg (HRS) tumor cells scattered within an abundant reactive cellular infiltrate (1). Previous studies have reported the association between Epstein-Barr virus (EBV) and cHL, but the epidemiological and clinical significance or role of EBV in the pathogenesis of cHL remains unclear. The frequency of EBV infection in patients with cHL is strikingly variable, ranging from 18% to as high as 100% in different countries (2e126). Indeed, the proportion of EBV-positive cHL varies

Address reprint requests to: Young-Sik Kim, MD, PhD, Department of Pathology, Korea University Ansan Hospital, 516, Gojan-1 Dong, Danwon-Gu, Ansan-Si, Gyeonggi-Do 425-707, Republic of Korea; Phone: (þ82) 31-412-5322; FAX: (þ82) 31-412-5324; E-mail: [email protected]. kr

according to the geographic region or ethnic group, age, sex, histologic subtype, and socioeconomic status (2e126). EBV-positive cHL is defined as the presence of EBV in tumor cells, which is identified by EBV-encoded RNA (EBER) in situ hybridization and/or latent membrane protein (LMP-1) immunohistochemistry in tissues (127). EBV-positive cHL is generally characterized by a high incidence in underdeveloped countries, a male predominance, and frequent occurrences of the mixed cellularity (MC) subtype, although the prognostic effect of EBV infection on cHL is controversial (2e30,34,114,121,123e126). However, there has not been any consensus on the prevalence or clinicopathologic significance of EBV-positive cHL according to geographic location, age, sex, and histologic subtype. To investigate the prevalence of EBVpositive cHL stratified by the different epidemiological and clinical variables, we conducted a meta-analysis by pooling the published studies of EBV infection in nonimmunocompromised patients with cHL.

0188-4409/$ - see front matter. Copyright Ó 2014 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2014.06.001

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Materials and Methods Data Collection and Selection Criteria We searched PubMed (http://www.ncbi.nlm.nih.gov/ pubmed) and EMBASE (www.embase.com) using the keywords ‘‘EBV’’ and ‘‘Hodgkin’s lymphoma.’’ We also manually searched the reference lists of the identified articles. Duplicate data or overlapping articles were excluded by examining the authors’ names and affiliations. Original articles reporting cases of EBV-positive cHL proven by EBER in situ hybridization and/or LMP-1 immunohistochemistry published before October 2012 were included, but we excluded cases of nodular lymphocytepredominant Hodgkin’s lymphoma (NLPHL) patients and cases of human immunodeficiency virus-associated lymphoma. NLPHL differs principally from the cHL in terms of morphology, phenotype, genotype, and clinical behavior so that it is now considered a separate disease entity. EBVpositive cHL cases were defined as EBER or LMP-1 signal must be unequivocally localized to HRS tumor cells, but not to the surrounding reactive lymphocytes (127). For identifying EBV-positive cHL cases, just one unequivocal HRS tumor cell expressing EBER or LMP-1 should be considered sufficient to entitle a case positive (127). When multiple articles were published by the same authors or institutions, the most recent or single informative article was selected. Articles lacking clinicopathological data for metaanalysis, review articles without original data, conference abstracts, case reports, and articles that included fewer than 15 cases of cHL were excluded. There were no geographic or language restrictions. The selection process of the articles is shown in Figure 1. Data Pooling and Statistics Meta-analysis was performed previously described (128). Briefly, effect sizes for each study were calculated by prevalence, odds ratio (OR), or hazard ratio (HR) and the corresponding 95% confidence interval (CI) using the Mantel-Haenszel method or the Cohen method. For studies without HRs for survival, we assessed HRs and CIs using a published approximation method (129). The prevalence rates, ORs, or HRs were combined using a random-effects model (DerSimonian-Laird method); p !0.05 was considered statistically significant. Statistical heterogeneity among studies was evaluated using the Cochrane Q test and I2 statistics; p !0.10 was considered statistically significant. The I2 statistics refers to the percentage of variation across studies that is due to heterogeneity rather than chance and does not inherently depend on the number of studies considered (I2 5 100%  [Qdf]/Q). For evaluating inconsistency of studies’ results, we assigned I2 statistics to low (I2 !25%), moderate (I2 5 25e75%), and high (I2 O75%) heterogeneities. Subgroup analysis was carried out when I2 value was

more than 75% or when the observed inconsistency have clinical implications. Sensitivity analyses were performed to examine the influence of each study on the pooled prevalence, OR, or HR by serially omitting an individual study and pooling the remaining studies. Publication bias was examined by funnel plots and Egger’s tests. Two-tailed p value !0.10 was considered statistically significant for the Egger’s tests. The pooled analysis was performed using Comprehensive Meta-analysis Software v.2.0 (Biostat, Englewood, NJ). Results Prevalence of EBV Infection in cHL A total of 119 studies reported the frequency of EBV infection among 13,045 cHL cases (Table 1) including 394 from Africa, 1188 from Central and South Americas, 3187 from Asia, 5774 from Europe, 1897 from North America, 28 from Australia, and 577 unclassified cases (2e120) (Table 2). On pooled analysis, EBV infection was found in 47.9% of patients with cHL (95% CI: 44.6e51.2) (Table 2). Geographic Regions The frequency of EBV-positive cHL differed among geographic regions on subgroup analysis and was 74.2% (95% CI: 65.1e81.6) for patients from Africa, 60.5% (95% CI: 53.8e66.9) from Central and South America, 55.5% (95% CI: 51.5e59.5) from Asia, 35.5% (95% CI: 31.8e39.4) from European countries, and 31.8% (95% CI: 25.3e39.1) from North America (Table 2). However, the frequency of EBV infection in patients with cHL did not differ between the subgroups according to the publication of the studies before or after the year 2000 and the EBV detection methods (Table 2). To identify whether socioeconomic development influences EBV infection in cHL patients, we carried out subgroup analyses on EBV prevalence in the continents according to the publication year. The subgroup analysis revealed that EBV infection in cHL was significantly decreased in Europe ( p 5 0.03) and North America ( p 5 0.002) before or after the year 2000, but it was not significant in East Asian nations including China, Hong Kong, Japan, South Korea, and Taiwan (Table 3). Age To evaluate the relationship between EBV infection and the age of patients with cHL, we divided cHL cases into pediatric and adult groups; as defined in the published articles, patients who were 14e15 years of age and older were considered adults. Sixty-three studies presented 1865 pediatric and 6750 adult cases (3e10,14e24,27,30e36,38e53, 55e68,78,79,91,99,118,121). In total, the frequency of EBV infection was 69.7% in pediatric patients with cHL (95% CI: 62.2e76.3; p !0.001, Q 5 309.9, I2 5 84.5)

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Figure 1. Flow diagram of article selection for meta-analysis.

and 41.1% in adult patients with cHL (95% CI: 37.1e45.2; p !0.001, Q 5 463.8, I2 5 88.8). In subgroup analyses of age distribution in EBV-positive cHL according to the geographic regions, the prevalence of EBV-positive cHL was more than 70% in pediatric patients from Africa, Asia, and Central and South America, and in adult patients from Africa (Supplementary Table 1). Sex The incidence of EBV infection in patients with cHL according to sex was compared in 50 studies (2e23,28e54,121). EBV was detected in 1802 of 4105 (44%) male patients with cHL and 844 of 3075 (27%) female patients with cHL (Figure 2). The overall OR for EBV infection in male patients with cHL was 1.754 (95% CI: 1.510e2.038; p !0.001, Q 5 70.2, I2 5 30.2). Histologic Subtype A total of 111 studies reported the frequency of EBV infection in cHL cases according to histologic subtypes (2e23,25e112,122). EBV was found in 2371 (66%) of 3612 mixed cellularity (MC) cHL cases, followed by in 162 (52%) of 310 lymphocyte depleted (LD) cases, in 92 (47%) of 195 lymphocyte rich (LR) cases, and in 2145 (29%) of 7302 nodular sclerosis (NS) cases. The OR for EBV in MC cHL cases was 3.799 (95% CI: 3.243e4.451; p !0.001, Q 5 236.8, I2 5 54.0) (Figure 3). EBV infection was found predominantly in MC subtype. The OR for EBV in NS cHL cases was 0.313 (95% CI: 0.263e0.372; p !0.001, Q 5 328.3, I2 5 60.5). However, EBV was not associated with LD (OR 5 1.104, 95% CI: 0.829e1.470; p 5 0.499, Q 5 82.2, I2 5 12.5) and LR

subtypes (OR 5 0.834, 95% CI: 0.554e1.257; p 5 0.385 Q 5 41.1, I2 5 24.5). Clinical Stage Thirty-one studies presented information on EBV infection according to the clinical stage of cHL (2e29,121,123,124). The studies were composed of 3157 cases with stage I or II cHL and 2179 cases with stages III or IV cHL. EBV was detected in 996 (32%) of the patients with low stage cHL and 799 (37%) of the patients with high stage cHL. EBV infection was more prevalent in the patients with high stage cHL than in those with low stage cHL (OR 5 1.212, 95% CI: 1.073e1.369; p 5 0.002, Q 5 30.1, I2 5 0.3) (Figure 4). Patient Survival Twelve studies including 2730 patients with cHL (2,5,7e9,15,17,24,25,30,114,125) and four studies including 1458 patients with cHL (5,24,30,126) reported unadjusted and adjusted overall survival outcomes according to the presence of EBV infection, respectively. No association was observed between EBV infection in patients with cHL and univariate (HR 5 1.303, 95% CI: 0.931e1.823; p 5 0.123, Q 5 22.4, I2 5 50.9) (Figure 5) or multivariate overall survival outcomes (HR 5 1.470, 95% CI: 0.688e3.142; p 5 0.320, Q 5 13.3, I2 5 77.5). Fourteen investigations addressed univariate event or failure-free survival outcomes of 2789 patients with cHL according to EBV infection status (2,4,5,7e9,14,15,25, 30,34,114,124,125). EBV infection status was not associated with univariate event or failure-free survival outcomes (HR 5 1.003, 95% CI: 0.765e1.315; p 5 0.981, Q 5 28.2,

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Table 1. Characteristics of individual studies included in the meta-analysis Study Belkaid MI (67)a Audouin J (73) Leoncini L (58)a Kusuda M (61)a Chetty R (81) Engel M (14) Korbi S (19) De Matteo E (56) Razzouk BI (66)a Vassallo J (11) Elgui de Oliveira D (68) Spector N (108) Araujo I (77) Figueiredo CP (16) Campos AH (116) Souza EM (2) Barros MH (34) Quijano SM (63) Monterroso V (20) Aybar A (85) Ambinder RF (65)a Zarate-Osorno A (23) Dirnhofer S (43) Chang KL (48) Zhou XG (39) Zeng W (100) Wang J (26) Qi ZL (89) Zhang Y (112) Huang X (31) Li HM (53) Zhao P (74) Chan JK (49) Radha K (82) Naresh KN (15) Karnik S (79) Dinand V (33) Katebi M (37) Rajabi MA (106) Benharroch D (41) Uhara H (111) Ohshima K (87) Teramoto N (102) Takahashi H (103) Mikata A (71) Kusuda M (61)a Takeuchi K (90) Funamoto Y (86) Asano N (107) Vasef MA (60)a Irshaid F (52) Huh J (59) Cho EY (70) Koh YW (30) Choi JW (40) Makar RR (38) Peh SC (62) Fatima S (55) Paulino AF (83) Al-Kuraya K (17)

Continent

Patient’s country

Publication year

Africa Africa Africa Africa Africa Africa Africa CS America CS America CS America CS America CS America CS America CS America CS America CS America CS America CS America CS America CS America CS America CS America CS America CS America Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia

Algeria Egypt Kenya Kenya South Africa South Africa Tunisia Argentina Brazil Brazil Brazil Brazil Brazil Brazil Brazil Brazil Brazil Colombia Costa Rica Dominican Republic Honduras Mexico Mexico Peru China China China China China China China China Hong Kong India India India India Iran Iran Israel Japan Japan Japan Japan Japan Japan Japan Japan Japan Jordan Jordan Korea Korea Korea Korea Kuwait Malaysia Pakistan Philippines Saudi Arabia

1995 2010 1996 1998 1997 2000 2002 2003 1997 2001 2002 2005 2006 2007 2009 2010 2011 2003 1998 2005 1993 1995 1999 1993 1993 1997 2003 2003 2010 2011 2011 2011 1995 1997 2000 2003 2007 2008 2008 1997 1990 1995 1996 1996 1997 1998 2001 2005 2006 2004 2010 1996 2008 2012 2012 2003 1997 2011 1996 2006

Detection method EBER, LMP-1 EBER, LMP-1 EBER EBER, LMP-1 EBER, LMP-1 EBER, LMP-1 EBER, LMP-1 EBER, LMP-1 EBER EBER, LMP-1 EBER LMP-1 EBER EBER, LMP-1 EBER EBER, LMP-1 EBER, LMP-1 EBER, LMP-1 LMP-1 LMP-1 EBER, LMP-1 EBER, LMP-1 EBER, LMP-1 EBER, LMP-1 EBER, LMP-1 LMP-1 EBER, LMP-1 LMP-1 EBER EBER EBER LMP-1 EBER LMP-1 EBER, LMP-1 LMP-1 EBER, LMP-1 EBER, LMP-1 LMP-1 EBER, LMP-1 EBER EBER, LMP-1 EBER, LMP-1 LMP-1 EBER, LMP-1 EBER, LMP-1 EBER, LMP-1 LMP-1 EBER EBER, LMP-1 LMP-1 EBER, LMP-1 EBER, LMP-1 EBER EBER EBER, LMP-1 EBER, LMP-1 LMP-1 EBER, LMP-1 EBER

EBV frequency (%) 18/25 28/45 85/90 36/45 43/67 32/47 54/75 76/168 15/25 50/78 61/92 38/83 78/83 22/46 85/169 51/97 43/96 45/65 16/36 16/25 10/10 18/26 35/57 30/32 16/28 16/32 37/62 5/16 5/18 62/157 12/48 51/60 15/22 14/39 86/110 79/96 139/143 28/30 25/98 31/99 7/27 15/28 14/29 28/61 20/42 23/40 43/103 16/30 149/314 8/28 18/30 59/86 28/51 55/155 16/30 58/99 41/67 60/98 9/19 42/135

(72.0) (62.2) (94.4) (80.0) (64.2) (68.1) (72.0) (45.2) (60.0) (64.1) (66.3) (45.8) (94.0) (47.8) (50.3) (52.6) (44.8) (69.2) (44.4) (64.0) (100) (69.2) (61.4) (93.8) (57.1) (50.0) (59.7) (31.3) (27.8) (39.5) (25.0) (85.0) (68.2) (35.9) (78.2) (82.3) (97.2) (93.3) (25.5) (31.3) (25.9) (53.6) (48.3) (45.9) (47.6) (57.5) (41.8) (53.3) (47.5) (28.6) (60.0) (68.6) (54.9) (35.5) (53.3) (58.6) (61.2) (61.2) (47.4) (31.1)

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Table 1 (continued ) Study Liu SM (46) Chang KC (57) Mitarnun W (80) Dogusoy G (27) Cavdar AO (47) Kaya H (54) € (110) Atao
glu O € Ozdil A (109) Yilmaz F (78) Aktas S (118) Al-Salam S (36) Chang KC (35) Krugmann J (7) Trimeche M (18) Cickusic E (29) Glavina-Durdov M (25) Macak J (51) Spacek M (13) Vestlev PM (12) Lauritzen AF (96) Hjalgrim H (32) Belkaid MI (67)a Schlaifer D (93) Chetaille B (114) Herbst H (97) Niedobitek G (88) Claviez A (5) Renne C (75) Karameris A (95) Papadimitriou CS (119) Tzardi M (94) Keresztes K (8) Leoncini L (58)a Valente G (101) Carbone A (98) Hohaus S (120) Oudejans JJ (28) Diepstra A (4) Kordek R (91) Bosch Prıncep R (42) Garcıa JF (113) Navarro A (76) Martin P (69) Enblad G (3) Axdorph U (21) Obermann EC (72) Khan G (64) Flavell KJ (44) Flavell KJ (10) Jarrett RF (24) Willett EV (84) Poppema S (92) Weiss LM (105) Ambinder RF (65)a Pinkus GS (104) Elenitoba-Johnson KS (50) Andriko JA (99) Razzouk BI (66)a Chang ET (45) Vasef MA (60)a Keegan TH (6)

Continent Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Asia Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe Europe N America N America N America N America N America N America N America N America N America N America

Patient’s country Taiwan Taiwan Thailand Turkey Turkey Turkey Turkey Turkey Turkey Turkey UAE Vietnam Austria Belgium Bosnia Croatia Czech R Czech R Denmark Denmark Denmark, Sweden France France France German German German German Greece Greece Greece Hungary Italy Italy Italy Italy Netherland Netherland Poland Spain Spain Spain Spain Sweden Sweden Switzerland UK UK UK UK UK Canada USA USA USA USA USA USA USA USA USA

Publication year 1998 2008 2004 1999 1999 2000 2001 2002 2005 2007 2008 2005 2003 2007 2007 2001 2000 2011 1992 1999 2007 1995 1995 2009 1996 2002 2005 2007 1992 1995 1996 2006 1996 1996 1998 2011 1996 2009 1996 2000 2003 2008 2011 1999 1999 2011 1993 2000 2003 2005 2007 1994 1991 1993 1994 1996 1997 1997 2004 2004 2005

Detection method EBER, LMP-1 EBER EBER LMP-1 LMP-1 LMP-1 LMP-1 EBER LMP-1 EBER, LMP-1 EBER, LMP-1 EBER EBER, LMP-1 EBER, LMP-1 EBER, LMP-1 LMP-1 EBER, LMP-1 EBER, LMP-1 LMP-1 EBER EBER, LMP-1 EBER, LMP-1 EBER EBER, LMP-1 EBER, LMP-1 EBER LMP-1 EBER EBER EBER, LMP-1 EBER, LMP-1 LMP-1 EBER EBER, LMP-1 LMP-1 EBER EBER EBER LMP-1 EBER, LMP-1 EBER, LMP-1 EBER EBER EBER, LMP-1 EBER, LMP-1 EBER EBER, LMP-1 EBER EBER EBER EBER EBER, LMP-1 EBER EBER, LMP-1 EBER, LMP-1 LMP-1 LMP-1 EBER EBER, LMP-1 EBER, LMP-1 EBER, LMP-1

EBV frequency (%) 44/69 85/161 60/100 21/41 14/19 22/27 9/21 26/37 26/36 52/63 17/42 38/41 31/119 37/111 38/77 23/92 47/142 29/165 26/56 21/50 142/499 7/20 19/40 30/145 123/353 22/30 258/752 55/155 11/38 12/25 16/39 47/107 31/64 41/56 9/43 20/63 24/60 141/412 45/131 20/44 98/247 16/49 40/96 31/112 30/92 4/20 25/67 87/339 73/255 154/461 46/148 19/67 11/23 9/23 48/172 9/28 16/28 15/25 95/398 9/30 246/922

(63.8) (52.8) (60.0) (51.2) (73.7) (81.5) (42.9) (70.3) (72.2) (82.5) (40.5) (92.7) (26.1) (33.3) (49.4) (25.0) (33.1) (17.6) (46.4) (42.0) (28.5) (35.0) (47.5) (20.7) (34.8) (73.3) (34.3) (35.5) (29.0) (48.0) (41.0) (43.9) (48.4) (73.2) (20.9) (31.8) (40.0) (34.2) (34.4) (45.5) (39.7) (32.7) (41.7) (27.7) (32.6) (20.0) (37.3) (25.7) (28.6) (33.4) (31.1) (28.4) (47.8) (39.1) (27.9) (32.1) (57.1) (60.0) (23.9) (30.0) (26.7)

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Table 1 (continued ) Study Natkunam Y (117) Chen YT (115) Boyle MJ (22) Herling M (9) Total

Continent

Patient’s country

N America N America Australia Unclassified

USA USA Australia USA, Italy, Greece

Publication year 2007 2010 1993 2003

Detection method EBER EBER EBER LMP-1

EBV frequency (%) 28/140 8/41 8/28 124/577 5303/13045

(20.0) (19.5) (28.6) (21.5) (40.7)

CS, central and south; N, north; EBV, Epstein-Barr virus; EBER, EBV-encoded RNA in situ hybridization; LMP-1, latent membrane protein-1. a Studies include populations from two continents.

I2 5 53.8). Five studies comprising 874 patients with cHL reported multivariate HRs and CIs on event or failure-free survival (4,10,12,30,126). No relationship was found between EBV and multivariate event or failure-free survival rates (HR 5 0.872, 95% CI: 0.573e1.328; p 5 0.523, Q 5 9.2, I2 5 56.5). Because the published studies of EBV-associated cHLs have different criteria in terms of age distribution, we could not combine patient’s survival data according to age (Supplementary Table 2). Sensitivity Analysis and Publication Bias The sensitivity analyses revealed that most studies did not affect the pooled prevalence, OR, or HR with the 95% CIs. However, studies by Naresh et al. (15) and Montalban et al. (126), which showed that EBV-positive cHL has more favorable survival, influenced the results of unadjusted and adjusted pooled overall survival, respectively. The funnel plots and Egger’s regression tests revealed that subgroup analyses of EBV prevalence in children from Africa, CS America, and Asia and in adults from CS America might have publication bias (Figure 6) (Supplementary Table 3). Discussion EBV can infect lymphoid B, T, and natural killer (NK) cells as well as epithelial cells (130). EBV causes not only

benign lymphoproliferative disease such as infectious mononucleosis, but also a variety of malignant lymphoid malignancies. EBV is closely associated with cHL, Burkitt’s lymphoma, extranodal NK T cell lymphoma, diffuse large B cell lymphoma of elderly, and newly defined T cell malignancies including systemic EBV-positive T cell lymphoproliferative disease of childhood and hydroa vacciniforme-like lymphoma (130). The results of our pooled analysis disclosed that the prevalence of EBV infection varies in patients with cHL according to the geographic region, patient’s age and sex, and histologic subtype. This meta-analysis revealed that cases of EBV-positive cHL frequently occurred in Africa (74%) and Central and South America (61%), in children and in male patients. In addition, EBV infection was more frequently found in patients with MC subtype than in those with the other subtypes of cHL and in patients with high stage cHL. This meta-analysis demonstrated that EBV-positive cHL is more frequently found in childhood, in underdeveloped and developing countries, and in male patients. In the subgroup analyses, EBV-positive cHL have O70% of prevalence in pediatric patients from Africa, Asia, and Central and South America, and in adult patients from Africa. The four-disease model of cHL has been proposed on the basis of EBV status and age at presentation (131). This model includes three groups of EBV-positive cHL cases

Table 2. EBV prevalence and subgroup analysis according to the continents, publication year and detection methods Category

Subcategory

Overall Continent

No. of studies

No. of cases (%)

Prevalence (%) (95% CI)

119

13045 (100.0)

47.9 (44.6e51.2)

p !0.001

Africa CS America Asia Europe N America Australia Unclassified

7 17 48 39 12 1 1

394 1188 3187 5774 1897 28 577

(3.0) (9.1) (24.5) (44.3) (14.5) (0.2) (4.4)

74.2 60.5 55.5 35.5 31.8 28.6 21.5

(65.1e81.6) (53.8e66.9) (51.5e59.5) (31.8e39.4) (25.3e39.1) (10.4e57.9) (9.6e41.4)

!2000 $2000

46 73

2801 (21.5) 10244 (78.5)

48.6 (43.3e53.9) 47.4 (43.3e51.5)

EBER or EBER/LMP-1 LMP-1 only

92 27

10383 (79.6) 2662 (20.4)

47.8 (44.0e51.6) 48.4 (41.3e55.5)

Publication year

0.727

Detection method

0.894

CI, confidence interval; CS, central and south; N, north; EBER, Epstein Barr virus-encoded RNA in situ hybridization; LMP-1, latent membrane protein-1.

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Table 3. EBV prevalence in the continents and subgroup analysis according to the publication year Category Africa CS America East Asia Asia except East Asia Europe N America

Publication year

No. of studies

No. of cases

!2000 $2000 !2000 $2000 !2000 $2000 !2000 $2000 !2000 $2000 !2000 $2000

4 3 6 11 10 13 7 18 16 23 7 5

227 167 186 1002 395 1205 353 1234 1246 4528 366 1531

Prevalence (%) (95% CI) 79.6 67.7 66.8 58.8 52.7 47.4 51.8 67.3 39.3 32.9 38.1 24.0

(66.5e88.5) (50.1e81.3) (53.1e78.1) (50.2e66.8) (44.3e61.0) (40.5e54.3) (34.3e68.8) (56.7e76.4) (34.6e44.1) (29.7e36.3) (31.1e45.6) (19.1e29.6)

p 0.220 0.315 0.340 0.133 0.030 0.002

CI, confidence interval; CS, central and south; N, north; East Asia includes China, Hong Kong, Korea, Japan, and Taiwan.

and a single largest group of EBV-negative cases (131). The first EBV-positive cHL accounts for most childhood cases (below the age of 10 years) in developing countries, suggesting an early exposure to EBV. The second occurs within the young adults (15e34 years) in developed countries, indicating a delayed exposure to EBV. The third group has a peak incidence of older adults (over the age of 55). Non-EBV-associated cHL is the largest group with a peak incidence of young adults, which is observed in developed countries. However, our meta-analysis could not investigate EBV prevalence in cHL according to age in more details because the age cut-offs between children, young adults, and older adults varied among the published studies. The four-disease model also supports the hypothesis that socioeconomic status influences epidemiological patterns of EBV infection in cHL patients (131,132). For instance, cHL patients in underdeveloped areas are characterized by high EBV association, an early childhood peak, predominance of mixed cellularity, and male dominance. In contrast, cHL patients in developed areas show low EBV association, a peak in young adulthood, predominance of nodular sclerosis, and less male dominance. Because a marked economic development occurs in East Asia than in the remaining groups, we examined the prevalence of EBV-associated cHL according to the publication year before or after 2000. Based on the results, East Asian countries had a decreasing tendency of EBV-positive cHL, but the difference was not significant. Rather, North American and European countries showed a significant decrease of EBV association in cHL patients. The complexity and impact of socioeconomic factors on EBV infection needs to be further studied. This meta-analysis confirmed that EBV-positive cHL is associated with MC histologic subtype. EBV was found in 66% of MC subtype (OR 5 3.8), whereas it was found in 29% of NS cHL cases (OR 5 0.3). The histologic subtypes of cHL are determined by HRS cell numbers and the amount of the reactive cellular infiltrate (133,134). The reactive infiltrate consists of T cells, NK cells,

B cells, eosinophils, mast cells, and fibroblasts (133,134). The presence of EBV in HRS cells might influence the composition of the reactive cell infiltrate surrounding HRS cells (133). In fact, the majority of reactive cells surrounding HRS cells in cHL are CD4þ memory T cells, which express variable activation markers and cytokines including a transcription profile of T helper type 2 (Th2) and regulatory T (Treg) cells (134). Recent studies have shown that EBNA-1 in EBV-positive HRS cells induces CCL20, thereby recruiting Treg cells (135) and that LMP-1 up-regulates IL-10 expression of Treg cells (136). Nevertheless, there is no difference in Treg cell numbers between EBV-positive and -negative cHL cases because all cHL cases have high CCL17 and CCL22 levels (136,137). EBV-positive HRS cells express CXCL9 and CXCL10 (138), and the reactive infiltrate have more CD8þ T cells and NK cells, compared with EBVnegative HRS cells (28). Moreover, EBV-positive HRS cells secrete EBI3 (88) and IL-10 (139), thereby suppressing anti-tumor responses of cytotoxic T cells. Because the microenvironment in cHL is greatly heterogeneous and actively interacts with HRS cells, the exact mechanisms by which EBV is closely associated with MC subtype remain speculative. EBV-positive cHL was related to advanced clinical stages. However, the status of EBV infection in patients with cHL was not associated with overall or event-free survivals. The relationship between EBV infection and the clinical stage of cHL is very controversial. Some reports have presented a significant correlation between EBV and advanced clinical stages (6,9,18,121), whereas other studies failed to demonstrate the correlation (2,14,22,23). The frequent presentation of EBV-positive cHL with advanced clinical stages shows a disparity because patients with EBV-positive cHL may have longer disease-free survival (10,15,126) or overall survival (15,126). This contradictory finding might be attributable to a heterogeneous population used in the previous studies, caused by differences in the patient’s country, age, and sex; histologic subtype; and

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Figure 2. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) of individual studies and pooled data for the association between EpsteinBarr virus-positive classical Hodgkin’s lymphoma and sex. The forest plot demonstrates the effect sizes and 95% CIs for each study and overall.

the number of study cases. For example, Jarrett et al. (24) underscored the stratification of EBV-positive cases of cHL according to the patient’s age and demonstrated that patients with EBV-associated cHL aged 16e34 years have slightly favorable outcomes in comparison with EBVnegative cases, whereas EBV-positive patients with cHL aged 50 years or older had a significantly poor prognosis.

Taken together, the results suggest that EBV status is not an independent factor for survival in patients with cHL. EBV infection is an early event in the development of cHL because it is clonal and latent in HRS cells (140). Stimulation of CD40 and B-cell receptor signaling pathways is essential for germinal center B-cell survival and selection. EBV in cHL expresses EBV nuclear antigen-1,

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Figure 3. Pooled estimates of the association between the presence of Epstein-Barr virus and the histologic subtype of classical Hodgkin’s lymphoma.

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Figure 4. Pooled estimates of the association between Epstein-Barr virus-positive classical Hodgkin’s lymphoma and clinical stage.

latent membrane protein (LMP)-1, and LMP-2A. Among these, LMP-1 mimics the activated CD40 receptor signaling and LMP2A contains an N-terminal cytoplasmic domain that resembles the component of B-cell receptor. Thus, Bcell receptor-lacking and pre-apoptotic germinal center B cells can be rescued by LMP-1 and LMP-2A signaling. Crippling mutation of immunoglobulin genes is almost exclusive to cases of EBV-positive cHL, whereas mutations of genes encoding inhibitors of nuclear factor-kB, in particular TNFAIP3, and expression of the multiple receptor tyrosine kinase pathways are more common in cases of EBV-negative cHL (140). The present meta-analysis has several limitations. The age cut-off between children and adults varied according to the published studies. Thus, we classified patients with

cHL into adult and children groups as defined in the published articles. However, we did not examine the prevalence of EBV infection between cases of young and old adults with cHL. In addition, we could not compare the results of the molecular biomarkers and signaling pathways between EBV-positive and -negative cases with cHL because of insufficient number of studies and inadequate information for a meta-analysis. In summary, this meta-analysis of 119 studies indicates that EBV-positive cHL has distinctive clinicopathological characteristics. The prevalence of EBV in patients with cHL showed obvious geographical variations; EBVpositive cHL is approximately two times more prevalent in Africa and Central South America than in North America and Europe. EBV-positive cHL occurs predominantly in

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Figure 5. Hazard ratio with corresponding 95% confidence intervals of individual studies and pooled data for the association between Epstein-Barr viruspositive classical Hodgkin’s lymphoma and univariate overall survival.

men and children and is highly associated with MC subtype. However, EBV infection is less commonly found in NS subtype cHLs. Clinically, EBV infection is associated

with cHL at higher clinical stages but has little effects on the event-free and overall survivals of patients with cHL.

Acknowledgments The study was supported by a Korea University grant (K1325291). Conflict of interest statement: None declared.

Supplementary Data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.arcmed.2014.06.001.

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Figure 6. Funnel plot of meta-analysis for the association of Epstein-Barr virus-positive classical Hodgkin’s lymphoma and clinical stage. Individual studies are represented by small circles. An area of the inverted V-shape is devoid of small negative studies, indicating publication bias.

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