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Medical History, Lifestyle, Family History, and Occupational Risk Factors for Marginal Zone Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

Medical History, Lifestyle, Family History, and Occupational Risk Factors for Marginal Zone... Abstract Background Marginal zone lymphoma (MZL), comprised of nodal, extranodal, and splenic subtypes, accounts for 5%–10% of non-Hodgkin lymphoma cases. A detailed evaluation of the independent effects of risk factors for MZL and its subtypes has not been conducted. Methods Data were pooled from 1052 MZL cases (extranodal [EMZL] = 633, nodal [NMZL] = 157, splenic [SMZL] = 140) and 13766 controls from 12 case–control studies. Adjusted unconditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). Results Novel findings for MZL subtypes include increased risk for B-cell activating autoimmune conditions (EMZL OR = 6.40, 95% CI = 4.24 to 9.68; NMZL OR = 7.80, 95% CI = 3.32 to 18.33; SMZL OR = 4.25, 95% CI = 1.49 to 12.14), hepatitis C virus seropositivity (EMZL OR = 5.29, 95% CI = 2.48 to 11.28), self-reported peptic ulcers (EMZL OR = 1.83, 95% CI = 1.35 to 2.49), asthma without other atopy (SMZL OR = 2.28, 95% CI = 1.23 to 4.23), family history of hematologic cancer (EMZL OR = 1.90, 95% CI = 1.37 to 2.62) and of non-Hodgkin lymphoma (NMZL OR = 2.82, 95% CI = 1.33 to 5.98), permanent hairdye use (SMZL OR = 6.59, 95% CI = 1.54 to 28.17), and occupation as a metalworker (NMZL OR = 3.56, 95% CI = 1.67 to 7.58). Reduced risks were observed with consumption of any alcohol (EMZL fourth quartile OR = 0.48, 95% CI = 0.28 to 0.82) and lower consumption of wine (NMZL first to third quartile ORs < 0.45) compared with nondrinkers, and occupation as a teacher (EMZL OR = 0.58, 95% CI = 0.37 to 0.88). Conclusion Our results provide new data suggesting etiologic heterogeneity across MZL subtypes although a common risk of MZL associated with B-cell activating autoimmune conditions was found. There are more than 40 major non-Hodgkin lymphoma (NHL) subtypes of which marginal zone lymphoma (MZL), an indolent subtype, accounts for approximately 5%–10% of cases (1,2). MZL is comprised of three distinct diseases, extranodal MZL (EMZL) of mucosa-associated lymphoid tissue, splenic MZL (SMZL), and nodal MZL (NMZL) (3,4). EMZL was first recognized in the early 1980s and included in the 1994 Revised European-American Lymphoma (REAL) classification (5) and in 2001, nodal and splenic MZL were added to the World Health Organization (WHO) classification (4). Differences in incidence of MZL across anatomic sites have been observed by age at diagnosis, sex, and race/ethnicity, suggesting that host and environmental factors related to MZL risk and susceptibility are heterogeneous across MZL subtypes (6). However, no large epidemiological studies of MZL subtypes have been previously published. There is a limited understanding of the etiology and risk factors associated with MZL development, due to the rarity, particularly of SMZL and NMZL. Other than autoimmune conditions, hepatitis C virus (HCV), Helicobacter pylori, and several less common bacterial infections, few risk factors have been identified (7,8). EMZL is the most common MZL subtype accounting for about 8% of all NHL and 70% of MZL (9). It typically affects the gastrointestinal tract, primarily the stomach (85%) (9). Other involved sites include the skin, salivary glands, thyroid, and lung. EMZL is associated with chronic antigenic stimulation including infections and autoimmune diseases (7,10). Reported causes of EMZL include H pylori infection for EMZL of the stomach, Chlamydia psittaci for ocular EMZL, and Borrelia burgdorferi for skin EMZL, Sjogren’s syndrome (SS) for salivary gland EMZL, and Hashimoto’s thyroiditis for thyroid EMZL (9) Antigenic effects are not site-specific, however, and there are geographic variations in prevalence of EMZL types. SMZL and NMZL account for about 20% and 10% of MZL, respectively (2% or less of all NHL) (11). SMZL has been associated with HCV infection and a tropical SMZL has been identified in regions of the world endemic for malaria (12). NMZL is the least well understood MZL and like SMZL, has been associated with HCV infection (13). To advance our understanding of the etiology of MZL, we investigated associations with lifestyle, medical history, family history, and occupational risk factors in a pooled analysis of data from 12 case–control studies from Europe, North America, and Australia as part of the International Lymphoma Epidemiology Consortium (InterLymph) NHL Subtypes Project. Methods Study Population Detailed methodology for the InterLymph NHL Subtypes Project is provided elsewhere in this issue. Studies eligible for inclusion met the following criteria: 1) case–control design, with incident, histologically confirmed cases of MZL and 2) availability of individual-level data for risk factors of interest by December 31, 2011. Contributing studies were approved by local ethics review committees. All participants provided informed consent before interview. NHL Subtype Ascertainment and Harmonization Cases were classified as MZL according to the WHO classification (3,4) and, where possible, into MZL subtypes according to the hierarchical classification of the InterLymph Pathology Working Group (Table 1) (14,15). Most studies had at least one expert hematopathologist confirm the diagnoses. The study review procedures and rules for NHL subtype classification were reviewed by an interdisciplinary team of pathologists and epidemiologists. Table 1. Characteristics of the case–control studies and participants included in the pooled analyses of marginal zone lymphoma, the InterLymph NHL Subtypes Project*   Controls  Cases  Total    No. (%)  No. (%)  No.  Total  13766 (92.9)  1052 (7.1)  14818  Study         North America          British Columbia  845 (6.1)  101 (9.6)  946    Mayo Clinic  1314 (9.5)  68 (6.5)  1382    NCI-SEER  1055 (7.7)  106 (10.1)  1161    Nebraska (newer)  533 (3.9)  35 (3.3)  568    UCSF2  457 (3.3)  187 (17.8)  644    University of Rochester  139 (1.0)  24 (2.3)  163    Yale  717 (5.2)  40 (3.8)  757   Europe          Engela  722 (5.2)  20 (1.9)  742    EpiLymph  2460 (17.9)  138 (13.1)  2598    Italy (Aviano-Naples)  504 (3.7)  14 (1.3)  518    SCALE  3187 (23.2)  117 (11.1)  3304    United Kingdom  1139 (8.3)  141 (13.4)  1280   Australia          New South Wales  694 (5.0)  61 (5.8)  755  Region         North America  5060 (36.8)  561 (53.3)  5621   Northern Europe  6542 (47.5)  343 (32.6)  6885   Southern Europe  1470 (10.7)  87 (8.3)  1557   Australia  694 (5.0)  61 (5.8)  755  Design         Population-based  9673 (70.3)  847 (80.5)  10520   Hospital-based  4093 (29.7)  205 (19.5)  4298  Age         <30  769 (5.6)  19 (1.8)  788   30–39  1133 (8.2)  49 (4.7)  1182   40–49  1974 (14.3)  137 (13.0)  2111   50–59  3323 (24.1)  265 (25.2)  3588   60–69  3835 (27.9)  316 (30.0)  4151   70–79  2474 (18.0)  224 (21.3)  2698   ≥80  258 (1.9)  39 (3.7)  297   Missing  0 (0.0)  3 (0.3)  3  Sex         Men  7206 (52.3)  492 (46.8)  7698   Women  6560 (47.7)  560 (53.2)  7120  Race/ethnicity         White, non-Hispanic  12854 (93.4)  917 (87.2)  13771   Black  199 (1.4)  20 (1.9)  219   Asian  189 (1.4)  52 (4.9)  241   Hispanic  121 (0.9)  27 (2.6)  148   Other/unknown/missing  403 (2.9)  36 (3.4)  439  Socioeconomic status         Low  4771 (34.7)  385 (36.6)  5156   Medium  4532 (32.9)  333 (31.7)  4865   High  4216 (30.6)  322 (30.6)  4538   Other/missing  247 (1.8)  12 (1.1)  259  NHL subclass         World Health Organization  —  1052 (100)  14818   Working Formulation  —  0 (0.0)  0  InterLymph hierarchical classification (14)         B-cell    1052 (100)     MZL    1052 (100)     SMZL    140 (13.3)  140   EMZL    633 (60.2)  633   NMZL    157 (14.9)  157   MZL, NOS    120 (11.4)  120   Missing    2 (0.2)  13768  Lymphoma site, detail         Not collected    134 (12.7)  134   Nodal    151 (14.4)  151   Extranodal lymphatic          Spleen    139 (13.2)  139    Other    6 (0.6)  6   Extranodal non-lymphatic          Stomach    125 (11.9)  125    Eye/orbit    70 (6.7)  70    Skin    61 (5.8)  61    Parotid or salivary gland    61 (5.8)  61    Intestine/colon/rectum    40 (3.8)  40    Thyroid    6 (0.6)  6    All other, specified    182 (17.3)  182    Site unknown    34 (3.2)  34   Systemic    42 (4.0)  42   Unknown/unclassifiable    1 (0.1)  1    Controls  Cases  Total    No. (%)  No. (%)  No.  Total  13766 (92.9)  1052 (7.1)  14818  Study         North America          British Columbia  845 (6.1)  101 (9.6)  946    Mayo Clinic  1314 (9.5)  68 (6.5)  1382    NCI-SEER  1055 (7.7)  106 (10.1)  1161    Nebraska (newer)  533 (3.9)  35 (3.3)  568    UCSF2  457 (3.3)  187 (17.8)  644    University of Rochester  139 (1.0)  24 (2.3)  163    Yale  717 (5.2)  40 (3.8)  757   Europe          Engela  722 (5.2)  20 (1.9)  742    EpiLymph  2460 (17.9)  138 (13.1)  2598    Italy (Aviano-Naples)  504 (3.7)  14 (1.3)  518    SCALE  3187 (23.2)  117 (11.1)  3304    United Kingdom  1139 (8.3)  141 (13.4)  1280   Australia          New South Wales  694 (5.0)  61 (5.8)  755  Region         North America  5060 (36.8)  561 (53.3)  5621   Northern Europe  6542 (47.5)  343 (32.6)  6885   Southern Europe  1470 (10.7)  87 (8.3)  1557   Australia  694 (5.0)  61 (5.8)  755  Design         Population-based  9673 (70.3)  847 (80.5)  10520   Hospital-based  4093 (29.7)  205 (19.5)  4298  Age         <30  769 (5.6)  19 (1.8)  788   30–39  1133 (8.2)  49 (4.7)  1182   40–49  1974 (14.3)  137 (13.0)  2111   50–59  3323 (24.1)  265 (25.2)  3588   60–69  3835 (27.9)  316 (30.0)  4151   70–79  2474 (18.0)  224 (21.3)  2698   ≥80  258 (1.9)  39 (3.7)  297   Missing  0 (0.0)  3 (0.3)  3  Sex         Men  7206 (52.3)  492 (46.8)  7698   Women  6560 (47.7)  560 (53.2)  7120  Race/ethnicity         White, non-Hispanic  12854 (93.4)  917 (87.2)  13771   Black  199 (1.4)  20 (1.9)  219   Asian  189 (1.4)  52 (4.9)  241   Hispanic  121 (0.9)  27 (2.6)  148   Other/unknown/missing  403 (2.9)  36 (3.4)  439  Socioeconomic status         Low  4771 (34.7)  385 (36.6)  5156   Medium  4532 (32.9)  333 (31.7)  4865   High  4216 (30.6)  322 (30.6)  4538   Other/missing  247 (1.8)  12 (1.1)  259  NHL subclass         World Health Organization  —  1052 (100)  14818   Working Formulation  —  0 (0.0)  0  InterLymph hierarchical classification (14)         B-cell    1052 (100)     MZL    1052 (100)     SMZL    140 (13.3)  140   EMZL    633 (60.2)  633   NMZL    157 (14.9)  157   MZL, NOS    120 (11.4)  120   Missing    2 (0.2)  13768  Lymphoma site, detail         Not collected    134 (12.7)  134   Nodal    151 (14.4)  151   Extranodal lymphatic          Spleen    139 (13.2)  139    Other    6 (0.6)  6   Extranodal non-lymphatic          Stomach    125 (11.9)  125    Eye/orbit    70 (6.7)  70    Skin    61 (5.8)  61    Parotid or salivary gland    61 (5.8)  61    Intestine/colon/rectum    40 (3.8)  40    Thyroid    6 (0.6)  6    All other, specified    182 (17.3)  182    Site unknown    34 (3.2)  34   Systemic    42 (4.0)  42   Unknown/unclassifiable    1 (0.1)  1  EMZL = extranodal marginal zone lymphoma; MZL = marginal zone lymphoma; NCI-SEER = National Cancer Institute-Surveillance, Epidemiology, and End Results; NHL = non-Hodgkin lymphoma; NMZL = nodal marginal zone lymphoma; NOS = not otherwise specified; SCALE = Scandinavian Lymphoma Etiology Study SMZL = splenic marginal zone lymphoma; UCSF = University of California, San Francisco. View Large Cases also were classified according to primary site. In most studies, primary site was recorded where known, regardless of disease stage. Initially, lymphoma site was categorized as nodal, extranodal lymphatic (spleen, Waldeyer’s ring, thymus), or extranodal extra-lymphatic (16). Specific primary sites (eg, stomach, eye) were recorded (Table 1). Cases were classified as systemic if disease was widespread or primary site was bone marrow, blood, or cerebrospinal fluid and no other site was listed. Risk Factor Ascertainment and Harmonization Each study collected data on putative NHL risk factors in a standardized, structured format by in-person or telephone interviews and/or self-administered questionnaires. Risk factors with data from at least four studies were selected for analysis. Each variable was harmonized and data were reviewed for consistency among related variables; details are provided elsewhere in this issue. Statistical Analysis Analyses were conducted using SAS software, version 9.2 (SAS Institute Inc, Cary, NC). Odds ratios (ORs) for MZL and each MZL subtype were computed as estimates of relative risk in unconditional logistic regression models adjusted for age, race/ethnicity, sex, and study (referred to as “basic adjusted models”). Statistical significance was evaluated using a nested likelihood ratio test, with P values less than .05 identifying putatively influential factors. Interstudy heterogeneity was evaluated conducting a separate logistic regression within each study and then quantifying the variability of the coefficients by the H statistic (17). Effect modification and confounding were evaluated for each risk factor. To address potential confounding, ORs were evaluated in a series of models adjusted for one other risk factor. A model then was fit that included all putative risk factors with missing categories created for each factor, followed by a forward step-wise logistic regression (“final model”). In these specific analyses, there was no evidence of confounding. Thus, the ORs are presented from the basic adjusted models. To facilitate comparisons across studies, findings are presented in the text for several uncommon factors with five or fewer exposed persons and in the tables to balance our presentation of MZL subtypes. Exploratory analyses conducted by EMZL primary sites were constrained due to small numbers of exposed cases within groups, usually less than three, and reported in brief in the text and in Supplementary Table 2, available online. Because controls for most original studies were frequency-matched by age and sex to all cases, not just MZL, we conducted sensitivity analyses using a subset of controls frequency-matched to MZL cases by age and sex. Results were similar, thus the full set of controls was used to increase statistical power. Results A total of 1052 MZL cases diagnosed from 1995 to 2008 and 13766 controls were included in these analyses (Table 1). A slight majority of the cases were from studies conducted in North America. Both cases and controls were largely non-Hispanic white although the proportion of minorities was greater among cases. Compared with controls, cases were somewhat older, a majority 60 years or older at diagnosis, and comprised of slightly more women than men. EMZL was the most common subtype (60%) and stomach is the most commonly reported extranodal site. All MZL Factors associated with increased MZL risk overall included: SS and systemic lupus erythematosus (SLE), as well as B-cell activating immune conditions overall; HCV seropositivity; peptic ulcers; asthma without other atopy; first-degree relative with a hematological malignancy (any or several specific types); decreasing years since quit smoking (the only smoking factor of 16 smoking-related variables analyzed); hair–dye use among women; and occupations as general carpenters, general laborers, painters, and metalworkers (Table 2). Factors inversely associated with MZL included increased recreational sun exposure, consumption of any type of alcohol and wine consumption, and occupation as a teacher. No associations were observed with body mass index, physical activity, blood transfusions, atopy/allergy variables other than asthma, number of siblings, menstrual and reproductive factors among women, and living or working on a farm. There also was no evidence of meaningful interstudy heterogeneity of effects. Table 2. Odds ratios (ORs) and 95% confidence intervals (CIs) for personal medical history, family history, lifestyle factors, and occupation associated with marginal zone lymphoma*   Controls  Cases      Factors  No. (%)  No. (%)  OR (95% CI)  P  Medical conditions  Autoimmune conditions   Sjögren syndrome    No  7374 (97.3)  582 (94.0)  1.00 (referent)  <.001    Yes  9 (0.1)  24 (3.9)  38.38 (17.04 to 86.48)      SLE    No  11904 (98.2)  873 (97.3)  1.00 (referent)  <.001    Yes  25 (0.2)  11 (1.2)  6.57 (3.11 to 13.86)      History of autoimmune disease†    None  13158 (95.6)  972 (92.4)  1.00 (referent)  <.001    B-cell activation  125 (0.9)  45 (4.3)  5.75 (3.97 to 8.33)      T-cell activation  471 (3.4)  33 (3.1)  1.05 (0.72 to 1.52)      Both  12 (0.1)  2 (0.2)  2.78 (0.60 to 12.77)    Other medical conditions           HCV infection    Seronegative  5259 (68.4)  354 (82.1)  1.00 (referent)  .001    Seropositive  95 (1.2)  14 (3.2)  3.04 (1.65 to 5.60)     Ulcer    No  9478 (81.3)  734 (78.7)  1.00 (referent)  .001    Yes  781 (6.7)  76 (8.1)  1.56 (1.21 to 2.03)     Asthma and other atopic conditions‡    No  10939 (80.3)  751 (73.1)  1.00 (referent)  .103    Asthma w/o other atopy  435 (3.2)  45 (4.4)  1.42 (1.03 to 1.97)      Asthma and allergy, hay fever, or eczema  762 (5.6)  56 (5.4)  0.93 (0.70 to 1.25)    Family history, at least one first degree           Any hematologic malignancy    No  8519 (86.2)  676 (77.3)  1.00 (referent)  <.001    Yes  492 (5.0)  78 (8.9)  1.73 (1.33 to 2.25)     Any hematologic malignancy, male relative    No  7940 (88.0)  672 (81.0)  1.00 (referent)  <.001    Yes  230 (2.5)  43 (5.2)  2.00 (1.41 to 2.83)     Any hematologic malignancy, female relative    No  7936 (87.9)  679 (81.8)  1.00 (referent)  .034    Yes  234 (2.6)  36 (4.3)  1.52 (1.05 to 2.21)     HL    No  7625 (89.5)  690 (84.6)  1.00 (referent)  .010    Yes  41 (0.5)  11 (1.3)  2.73 (1.36 to 5.50)     HL, male relative    No  7642 (89.7)  694 (85.0)  1.00 (referent)  .028    Yes  24 (0.3)  7 (0.9)  2.99 (1.23 to 7.28)     HL, female relative    No  7110 (91.1)  666 (85.8)  1.00 (referent)  .186    Yes  18 (0.2)  4 (0.5)  2.27 (0.74 to 6.92)     NHL    No  8085 (88.2)  703 (82.3)  1.00 (referent)  .020    Yes  205 (2.2)  31 (3.6)  1.65 (1.10 to 2.46)     NHL, male relative    No  8339 (92.4)  713 (85.9)  1.00 (referent)  .048    Yes  93 (1.0)  15 (1.8)  1.85 (1.04 to 3.27)     NHL, female relative    No  8061 (89.3)  699 (84.2)  1.00 (referent)  .153    Yes  109 (1.2)  16 (1.9)  1.52 (0.88 to 2.63)     Leukemia§    No  7930 (87.9)  678 (81.7)  1.00 (referent)  .010    Yes  240 (2.7)  37 (4.5)  1.66 (1.15 to 2.38)     Leukemia, male relative    No  8039 (89.1)  695 (83.7)  1.00 (referent)  .062    Yes  131 (1.5)  20 (2.4)  1.64 (1.00 to 2.67)     Leukemia, female relative    No  8067 (89.4)  698 (84.1)  1.00 (referent)  .069    Yes  103 (1.1)  17 (2.0)  1.69 (0.99 to 2.89)     Multiple myeloma||    No  7631 (89.6)  699 (85.7)  1.00 (referent)  .387    Yes  35 (0.4)  2 (0.2)  0.55 (0.13 to 2.37)    Lifestyle factors¶           Recreational sun exposure (h/wk)    Quartile 1 (low)  2234 (20.6)  198 (27.3)  1.00 (referent)  .001    Quartile 2  2332 (21.6)  122 (16.9)  0.66 (0.52 to 0.84)      Quartile 3  2159 (20.0)  152 (21.0)  0.78 (0.62 to 0.97)      Quartile 4 (high)  2983 (27.6)  155 (21.4)  0.68 (0.54 to 0.85)     History of cigarette smoking     No  5463 (42.3)  390 (41.0)  1.00 (referent)  .191    Yes  6531 (50.5)  480 (50.5)  1.10 (0.95 to 1.28)     Years since quit cigarette smoking    Nonsmoker  5463 (42.3)  390 (41.0)  1.00 (referent)  .018    Former, >25 y  1250 (9.7)  112 (11.8)  1.07 (0.84 to 1.36)      Former, 16–25 y  1075 (8.3)  78 (8.2)  0.96 (0.74 to 1.25)      Former, 6–15 y  1064 (8.2)  70 (7.4)  1.00 (0.76 to 1.32)      Former, <5 y   559 (4.3)  48 (5.0)  1.62 (1.17 to 2.24)      Former, unknown years  59 (0.5)  8 (0.8)  3.24 (1.49 to 7.05)      Current smoker  2448 (18.9)  157 (16.5)  1.13 (0.92 to 1.39)     Any type of alcohol (g/wk)    Nondrinker  2121 (17.3)  225 (25.3)  1.00 (referent)  .017    Quartile 1 (low)  1384 (11.3)  141 (15.8)  0.76 (0.59 to 0.98)      Quartile 2  1258 (10.3)  114 (12.8)  0.78 (0.60 to 1.02)      Quartile 3  1108 (9.1)  73 (8.2)  0.60 (0.44 to 0.82)      Quartile 4 (high)  888 (7.3)  48 (5.4)  0.61 (0.42 to 0.88)      Drinker, grams unknown  1079 (8.8)  68 (7.6)  0.96 (0.59 to 1.57)     Wine (g/wk)    Nondrinker  2121 (17.3)  225 (25.3)  1.00 (referent)  .002    Quartile 1 (low)  1223 (10.0)  126 (14.2)  0.77 (0.59 to 1.00)      Quartile 2  981 (8.0)  79 (8.9)  0.62 (0.46 to 0.84)      Quartile 3  1119 (9.2)  77 (8.7)  0.60 (0.44 to 0.80)      Quartile 4 (high)  643 (5.3)  24 (2.7)  0.59 (0.37 to 0.95)      Drinker, grams unknown  1079 (8.8)  68 (7.6)  0.97 (0.60 to 1.58)      Drinker, liquor and beer only   672 (5.5)  70 (7.9)  1.03 (0.75 to 1.41)     Ever used hair dyes (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .330    Ever hair dye  2412 (38.1)  181 (41.1)  1.17 (0.85 to 1.61)     Type of hair dye used (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .078    Temporary only   64 (1.0)  3 (0.7)  0.49 (0.15 to 1.67)      Permanent  2053 (32.4)  161 (36.6)  1.28 (0.92 to 1.78)      Ever hair dye, type unknown  295 (4.7)  17 (3.9)  0.67 (0.32 to 1.41)     Color of hair dye used (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .672    Light  735 (11.6)  53 (12.0)  1.23 (0.82 to 1.84)      Dark  1368 (21.6)  109 (24.8)  1.19 (0.84 to 1.69)      Ever hair dye, color unknown  309 (4.9)  19 (4.3)  0.91 (0.44 to 1.89)     Total years of hair dye use (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .196    ≤8 y  921 (14.5)  64 (14.5)  1.16 (0.79 to 1.71)      9–19 y  677 (10.7)  41 (9.3)  0.96 (0.63 to 1.47)      ≥20 y  770 (12.1)  76 (7.3)  1.40 (0.97 to 2.03)      Duration unknown  44 (0.69)  0 (0)  —     Used hair dyes prior to 1980 (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .255    Ever hair dye use, before 1980  895 (14.1)  77 (17.5)  1.44 (0.95 to 2.19)      Hair dye use, only during or after 1980  990 (15.6)  58 (13.2)  1.33 (0.86 to 2.06)      Hair dye use, period unknown  527 (8.3)  46 (10.5)  0.78 (0.45 to 1.35)     Physical activity    None  716 (10.1)  54 (10.5)  1.00 (referent)  .982    Mild  474 (6.7)  45 (8.8)  1.04 (0.66 to 1.63)      Moderate  934 (13.2)  80 (15.6)  0.96 (0.64 to 1.43)      Vigorous  3037 (43.0)  198 (38.7)  0.99 (0.71 to 1.37)    Occupation           Painter    No  8015 (98.2)  624 (97.2)  1.00 (referent)  .083    Yes  135 (1.7)  15 (2.3)  1.68 (0.97 to 2.92)     Teacher    No  7350 (90.0)  603 (93.9)  1.00 (referent)  <.001    Yes  800 (9.8)  36 (5.6)  0.50 (0.35 to 0.70)     General carpenter#    No  7362 (98.8)  587 (97.5)  1.00 (referent)  .017    Yes  60 (0.8)  12 (2.0)  2.34 (1.23 to 4.45)     General unspecified laborer    No  7708 (94.4)  589 (91.7)  1.00 (referent)  .069    Yes  442 (5.4)  50 (7.8)  1.35 (0.99 to 1.84)     Metal worker    No  7693 (94.2)  598 (93.1)  1.00 (referent)  .140    Yes  457 (5.6)  41 (6.4)  1.30 (0.93 to 1.83)      Controls  Cases      Factors  No. (%)  No. (%)  OR (95% CI)  P  Medical conditions  Autoimmune conditions   Sjögren syndrome    No  7374 (97.3)  582 (94.0)  1.00 (referent)  <.001    Yes  9 (0.1)  24 (3.9)  38.38 (17.04 to 86.48)      SLE    No  11904 (98.2)  873 (97.3)  1.00 (referent)  <.001    Yes  25 (0.2)  11 (1.2)  6.57 (3.11 to 13.86)      History of autoimmune disease†    None  13158 (95.6)  972 (92.4)  1.00 (referent)  <.001    B-cell activation  125 (0.9)  45 (4.3)  5.75 (3.97 to 8.33)      T-cell activation  471 (3.4)  33 (3.1)  1.05 (0.72 to 1.52)      Both  12 (0.1)  2 (0.2)  2.78 (0.60 to 12.77)    Other medical conditions           HCV infection    Seronegative  5259 (68.4)  354 (82.1)  1.00 (referent)  .001    Seropositive  95 (1.2)  14 (3.2)  3.04 (1.65 to 5.60)     Ulcer    No  9478 (81.3)  734 (78.7)  1.00 (referent)  .001    Yes  781 (6.7)  76 (8.1)  1.56 (1.21 to 2.03)     Asthma and other atopic conditions‡    No  10939 (80.3)  751 (73.1)  1.00 (referent)  .103    Asthma w/o other atopy  435 (3.2)  45 (4.4)  1.42 (1.03 to 1.97)      Asthma and allergy, hay fever, or eczema  762 (5.6)  56 (5.4)  0.93 (0.70 to 1.25)    Family history, at least one first degree           Any hematologic malignancy    No  8519 (86.2)  676 (77.3)  1.00 (referent)  <.001    Yes  492 (5.0)  78 (8.9)  1.73 (1.33 to 2.25)     Any hematologic malignancy, male relative    No  7940 (88.0)  672 (81.0)  1.00 (referent)  <.001    Yes  230 (2.5)  43 (5.2)  2.00 (1.41 to 2.83)     Any hematologic malignancy, female relative    No  7936 (87.9)  679 (81.8)  1.00 (referent)  .034    Yes  234 (2.6)  36 (4.3)  1.52 (1.05 to 2.21)     HL    No  7625 (89.5)  690 (84.6)  1.00 (referent)  .010    Yes  41 (0.5)  11 (1.3)  2.73 (1.36 to 5.50)     HL, male relative    No  7642 (89.7)  694 (85.0)  1.00 (referent)  .028    Yes  24 (0.3)  7 (0.9)  2.99 (1.23 to 7.28)     HL, female relative    No  7110 (91.1)  666 (85.8)  1.00 (referent)  .186    Yes  18 (0.2)  4 (0.5)  2.27 (0.74 to 6.92)     NHL    No  8085 (88.2)  703 (82.3)  1.00 (referent)  .020    Yes  205 (2.2)  31 (3.6)  1.65 (1.10 to 2.46)     NHL, male relative    No  8339 (92.4)  713 (85.9)  1.00 (referent)  .048    Yes  93 (1.0)  15 (1.8)  1.85 (1.04 to 3.27)     NHL, female relative    No  8061 (89.3)  699 (84.2)  1.00 (referent)  .153    Yes  109 (1.2)  16 (1.9)  1.52 (0.88 to 2.63)     Leukemia§    No  7930 (87.9)  678 (81.7)  1.00 (referent)  .010    Yes  240 (2.7)  37 (4.5)  1.66 (1.15 to 2.38)     Leukemia, male relative    No  8039 (89.1)  695 (83.7)  1.00 (referent)  .062    Yes  131 (1.5)  20 (2.4)  1.64 (1.00 to 2.67)     Leukemia, female relative    No  8067 (89.4)  698 (84.1)  1.00 (referent)  .069    Yes  103 (1.1)  17 (2.0)  1.69 (0.99 to 2.89)     Multiple myeloma||    No  7631 (89.6)  699 (85.7)  1.00 (referent)  .387    Yes  35 (0.4)  2 (0.2)  0.55 (0.13 to 2.37)    Lifestyle factors¶           Recreational sun exposure (h/wk)    Quartile 1 (low)  2234 (20.6)  198 (27.3)  1.00 (referent)  .001    Quartile 2  2332 (21.6)  122 (16.9)  0.66 (0.52 to 0.84)      Quartile 3  2159 (20.0)  152 (21.0)  0.78 (0.62 to 0.97)      Quartile 4 (high)  2983 (27.6)  155 (21.4)  0.68 (0.54 to 0.85)     History of cigarette smoking     No  5463 (42.3)  390 (41.0)  1.00 (referent)  .191    Yes  6531 (50.5)  480 (50.5)  1.10 (0.95 to 1.28)     Years since quit cigarette smoking    Nonsmoker  5463 (42.3)  390 (41.0)  1.00 (referent)  .018    Former, >25 y  1250 (9.7)  112 (11.8)  1.07 (0.84 to 1.36)      Former, 16–25 y  1075 (8.3)  78 (8.2)  0.96 (0.74 to 1.25)      Former, 6–15 y  1064 (8.2)  70 (7.4)  1.00 (0.76 to 1.32)      Former, <5 y   559 (4.3)  48 (5.0)  1.62 (1.17 to 2.24)      Former, unknown years  59 (0.5)  8 (0.8)  3.24 (1.49 to 7.05)      Current smoker  2448 (18.9)  157 (16.5)  1.13 (0.92 to 1.39)     Any type of alcohol (g/wk)    Nondrinker  2121 (17.3)  225 (25.3)  1.00 (referent)  .017    Quartile 1 (low)  1384 (11.3)  141 (15.8)  0.76 (0.59 to 0.98)      Quartile 2  1258 (10.3)  114 (12.8)  0.78 (0.60 to 1.02)      Quartile 3  1108 (9.1)  73 (8.2)  0.60 (0.44 to 0.82)      Quartile 4 (high)  888 (7.3)  48 (5.4)  0.61 (0.42 to 0.88)      Drinker, grams unknown  1079 (8.8)  68 (7.6)  0.96 (0.59 to 1.57)     Wine (g/wk)    Nondrinker  2121 (17.3)  225 (25.3)  1.00 (referent)  .002    Quartile 1 (low)  1223 (10.0)  126 (14.2)  0.77 (0.59 to 1.00)      Quartile 2  981 (8.0)  79 (8.9)  0.62 (0.46 to 0.84)      Quartile 3  1119 (9.2)  77 (8.7)  0.60 (0.44 to 0.80)      Quartile 4 (high)  643 (5.3)  24 (2.7)  0.59 (0.37 to 0.95)      Drinker, grams unknown  1079 (8.8)  68 (7.6)  0.97 (0.60 to 1.58)      Drinker, liquor and beer only   672 (5.5)  70 (7.9)  1.03 (0.75 to 1.41)     Ever used hair dyes (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .330    Ever hair dye  2412 (38.1)  181 (41.1)  1.17 (0.85 to 1.61)     Type of hair dye used (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .078    Temporary only   64 (1.0)  3 (0.7)  0.49 (0.15 to 1.67)      Permanent  2053 (32.4)  161 (36.6)  1.28 (0.92 to 1.78)      Ever hair dye, type unknown  295 (4.7)  17 (3.9)  0.67 (0.32 to 1.41)     Color of hair dye used (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .672    Light  735 (11.6)  53 (12.0)  1.23 (0.82 to 1.84)      Dark  1368 (21.6)  109 (24.8)  1.19 (0.84 to 1.69)      Ever hair dye, color unknown  309 (4.9)  19 (4.3)  0.91 (0.44 to 1.89)     Total years of hair dye use (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .196    ≤8 y  921 (14.5)  64 (14.5)  1.16 (0.79 to 1.71)      9–19 y  677 (10.7)  41 (9.3)  0.96 (0.63 to 1.47)      ≥20 y  770 (12.1)  76 (7.3)  1.40 (0.97 to 2.03)      Duration unknown  44 (0.69)  0 (0)  —     Used hair dyes prior to 1980 (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .255    Ever hair dye use, before 1980  895 (14.1)  77 (17.5)  1.44 (0.95 to 2.19)      Hair dye use, only during or after 1980  990 (15.6)  58 (13.2)  1.33 (0.86 to 2.06)      Hair dye use, period unknown  527 (8.3)  46 (10.5)  0.78 (0.45 to 1.35)     Physical activity    None  716 (10.1)  54 (10.5)  1.00 (referent)  .982    Mild  474 (6.7)  45 (8.8)  1.04 (0.66 to 1.63)      Moderate  934 (13.2)  80 (15.6)  0.96 (0.64 to 1.43)      Vigorous  3037 (43.0)  198 (38.7)  0.99 (0.71 to 1.37)    Occupation           Painter    No  8015 (98.2)  624 (97.2)  1.00 (referent)  .083    Yes  135 (1.7)  15 (2.3)  1.68 (0.97 to 2.92)     Teacher    No  7350 (90.0)  603 (93.9)  1.00 (referent)  <.001    Yes  800 (9.8)  36 (5.6)  0.50 (0.35 to 0.70)     General carpenter#    No  7362 (98.8)  587 (97.5)  1.00 (referent)  .017    Yes  60 (0.8)  12 (2.0)  2.34 (1.23 to 4.45)     General unspecified laborer    No  7708 (94.4)  589 (91.7)  1.00 (referent)  .069    Yes  442 (5.4)  50 (7.8)  1.35 (0.99 to 1.84)     Metal worker    No  7693 (94.2)  598 (93.1)  1.00 (referent)  .140    Yes  457 (5.6)  41 (6.4)  1.30 (0.93 to 1.83)    * Basic model adjusted for age, sex, race/ethnicity, and study. For exposures with more than two groups, ie, exposed and unexposed, the P value is the P for trend. HCV = hepatitis c virus; HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma; SLE = systemic lupus erythematosus. † Includes self-reported history of specific autoimmune diseases occurring ≥2 years prior to diagnosis/interview (except the New South Wales study, which did not ascertain date of onset). Autoimmune diseases were classified according to whether they are primarily mediated by B-cell or T-cell responses. B-cell activating diseases included Hashimoto thyroiditis, hemolytic anemia, myasthenia gravis, pernicious anemia, rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus erythematosus. T-cell activating diseases included celiac disease, immune thrombocytopenic purpura, inflammatory bowel disorder (Crohn’s disease, ulcerative colitis), multiple sclerosis, polymyositis or dermatomyositis, psoriasis, sarcoidosis, systemic sclerosis or scleroderma, and type 1 diabetes. ‡ Atopic disorders include asthma, eczema, hay fever, or other allergies, excluding drug allergies. § Based on International Classification of Diseases (ICD)-9 and ICD10 classification. || Not presented by sex of relative due to small number of exposed cases. ¶ Recreational sun exposure (hours per week, study-specific quartiles available upon request; alcohol consumption in grams of ethanol per week (alcohol: <44.40, 44.40–110.68, 110.69–251.99, ≥252.00, beer: <12.90, 12.90–39.85, 39.86–111.61, ≥111.62, liquor: <6.99, 6.99–23.85, 23.85–83.99, ≥84.00; wine: <14.10, 14.10–55.16, 55.17–167.99, ≥168.00). # An International Standard of Occupations (ISCO) category that includes woodworkers. View Large Exploratory analyses were next conducted by sex (data not shown). Results generally were comparable by sex (P heterogeneity > .05), although for selected risk factors, the exposure prevalence and/or risk estimates suggested some variability. Specifically, autoimmune conditions were reported by 10.2% of women and 4.6% of men with MZL, with stronger effects of B-cell activated immune conditions in women (OR = 6.69, 95% confidence interval [CI] = 4.38 to 10.23) than men (OR = 3.56, 95% CI = 1.57 to 8.06) mainly due to SS (women: 6.1% cases, 0.2% controls, OR = 34.7, 95% CI = 15.0 to 79.8; men: 2.1% cases, 0 controls) and SLE (women: 2.1% cases, 0.2% controls, OR = 7.46, 95% CI = 3.34 to 16.6; 0 men). History of peptic ulcers had a stronger and statistically significant effect in men (OR = 1.79, 95% CI = 1.28 to 2.50) than women (OR = 1.31, 95% CI = 0.87 to 1.97). Women were more likely to report a family history than were men (any hematological malignancy; women: OR = 1.98, 95% CI = 1.40 to 2.78; men: OR = 1.48, 95% CI = 0.98 to 2.24) with the exception of a family history of NHL (women: OR = 1.28, 95% CI = 0.72 to 2.30; men: OR = 2.21, 95% CI = 1.27 to 3.86). MZL Subtypes Factors that were significantly associated with MZL were next evaluated for the subtypes of EMZL (N = 633), NMZL (N = 157), and SMZL (N = 140) (Tables 3–5). Risk for all three subtypes was increased with B-cell activating autoimmune conditions (EMZL OR = 6.40, 95% CI = 4.24 to 9.68; NMZL OR = 7.80, 95% CI = 3.32 to 18.33; SMZL OR = 4.25, 95% CI = 1.49 to 12.14; Table 3), particularly SS and SLE. HCV seropositivity (OR = 5.29, 95% CI = 2.48 to 11.28) and peptic ulcers (OR = 1.83, 95% CI = 1.35 to 2.49) were associated with EMZL risk, whereas asthma without other atopy was associated with SMZL (OR = 2.28, 95% CI = 1.23 to 4.23). There were null associations of HCV serostatus, peptic ulcers, and asthma without other atopy with NMZL risk. Table 3. Odds ratios (ORs) and 95% confidence intervals (CIs) for personal medical history and family history associated with marginal zone lymphoma subtypes*     EMZL (n = 633)      NMZL (n = 157)      SMZL (n = 140)      Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)  P  Ctrls/Ca  OR (95% CI)  P  Autoimmune medical conditions   Sjögren syndrome    No  6536/358  1.00 (referent)  .000  4199/122  1.00 (referent)  <.001  5363/18  1.00 (referent)  .805    Yes  9/19  40.25 (17.5 to 92.6)    4/5  141 (25.01 to 800)    8/0  —     SLE    No  11904/543  1.00 (referent)  <.001  7434/63  1.00 (referent)  .026  9893/81  1.00 (referent)  .231    Yes  25/8  8.44 (3.58 to 19.91)    23/2  9.24 (1.95 to 43.74)    23/1  4.61 (0.59 to 35.87)     Autoimmune disease‡    None  13158/575  1.00 (referent)  <.001  8594/143  1.00 (referent)  <.001  12468/134  1.00 (referent)  .126    B-cell activation  125/34  6.40 (4.24 to 9.68)    89/7  7.80 (3.32 to 18.33)    122/4  4.25 (1.49 to 12.14)      T-cell activation  471/23  1.08 (0.69 to 1.67)    242/6  1.48 (0.62 to 3.54)    447/2  0.70 (0.17 to 2.87)      Both  12/1  2.07 (0.26 to 16.32)    11/1  11.67 (1.33 to 103)    12/0  —    Other medical conditions   HCV infection    Seronegative  5259/211  1.00 (referent)  <.001  2951/31  1.00 (referent)  .250  3410/64  1.00 (referent)  .864    Seropositive  95/10  5.29 (2.48 to 11.28)    48/1  4.36 (0.54 to 35.38)    93/1  0.84 (0.11 to 6.28)     Ulcer    No  9478/430  1.00 (referent)  <.001  4979/122  1.00 (referent)  .827  9478/113  1.00 (referent)  .682    Yes  781/53  1.83 (1.35 to 2.49)    478/7  1.09 (0.49 to 2.43)    781/11  1.15 (0.61 to 2.17)     Asthma and other atopic conditions§    No  10939/467  1.00 (referent)  .171  6531/101  1.00 (referent)  .862  10288/114  1.00 (referent)  .011    Asthma no other atopy  435/28  1.50 (1.00 to 2.24)    294/3  0.77 (0.24 to 2.50)    404/12  2.28 (1.23 to 4.23)      Asthma, other atopy  762/39  1.04 (0.74 to 1.47)    496/11  1.10 (0.57 to 2.13)    727/4  0.46 (0.17 to 1.26)        EMZL (n = 633)      NMZL (n = 157)      SMZL (n = 140)      Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)  P  Ctrls/Ca  OR (95% CI)  P  Autoimmune medical conditions   Sjögren syndrome    No  6536/358  1.00 (referent)  .000  4199/122  1.00 (referent)  <.001  5363/18  1.00 (referent)  .805    Yes  9/19  40.25 (17.5 to 92.6)    4/5  141 (25.01 to 800)    8/0  —     SLE    No  11904/543  1.00 (referent)  <.001  7434/63  1.00 (referent)  .026  9893/81  1.00 (referent)  .231    Yes  25/8  8.44 (3.58 to 19.91)    23/2  9.24 (1.95 to 43.74)    23/1  4.61 (0.59 to 35.87)     Autoimmune disease‡    None  13158/575  1.00 (referent)  <.001  8594/143  1.00 (referent)  <.001  12468/134  1.00 (referent)  .126    B-cell activation  125/34  6.40 (4.24 to 9.68)    89/7  7.80 (3.32 to 18.33)    122/4  4.25 (1.49 to 12.14)      T-cell activation  471/23  1.08 (0.69 to 1.67)    242/6  1.48 (0.62 to 3.54)    447/2  0.70 (0.17 to 2.87)      Both  12/1  2.07 (0.26 to 16.32)    11/1  11.67 (1.33 to 103)    12/0  —    Other medical conditions   HCV infection    Seronegative  5259/211  1.00 (referent)  <.001  2951/31  1.00 (referent)  .250  3410/64  1.00 (referent)  .864    Seropositive  95/10  5.29 (2.48 to 11.28)    48/1  4.36 (0.54 to 35.38)    93/1  0.84 (0.11 to 6.28)     Ulcer    No  9478/430  1.00 (referent)  <.001  4979/122  1.00 (referent)  .827  9478/113  1.00 (referent)  .682    Yes  781/53  1.83 (1.35 to 2.49)    478/7  1.09 (0.49 to 2.43)    781/11  1.15 (0.61 to 2.17)     Asthma and other atopic conditions§    No  10939/467  1.00 (referent)  .171  6531/101  1.00 (referent)  .862  10288/114  1.00 (referent)  .011    Asthma no other atopy  435/28  1.50 (1.00 to 2.24)    294/3  0.77 (0.24 to 2.50)    404/12  2.28 (1.23 to 4.23)      Asthma, other atopy  762/39  1.04 (0.74 to 1.47)    496/11  1.10 (0.57 to 2.13)    727/4  0.46 (0.17 to 1.26)    * Ca = cases; Ctrls = controls; EMZL = extranodal marginal zone lymphoma; HCV = hepatitis c virus; NMZL = nodal marginal zone lymphoma; SLE = systemic lupus erythematosus; SMZL = splenic marginal zone lymphoma. † Basic model adjusted for age, sex, race/ethnicity, and study. For exposures with more than two categories, ie, exposed and unexposed, the P value is the P for trend. ‡ Includes self-reported history of specific autoimmune diseases occurring ≥2 years prior to diagnosis/interview (except the New South Wales study, which did not ascertain date of onset). Autoimmune diseases were classified according to whether they are primarily mediated by B-cell or T-cell responses. B-cell activating diseases included Hashimoto thyroiditis, hemolytic anemia, myasthenia gravis, pernicious anemia, rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus erythematosus. T-cell activating diseases included celiac disease, immune thrombocytopenic purpura, inflammatory bowel disorder (Crohn’s disease, ulcerative colitis), multiple sclerosis, polymyositis or dermatomyositis, psoriasis, sarcoidosis, systemic sclerosis or scleroderma, and type 1 diabetes. § Atopic disorders include asthma, eczema, hay fever, or other allergies, excluding drug allergies. View Large Table 4. Odds ratios (ORs) and 95% confidence intervals (CIs) for family history of hematologic malignancies associated with subtypes of marginal zone lymphoma     EMZL      NMZL      SMZL    Family history, at least one first degree  Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)†  P  Any hematologic malignancy   No  8519/357  1.00 (referent)  <.001  6928/96  1.00 (referent)  .23  8016/112  1.00 (referent)  .69   Yes  492/49  1.90 (1.37 to 2.62)    443/13  1.48 (0.80 to 2.74)    457/7  1.18 (0.54 to 2.56)    Any hematologic malignancy, male relative   No  7940/352  1.00 (referent)  <.001  6330/99  1.00 (referent)  .44  7419/110  1.00 (referent)  .31   Yes  230/27  2.20 (1.44 to 3.37)    200/6  1.44 (0.60 to 3.45)    213/5  1.66 (0.66 to 4.16)    Any hematologic malignancy, female relative   No  7936/356  1.00 (referent)  .04  6315/97  1.00 (referent)  .18  7416/113  1.00 (referent)  .64   Yes  234/23  1.65 (1.05 to 2.60)    215/8  1.74 (0.81 to 3.76)    216/2  0.73 (0.18 to 3.00)    HL†   No  7625/362  1.00 (referent)  .06  6496/103  1.00 (referent)  .25  7090/113  1.00 (referent)  .60   Yes  41/6  2.59 (1.06 to 6.30)    34/2  2.73 (0.59 to 12.62)    38/1  1.90 (0.24 to 13.62)    NHL‡   No  8085/376  1.00 (referent)  .16  6454/98  1.00 (referent)  .01  7557/115  1.00 (referent)  .24   Yes  205/15  1.52 (0.87 to 2.65)    196/9  2.82 (1.33 to 5.98)    195/1  0.37 (0.05 to 2.65)    NHL, male relative   No  8339/378  1.00 (referent)  .08  6702/104  1.00 (referent)  .12  7803/118  1.00 (referent)  .12   Yes  93/8  2.06 (0.97 to 4.41)    90/4  2.60 (0.87 to 7.79)    91/0  —    NHL, female relative   No  8061/371  1.00 (referent)  .44  6427/100  1.00 (referent)  .05  7531/114  1.00 (referent)  .71   Yes  109/8  1.36 (0.64 to 2.87)    103/5  3.00 (1.12 to 7.98)    101/1  0.70 (0.10 to 5.11)    Leukemia§   No  7930/355  1.00 (referent)  .005  6323/102  1.00 (referent)  .55  7404/111  1.00 (referent)  .75   Yes  240/24  2.00 (1.28 to 3.13)    207/3  0.71 (0.22 to 2.32)    228/4  1.18 (0.43 to 3.25)    Leukemia, male relative   No  8039/366  1.00 (referent)  .04  6423/104  1.00 (referent)  .38  7510/112  1.00 (referent)  .48   Yes  131/13  1.96 (1.08 to 3.55)    107/1  0.45 (0.06 to 3.39)    122/3  1.56 (0.48 to 5.05)    Leukemia, female relative   No  8067/368  1.00 (referent)  .06  6436/103  1.00 (referent)  .99  7532/114  1.00 (referent)  .75   Yes  103/11  1.97 (1.03 to 3.77)    94/2  0.99 (0.23 to 4.23)    100/1  0.73 (0.10 to 5.35)    MM‡   No  7631/368  1.00 (referent)  .03  6496/104  1.00 (referent)  .88  7103/113  1.00 (referent)  .30   Yes  35/0  —    34/1  1.17 (0.15 to 9.41)    25/1  3.61 (0.46 to 28.20)        EMZL      NMZL      SMZL    Family history, at least one first degree  Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)†  P  Any hematologic malignancy   No  8519/357  1.00 (referent)  <.001  6928/96  1.00 (referent)  .23  8016/112  1.00 (referent)  .69   Yes  492/49  1.90 (1.37 to 2.62)    443/13  1.48 (0.80 to 2.74)    457/7  1.18 (0.54 to 2.56)    Any hematologic malignancy, male relative   No  7940/352  1.00 (referent)  <.001  6330/99  1.00 (referent)  .44  7419/110  1.00 (referent)  .31   Yes  230/27  2.20 (1.44 to 3.37)    200/6  1.44 (0.60 to 3.45)    213/5  1.66 (0.66 to 4.16)    Any hematologic malignancy, female relative   No  7936/356  1.00 (referent)  .04  6315/97  1.00 (referent)  .18  7416/113  1.00 (referent)  .64   Yes  234/23  1.65 (1.05 to 2.60)    215/8  1.74 (0.81 to 3.76)    216/2  0.73 (0.18 to 3.00)    HL†   No  7625/362  1.00 (referent)  .06  6496/103  1.00 (referent)  .25  7090/113  1.00 (referent)  .60   Yes  41/6  2.59 (1.06 to 6.30)    34/2  2.73 (0.59 to 12.62)    38/1  1.90 (0.24 to 13.62)    NHL‡   No  8085/376  1.00 (referent)  .16  6454/98  1.00 (referent)  .01  7557/115  1.00 (referent)  .24   Yes  205/15  1.52 (0.87 to 2.65)    196/9  2.82 (1.33 to 5.98)    195/1  0.37 (0.05 to 2.65)    NHL, male relative   No  8339/378  1.00 (referent)  .08  6702/104  1.00 (referent)  .12  7803/118  1.00 (referent)  .12   Yes  93/8  2.06 (0.97 to 4.41)    90/4  2.60 (0.87 to 7.79)    91/0  —    NHL, female relative   No  8061/371  1.00 (referent)  .44  6427/100  1.00 (referent)  .05  7531/114  1.00 (referent)  .71   Yes  109/8  1.36 (0.64 to 2.87)    103/5  3.00 (1.12 to 7.98)    101/1  0.70 (0.10 to 5.11)    Leukemia§   No  7930/355  1.00 (referent)  .005  6323/102  1.00 (referent)  .55  7404/111  1.00 (referent)  .75   Yes  240/24  2.00 (1.28 to 3.13)    207/3  0.71 (0.22 to 2.32)    228/4  1.18 (0.43 to 3.25)    Leukemia, male relative   No  8039/366  1.00 (referent)  .04  6423/104  1.00 (referent)  .38  7510/112  1.00 (referent)  .48   Yes  131/13  1.96 (1.08 to 3.55)    107/1  0.45 (0.06 to 3.39)    122/3  1.56 (0.48 to 5.05)    Leukemia, female relative   No  8067/368  1.00 (referent)  .06  6436/103  1.00 (referent)  .99  7532/114  1.00 (referent)  .75   Yes  103/11  1.97 (1.03 to 3.77)    94/2  0.99 (0.23 to 4.23)    100/1  0.73 (0.10 to 5.35)    MM‡   No  7631/368  1.00 (referent)  .03  6496/104  1.00 (referent)  .88  7103/113  1.00 (referent)  .30   Yes  35/0  —    34/1  1.17 (0.15 to 9.41)    25/1  3.61 (0.46 to 28.20)    * Ca = cases; Ctrls = controls; EMZL = extranodal marginal zone lymphoma; HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma; MM = multiple myeloma NMZL = nodal marginal zone lymphoma; SMZL = splenic marginal zone lymphoma. † Basic model adjusted for age, sex, race/ethnicity, and study. For exposures with more than two categories, ie, exposed and unexposed, the P value is the P for trend. ‡ Not presented by sex of relative due to small number of exposed cases; all P values were >.10. § Based on International Classification of Diseases (ICD)-9 and ICD10 classification. View Large Table 5. Odds ratios (ORs) and 95% confidence intervals (CIs) for lifestyle factors and occupation associated with subtypes of marginal zone lymphoma*     EMZL      NMZL      SMZL    Lifestyle factors†  Ctrls/Ca  OR (95% CI)‡  P  Ctrls/Ca  OR (95% CI)‡  P  Ctrls/Ca  OR (95% CI)‡  P  Recreational sun exposure (h/wk)   Quartile 1 (low)  2234/105  1.00 (referent)  .14  1311/12  1.00 (referent)  .84  2059/34  1.00 (referent)  .33   Quartile 2  2332/72  0.74 (0.54 to 1.00)    1343/11  0.86 (0.37 to 1.98)    2160/18  0.59 (0.33 to 1.08)     Quartile 3  2159/88  0.92 (0.68 to 1.23)    1367/12  0.92 (0.40 to 2.14)    1975/28  0.80 (0.47 to 1.35)     Quartile 4 (high)  2983/96  0.76 (0.56 to 1.01)    1394/16  1.21 (0.54 to 2.72)    2799/25  0.70 (0.40 to 1.22)    History of cigarette smoking    No  5463/235  1.00 (referent)  .49  3355/58  1.00 (referent)  .82  5141/55  1.00 (referent)  .95   Yes  6531/275  1.07 (0.89 to 1.29)    3821/57  0.96 (0.64 to 1.42)    6137/68  1.01 (0.69 to 1.48)    Years since quit cigarette smoking   Never smoker  5463/235  1.00 (referent)  .05  3355/58  1.00 (referent)  .74  5141/55  1.00 (referent)  .53   Former, >25 y   1250/68  1.10 (0.82 to 1.48)    881/30  1.01 (0.57 to 1.78)    1156/10  0.69 (0.35 to 1.39)     Former, 16–25 y   1075/43  0.91 (0.65 to 1.29)    658/8  0.59 (0.27 to 1.28)    1013/18  1.46 (0.84 to 2.55)     Former, 6-15 y  1064/41  0.99 (0.70 to 1.41)    1631/0  1.03 (0.50 to 2.11)    971/9  0.86 (0.42 to 1.77)     Former, <5 y  559/29  1.55 (1.03 to 2.33)    278/4  1.58 (0.54 to 4.67)    531/7  1.57 (0.70 to 3.54)     Former, unknown years  59/8  3.58 (1.65 to 7.78)    23/0  —    48/0  —     Current smoker  2448/83  1.01 (0.77 to 1.32)    1282/15  1.14 (0.62 to 2.09)    2342/22  1.00 (0.59 to 1.68)    Any alcohol (g/wk)   Nondrinker  2121/112  1.00 (referent)  .01  1883/46  1.00 (referent)  .09  1855/42  1.00 (referent)  .38   Quartile 1 (low)  1384/95  0.93 (0.68 to 1.27)    976/22  0.50 (0.29 to 0.88)    992/13  0.59 (0.30 to 1.16)     Quartile 2  1258/68  0.91 (0.64 to 1.29)    729/12  0.41 (0.21 to 0.83)    1011/13  0.51 (0.26 to 1.01)     Quartile 3  1108/33  0.55 (0.36 to 0.84)    589/14  0.66 (0.34 to 1.30)    904/16  0.76 (0.39 to 1.48)     Quartile 4 (high)  888/19  0.48 (0.28 to 0.82)    487/7  0.78 (0.32 to 1.89)    801/12  0.75 (0.36 to 1.59)     Drinker, grams unknown  1079/52  1.15 (0.64 to 2.08)    1079/3  1.01 (0.14 to 7.18)    1079/10  0.65 (0.21 to 1.98)    Wine (g/wk)   Nondrinker  2121/112  1.00 (referent)  .09  1883/46  1.00 (referent)  .003  1855/42  1.00 (referent)  .63   Quartile 1 (low)  1223/82  0.93 (0.67 to 1.29)    792/14  0.38 (0.20 to 0.72)    919/13  0.57 (0.28 to 1.16)     Quartile 2  981/42  0.61 (0.41 to 0.92)    507/10  0.37 (0.17 to 0.78)    691/13  0.73 (0.36 to 1.48)     Quartile 3  1119/42  0.65 (0.43 to 0.98)    614/12  0.45 (0.22 to 0.90)    963/14  0.58 (0.30 to 1.13)     Quartile 4 (high)  643/14  0.70 (0.37 to 1.31)    415/4  1.06 (0.33 to 3.42)    624/6  0.67 (0.26 to 1.69)     Drinker, grams unknown  1079/52  1.18 (0.65 to 2.14)    1079/3  1.02 (0.14 to 7.39)    1079/10  0.63 (0.21 to 1.95)     Liquor, beer only   672/36  1.07 (0.70 to 1.65)    1453/5  1.36 (0.69 to 2.67)    511/8  0.65 (0.28 to 1.47)    Ever used hairdye (women only)   Never hair dye  856/36  1.00 (referent)  .84  856/10  1.00 (referent)  .60  658/2  1.00 (referent)  .001   Ever hair dye  2412/100  0.96 (0.64 to 1.43)    2412/27  0.82 (0.39 to 1.73)    1893/30  6.54 (1.53 to 27.85)    Type of hairdye used (women only)   Never hair dye  856/36  1.00 (referent)  .29  856/10  1.00 (referent)  .86  658/2  1.00 (referent)  .01   Temporary only   64/2  0.41 (0.09 to 1.80)    64/1  0.46 (0.06 to 3.89)    52/0  —     Permanent  2053/88  1.06 (0.70 to 1.61)    2053/21  0.87 (0.39 to 1.94)    1549/28  6.59 (1.54 to 28.17)     Type unknown  295/10  0.55 (0.21 to 1.43)    295/5  0.70 (0.18 to 2.73)    292/2  5.93 (0.56 to 63.09)    Color of hairdye used (women only)   Never hair dye  856/36  1.00 (referent)  .92  856/10  1.00 (referent)  .73  658/2  1.00 (referent)  .004   Light  735/26  0.85 (0.50 to 1.45)    735/5  0.63 (0.20 to 1.93)    539/13  9.69 (2.12 to 44.34)     Dark  1368/62  1.00 (0.65 to 1.55)    1368/18  0.98 (0.43 to 2.26)    1047/15  5.30 (1.19 to 23.66)     Color unknown  309/12  1.02 (0.39 to 2.70)    309/4  0.59 (0.12 to 2.77)    307/2  4.53 (0.44 to 46.94)    Used hair dyes before 1980 (women only)   Never hair dye  856/36  1.00 (referent)  .92  856/10  1.00 (referent)  .61  658/2  1.00 (referent)  .001   Use before 1980  735/26  0.85 (0.50 to 1.45)    895/9  0.55 (0.20 to 1.51)    601/16  14.85 (1.94 to 114)     Use only during or after 1980  1368/62  1.00 (0.65 to 1.55)    990/7  0.67 (0.23 to 1.90)    766/8  7.05 (0.86 to 58.04)     Use, period unknown  309/12  1.02 (0.39 to 2.70)    1527/1  1.52 (0.12 to 5.69)    526/6  2.34 (0.31 to 17.48)    Physical activity   None  716/25  1.00 (referent)  .84  716/5  1.00 (referent)  .95  674/16  1.00 (referent)  .06   Mild  474/29  0.84 (0.47 to 1.49)    474/7  0.77 (0.23 to 2.55)    425/8  1.14 (0.41 to 3.20)     Moderate  934/55  0.85 (0.50 to 1.43)    934/14  0.79 (0.27 to 2.36)    902/9  0.57 (0.22 to 1.53)     Vigorous  3037/110  0.80 (0.50 to 1.28)    3037/18  0.73 (0.26 to 2.08)    2443/23  0.44 (0.22 to 0.90)    Occupation   Painter    No  8015/330  1.00 (referent)  .97  6914/78  1.00 (referent)  .29  7300/113  1.00 (referent)  .50    Yes  135/4  1.02 (0.37 to 2.83)    110/2  2.43 (0.57 to 10.40)    133/3  1.54 (0.47 to 5.00)     Teacher    No  7350/310  1.00 (referent)  .007  6369/75  1.00 (referent)  .16  6769/112  1.00 (referent)  .01    Yes  800/24  0.58 (0.37 to 0.88)    655/5  0.54 (0.22 to 1.36)    664/4  0.33 (0.12 to 0.91)     General carpenter    No  7362/293  1.00 (referent)  .43  6255/76  1.00 (referent)  .69  7362/113  1.00 (referent)  .10    Yes  60/4  1.55 (0.55 to 4.39)    41/1  1.56 (0.20 to 11.93)    60/3  3.21 (0.95 to 10.88)     General unspecified laborer    No  7708/314  1.00 (referent)  .92  6678/73  1.00 (referent)  .29  7040/103  1.00 (referent)  .03    Yes  442/20  0.98 (0.61 to 1.56)    346/7  1.58 (0.70 to 3.56)    393/13  2.10 (1.15 to 3.84)     Metal worker    No  7693/320  1.00 (referent)  .91  6647/71  1.00 (referent)  .004  6992/108  1.00 (referent)  .74    Yes  457/14  1.03 (0.59 to 1.81)    377/9  3.56 (1.67 to 7.58)    441/8  1.14 (0.54 to 2.39)        EMZL      NMZL      SMZL    Lifestyle factors†  Ctrls/Ca  OR (95% CI)‡  P  Ctrls/Ca  OR (95% CI)‡  P  Ctrls/Ca  OR (95% CI)‡  P  Recreational sun exposure (h/wk)   Quartile 1 (low)  2234/105  1.00 (referent)  .14  1311/12  1.00 (referent)  .84  2059/34  1.00 (referent)  .33   Quartile 2  2332/72  0.74 (0.54 to 1.00)    1343/11  0.86 (0.37 to 1.98)    2160/18  0.59 (0.33 to 1.08)     Quartile 3  2159/88  0.92 (0.68 to 1.23)    1367/12  0.92 (0.40 to 2.14)    1975/28  0.80 (0.47 to 1.35)     Quartile 4 (high)  2983/96  0.76 (0.56 to 1.01)    1394/16  1.21 (0.54 to 2.72)    2799/25  0.70 (0.40 to 1.22)    History of cigarette smoking    No  5463/235  1.00 (referent)  .49  3355/58  1.00 (referent)  .82  5141/55  1.00 (referent)  .95   Yes  6531/275  1.07 (0.89 to 1.29)    3821/57  0.96 (0.64 to 1.42)    6137/68  1.01 (0.69 to 1.48)    Years since quit cigarette smoking   Never smoker  5463/235  1.00 (referent)  .05  3355/58  1.00 (referent)  .74  5141/55  1.00 (referent)  .53   Former, >25 y   1250/68  1.10 (0.82 to 1.48)    881/30  1.01 (0.57 to 1.78)    1156/10  0.69 (0.35 to 1.39)     Former, 16–25 y   1075/43  0.91 (0.65 to 1.29)    658/8  0.59 (0.27 to 1.28)    1013/18  1.46 (0.84 to 2.55)     Former, 6-15 y  1064/41  0.99 (0.70 to 1.41)    1631/0  1.03 (0.50 to 2.11)    971/9  0.86 (0.42 to 1.77)     Former, <5 y  559/29  1.55 (1.03 to 2.33)    278/4  1.58 (0.54 to 4.67)    531/7  1.57 (0.70 to 3.54)     Former, unknown years  59/8  3.58 (1.65 to 7.78)    23/0  —    48/0  —     Current smoker  2448/83  1.01 (0.77 to 1.32)    1282/15  1.14 (0.62 to 2.09)    2342/22  1.00 (0.59 to 1.68)    Any alcohol (g/wk)   Nondrinker  2121/112  1.00 (referent)  .01  1883/46  1.00 (referent)  .09  1855/42  1.00 (referent)  .38   Quartile 1 (low)  1384/95  0.93 (0.68 to 1.27)    976/22  0.50 (0.29 to 0.88)    992/13  0.59 (0.30 to 1.16)     Quartile 2  1258/68  0.91 (0.64 to 1.29)    729/12  0.41 (0.21 to 0.83)    1011/13  0.51 (0.26 to 1.01)     Quartile 3  1108/33  0.55 (0.36 to 0.84)    589/14  0.66 (0.34 to 1.30)    904/16  0.76 (0.39 to 1.48)     Quartile 4 (high)  888/19  0.48 (0.28 to 0.82)    487/7  0.78 (0.32 to 1.89)    801/12  0.75 (0.36 to 1.59)     Drinker, grams unknown  1079/52  1.15 (0.64 to 2.08)    1079/3  1.01 (0.14 to 7.18)    1079/10  0.65 (0.21 to 1.98)    Wine (g/wk)   Nondrinker  2121/112  1.00 (referent)  .09  1883/46  1.00 (referent)  .003  1855/42  1.00 (referent)  .63   Quartile 1 (low)  1223/82  0.93 (0.67 to 1.29)    792/14  0.38 (0.20 to 0.72)    919/13  0.57 (0.28 to 1.16)     Quartile 2  981/42  0.61 (0.41 to 0.92)    507/10  0.37 (0.17 to 0.78)    691/13  0.73 (0.36 to 1.48)     Quartile 3  1119/42  0.65 (0.43 to 0.98)    614/12  0.45 (0.22 to 0.90)    963/14  0.58 (0.30 to 1.13)     Quartile 4 (high)  643/14  0.70 (0.37 to 1.31)    415/4  1.06 (0.33 to 3.42)    624/6  0.67 (0.26 to 1.69)     Drinker, grams unknown  1079/52  1.18 (0.65 to 2.14)    1079/3  1.02 (0.14 to 7.39)    1079/10  0.63 (0.21 to 1.95)     Liquor, beer only   672/36  1.07 (0.70 to 1.65)    1453/5  1.36 (0.69 to 2.67)    511/8  0.65 (0.28 to 1.47)    Ever used hairdye (women only)   Never hair dye  856/36  1.00 (referent)  .84  856/10  1.00 (referent)  .60  658/2  1.00 (referent)  .001   Ever hair dye  2412/100  0.96 (0.64 to 1.43)    2412/27  0.82 (0.39 to 1.73)    1893/30  6.54 (1.53 to 27.85)    Type of hairdye used (women only)   Never hair dye  856/36  1.00 (referent)  .29  856/10  1.00 (referent)  .86  658/2  1.00 (referent)  .01   Temporary only   64/2  0.41 (0.09 to 1.80)    64/1  0.46 (0.06 to 3.89)    52/0  —     Permanent  2053/88  1.06 (0.70 to 1.61)    2053/21  0.87 (0.39 to 1.94)    1549/28  6.59 (1.54 to 28.17)     Type unknown  295/10  0.55 (0.21 to 1.43)    295/5  0.70 (0.18 to 2.73)    292/2  5.93 (0.56 to 63.09)    Color of hairdye used (women only)   Never hair dye  856/36  1.00 (referent)  .92  856/10  1.00 (referent)  .73  658/2  1.00 (referent)  .004   Light  735/26  0.85 (0.50 to 1.45)    735/5  0.63 (0.20 to 1.93)    539/13  9.69 (2.12 to 44.34)     Dark  1368/62  1.00 (0.65 to 1.55)    1368/18  0.98 (0.43 to 2.26)    1047/15  5.30 (1.19 to 23.66)     Color unknown  309/12  1.02 (0.39 to 2.70)    309/4  0.59 (0.12 to 2.77)    307/2  4.53 (0.44 to 46.94)    Used hair dyes before 1980 (women only)   Never hair dye  856/36  1.00 (referent)  .92  856/10  1.00 (referent)  .61  658/2  1.00 (referent)  .001   Use before 1980  735/26  0.85 (0.50 to 1.45)    895/9  0.55 (0.20 to 1.51)    601/16  14.85 (1.94 to 114)     Use only during or after 1980  1368/62  1.00 (0.65 to 1.55)    990/7  0.67 (0.23 to 1.90)    766/8  7.05 (0.86 to 58.04)     Use, period unknown  309/12  1.02 (0.39 to 2.70)    1527/1  1.52 (0.12 to 5.69)    526/6  2.34 (0.31 to 17.48)    Physical activity   None  716/25  1.00 (referent)  .84  716/5  1.00 (referent)  .95  674/16  1.00 (referent)  .06   Mild  474/29  0.84 (0.47 to 1.49)    474/7  0.77 (0.23 to 2.55)    425/8  1.14 (0.41 to 3.20)     Moderate  934/55  0.85 (0.50 to 1.43)    934/14  0.79 (0.27 to 2.36)    902/9  0.57 (0.22 to 1.53)     Vigorous  3037/110  0.80 (0.50 to 1.28)    3037/18  0.73 (0.26 to 2.08)    2443/23  0.44 (0.22 to 0.90)    Occupation   Painter    No  8015/330  1.00 (referent)  .97  6914/78  1.00 (referent)  .29  7300/113  1.00 (referent)  .50    Yes  135/4  1.02 (0.37 to 2.83)    110/2  2.43 (0.57 to 10.40)    133/3  1.54 (0.47 to 5.00)     Teacher    No  7350/310  1.00 (referent)  .007  6369/75  1.00 (referent)  .16  6769/112  1.00 (referent)  .01    Yes  800/24  0.58 (0.37 to 0.88)    655/5  0.54 (0.22 to 1.36)    664/4  0.33 (0.12 to 0.91)     General carpenter    No  7362/293  1.00 (referent)  .43  6255/76  1.00 (referent)  .69  7362/113  1.00 (referent)  .10    Yes  60/4  1.55 (0.55 to 4.39)    41/1  1.56 (0.20 to 11.93)    60/3  3.21 (0.95 to 10.88)     General unspecified laborer    No  7708/314  1.00 (referent)  .92  6678/73  1.00 (referent)  .29  7040/103  1.00 (referent)  .03    Yes  442/20  0.98 (0.61 to 1.56)    346/7  1.58 (0.70 to 3.56)    393/13  2.10 (1.15 to 3.84)     Metal worker    No  7693/320  1.00 (referent)  .91  6647/71  1.00 (referent)  .004  6992/108  1.00 (referent)  .74    Yes  457/14  1.03 (0.59 to 1.81)    377/9  3.56 (1.67 to 7.58)    441/8  1.14 (0.54 to 2.39)    * Ca = cases; Ctrls = controls; EMZL = extranodal marginal zone lymphoma; NMZL = nodal marginal zone lymphoma; SMZL = splenic marginal zone lymphoma. † Recreational sun exposure (hours per week, study-specific quartiles available upon request; alcohol consumption in g of ethanol per week (alcohol: <44.40, 44.40–110.68, 110.69–251.99, ≥252.00, beer: <12.90, 12.90–39.85, 39.86–111.61, ≥111.62, liquor: <6.99, 6.99–23.85, 23.85–83.99, ≥84.00; wine: <14.10, 14.10–55.16, 55.17–167.99, ≥168.00). ‡ c model adjusted for age, sex, race/ethnicity, and study. For exposures with more than two categories, ie, exposed and unexposed, the P value is the P for trend. View Large EMZL was associated with family history of any hematologic cancer (OR = 1.90, 95% CI = 1.37 to 2.62, Table 4), particularly leukemia (OR = 2.00, 95% CI = 1.28 to 5.13), whereas NMZL was associated with a family history of NHL (OR = 2.82, 95% CI = 1.33 to 5.98). Although the magnitude of the ORs suggested increased risk of SMZL with a family history of several specific hematologic cancers, estimates were imprecise. Associations between lifestyle factors and MZL subtypes were heterogeneous (Table 5). Ever smoking of cigarettes was not associated with EMZL, NMZL, or SMZL. However, compared with never smokers, risk of EMZL was elevated for those who quit less than 5 years before diagnosis/interview (OR = 1.55, 95% CI = 1.03 to 2.33) but was not elevated for longer duration of quitting or for current smokers. Alcohol consumption was inversely associated with EMZL risk (fourth quartile vs nondrinkers, OR = 0.48, 95% CI = 0.28 to 0.82). In contrast, NMZL risk was decreased for lower levels of consumption of any alcohol and particularly wine, whereas there was no association for the highest quartile of intake. Consumption of any alcohol or wine was not associated with SMZL. Among women, SMZL risk was increased with hairdye use including ever use (OR = 6.54, 95% CI = 1.53 to 27.85), use of permanent dyes (OR = 6.59, 95% CI = 1.54 to 28.17), and light color (OR = 9.69, 95% CI = 2.12 to 44.34) (Table 5). Further analyses of hair–dye characteristics for SMZL risk (Supplementary Table 1, available online) showed that permanent dyes, regardless of color, were associated with increased risk, although risk was greater for light (>10-fold) than for dark (>5.5-fold) color dyes and greatest for use before 1980 (light permanent OR ~19; dark permanent OR ~10), acknowledging small numbers of exposed women. Associations for hairdye use factors with risk of EMZL and of NMZL were null. Occupation as a teacher was inversely associated with EMZL (OR = 0.58, 95% CI = 0.37 to 0.88) and SMZL (OR = 0.33, 95% CI = 0.12 to 0.91) risk. Occupation as a general laborer was associated with increased SMZL risk (OR = 2.10, 95% CI = 1.15 to 3.84) and as a metalworker with increased NMZL risk (OR = 3.56, 95% CI = 1.67 to 7.58). Exploratory analyses (Supplementary Table 2, available online) were conducted by the common EMZL primary sites, stomach, eye/orbit, skin, and parotid/salivary gland. Increased risk of EMZL of the stomach, skin, and especially the parotid/salivary gland was associated with autoimmune conditions. Specifically, parotid EMZL was associated with B-cell activating autoimmune conditions (OR = 40.2, 95% CI = 20.1 to 80.4), SS (OR = 506, 95% CI = 165 to 1554), SLE (OR = 27.6, 95% CI = 5.4 to 141), and myositis (OR = 41.5, 95% CI = 7.08 to 243), whereas stomach EMZL was associated with SLE (OR = 14.2, 95% CI = 2.99 to 67.3) and skin EMZL with hemolytic anemia (OR = 23, 95% CI = 1.91 to 277). Other medical conditions associated with increased risk of skin EMZL were atopy and hayfever with other atopy (OR = 1.74, 95% CI = 1.01 to 3.01; OR = 2.24, 95% CI = 1.11 to 4.54, respectively). Risk of stomach EMZL was increased for those with peptic ulcer (OR = 3.97, 95% CI = 2.38 to 6.64), whereas risk of eye/orbit EMZL was decreased for those with eczema (OR = 0.23, 95% CI = 0.06 to 0.96). Family history of any hematologic cancer was associated with a greater than threefold increased risk of skin EMZL and Hodgkin lymphoma with a nearly 20-fold increased risk. Occupation as a teacher was associated with a decreased risk of stomach EMZL (OR = 0.12, 95% CI = 0.02 to 0.88). Occupationally related increased risks unique to the analyses by site were a nearly ninefold increased risk of EMZL of the eye/orbit and a greater than sevenfold risk of parotid/salivary gland among bakers, and a 25-fold increase risk of skin EMZL among petroleum workers. Alcohol consumption was related with decreased risks of stomach, eye/orbit, and parotid/salivary gland. Recognizing that most of these analyses were based on few exposed cases, often less than three, results require confirmation and should be interpreted conservatively. Discussion Our large pooled analysis of MZL from 12 case–control studies conducted on three continents and including more than 1000 cases and 13000 controls has allowed for the first time a broad evaluation of a number of potential epidemiological risk factors for MZL subtypes and across all MZL. The study size and extensive risk factor data enabled multivariable modeling to evaluate confounding among risk factors, facilitated the detailed assessment of MZL subtypes, and enabled exploratory analyses of MZL by sex. Although several MZL findings presented here are consistent with results from smaller previous pooled analyses within InterLymph, including family history (18), autoimmune disease (19), atopy (20), hairdye (21), HCV (22), and recreational sun exposure (23), our larger sample size, simultaneous assessment of multiple exposures, and systematic assessment of MZL subtypes highlight the potential heterogeneity of risk factors across MZL subtypes including several specific autoimmune conditions, peptic ulcers, HCV seropositivity, family history of hematological malignancies, hairdye use in women, and alcohol consumption, particularly wine. Despite the large total number of MZL cases, results from analyses of NMZL and SMZL were based on a relatively small number of cases and thus should be interpreted cautiously. Associations between family history and EMZL and NMZL subtypes observed in these analyses are new, however, the patterns are consistent with our overall MZL results and previously published results for NHL (24) and MZL (18). Inherited genetic factors may explain some MZL risk (18) although other shared environmental factors within families, particularly among siblings also may contribute to the observed effects (24). Small differential effects by sex of the case and of the relative with cancer could be due to potential recall bias between men and women and between cases and controls (25). The inverse association between alcohol consumption, particularly for wine, has not been published previously for MZL and MZL subtypes although a recent meta-analysis of published NHL studies provides some support for a general association (26). Compared with nondrinkers, ORs tended to decrease with increased consumption for MZL and EMZL, whereas for NMZL, the ORs for increasing consumption were not linear, although CIs for point estimates overlapped. Whether other unmeasured underlying lifestyle behaviors may be confounding this association and contributing to the seemingly different subtype patterns is uncertain. Body mass index, physical activity, socio-economic status (SES), and smoking showed weak associations with MZL and MZL subtypes and did not alter the observed alcohol association. The most novel result was the strong and consistent increased risk of SMZL with regular hairdye use. However, as hairdye use was available for only about 20% of SMZL cases and there were few exposed participants in some categories of use, results should be considered hypothesis generating. The associations with various hairdye characteristics including type, color, and period of use increase the plausibility of a relationship. An earlier InterLymph analysis of hairdye that did not assess MZL subtypes found no association with MZL overall (21) consistent with our overall MZL results. The pattern of association suggests that exposure to chemicals in hairdye may confer an increased SMZL risk. If true, specific chemicals and the biological mechanisms that increase risk for some subtypes and MZL of the spleen, but not other nodal or extranodal sites, remain to be elucidated. The observed associations with SS and SLE that were stronger among women, for EMZL and NMZL, are consistent with data from previous case–control and cohort studies (19,27,28). Lymphomagenesis in autoimmune disease is most well studied for SS, yet the complex process remains unclear with chronic antigenic stimulation, mutations, and translocations all playing a role (29,30). Clarifying common biological pathways in autoimmune disease and lymphomagenesis might help to improve treatment results for autoimmune conditions and simultaneously prevent their progression to MZL. Data presented here support or confirm associations of several infectious conditions with MZL subtypes. History of peptic ulcers was assessed as a proxy for H. pylori infection and the increased risks, specifically for EMZL of the stomach, are consistent with other published data (10) and with an H. pylori infectious etiology. Further, the strong association between HCV seropositivity and EMZL in our analyses is consistent with a reported causative role for HCV in MZL, particularly EMZL mucosa-associated lymphoid tissue [reviewed in (31)]. There were no data to explore the role of other putative infectious agents including B. burgdorferi and C. psittaci. In our subtype analyses, the increased risk of EMZL and SMZL observed for asthma without atopic conditions was previously reported for MZL (20). These results contrast with those from other NHL subtypes that showed inverse associations (20) and are inconsistent with the premise that factors hypothesized to contribute to a tumor protective immune milieu, that is, allergy, atopy and the environmental factors, number of siblings, and farm living, confer a reduced risk (32). This inconsistency in reported associations between asthma and lymphoma remain to be clarified but could be associated with reverse causality given results from a lymphoma case–control study that showed an inverse association between lymphoma stage and serum immunoglobulin levels as well as an increase in IgE levels from pre- to posttreatment (33). The asthma association also may be partly explained by differences in host immunological response and airway immunopathology between atopic and nonatopic asthmatics (34,35). The atopy association is complex and whether these immune-related differences may contribute to variability in pathogenesis of lymphoma subtypes requires further study. Occupational associations with MZL and MZL subtypes are understudied and associations for metalworkers, general laborers, and carpenters are novel to our analyses. Related occupational exposures to solvents and other chemicals that have some or limited evidence of being associated with NHL (36,37) may explain these findings. In contrast, we did not confirm an increased risk of ocular MZL that previously was reported among animal breeders/slaughterers (38). Also, the inverse association of teaching with MZL, EMZL, and SMZL in our study contrasted with results from a Singapore study that showed increased NHL risk among teachers but did not assess NHL subtypes (39). Exposure to infectious agents was proposed for both the teaching and animal-related occupational associations but based on the hygiene hypothesis, this explanation also would support an inverse association, as we found for teachers. Given the inconsistency in results and weak evidence for most occupationally related exposures, further careful study of work-place exposures is warranted. This study is the first to broadly examine the association between a number of known and suspected risk factors for NHL with MZL and MZL subtypes and assess them in a multivariable setting. Our results provide some intriguing novel findings that emphasize the etiological heterogeneity across NHL subtypes but also across MZL subtypes. The large sample size also allowed for exploration of effects by sex for MZL, although sex-stratified analyses by MZL subtype were not possible. The number of statistical tests conducted and the small number of exposed in some analyses may have resulted in chance findings, so novel results require follow-up. Additionally, recall bias, misclassification of exposures and conditions, and selection bias may have occurred. Misclassification of MZL including primary site, also may have biased our results, particularly for NMZL, the most difficult MZL subtype to diagnose (40). Our use of the InterLymph NHL classification (14,15), combined with site information, helped to diminish additional misclassification when harmonizing data across studies. Finally, including populations from different regions and continents allowed us to estimate effects with greater power than in individual studies and enhances the generalizability of our findings. Our novel findings by subtype require confirmation and larger studies are needed to assess the exploratory results by sex and by primary site of EMZL. However, these results may provide important clues to better define populations at high risk of MZL and are useful for hypothesis generating to inform future research. Studies are warranted to further elucidate lymphomagenesis of MZL and MZL subtypes. Funding This pooled analysis was supported by the Intramural Research Program of the National Cancer Institute/National Institutes of Health and National Cancer Institute/National Institutes of Health (R01 CA14690, U01 CA118444, and R01 CA92153-S1). InterLymph annual meetings during 2010–2013 were supported by the Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute/National Institutes of Health (2010–2013); Lymphoma Coalition (2010–2013); National Institutes of Health Office of Rare Diseases Research (2010); National Cancer Institute/National Institutes of Health (R13 CA159842 01) (2011); University of Cagliari, Provincial Administration of Cagliari, Banca di Credito Sardo, and Consorzio Industriale Sardo, Italy (2011); Intramural Research Program of the National Cancer Institute/National Institutes of Health (2012); and Faculté de Médecine de Dijon, Institut de Veille Sanitaire, Registre des hémopathies malignes de Côte d’Or, INSERM, Institut National du Cancer, Université de Bourgogne, Groupe Ouest Est d’Etude des Leucémies et Autres Maladies du Sang (GOELAMS), l’Institut Bergonié, The Lymphoma Study Association (LYSA), Registre Régional des Hémopathies de Basse Normandie, and the City of Dijon, France (2013). Meeting space at the 2013 Annual Meeting of the American Association for Cancer Research (AACR) was provided by the Molecular Epidemiology Group (MEG) of the AACR. Pooling of the occupation data was supported by the National Cancer Institute/National Institutes of Health (R03CA125831). Individual studies were supported by: the Canadian Institutes for Health Research (CIHR), Canadian Cancer Society, and Michael Smith Foundation for Health Research (British Columbia); Intramural Research Program of the National Cancer Institute/National Institutes of Health (Iowa/Minnesota); National Cancer Institute/National Institutes of Health (N01-CP-ES-11027) (Kansas); National Cancer Institute/National Institutes of Health (R01 CA50850) (Los Angeles); National Cancer Institute/National Institutes of Health (R01 CA92153 and P50 CA97274), Lymphoma Research Foundation (164738), and the Henry J. Predolin Foundation (Mayo Clinic); Intramural Research Program of the National Cancer Institute/National Institutes of Health and Public Health Service (contracts N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, and N02-PC-71105) (NCI-SEER); National Cancer Institute/National Institutes of Health (R01CA100555 and R03CA132153) and American Institute for Cancer Research (99B083) (Nebraska [newer]); National Cancer Institute/National Institutes of Health (N01-CP-95618) and State of Nebraska Department of Health (LB-506) (Nebraska [older]); National Cancer Institute/National Institutes of Health (R01CA45614, RO1CA154643-01A1, and R01CA104682) (UCSF1); National Cancer Institute/National Institutes of Health (CA143947, CA150037, R01CA087014, R01CA104682, RO1CA122663, and RO1CA154643-01A1) (UCSF2); National Heart Lung and Blood Institute/National Institutes of Health (hematology training grant award T32 HL007152), National Center for Research Resources/National Institutes of Health (UL 1 RR024160), and National Cancer Institute/National Institutes of Health (K23 CA102216 and P50 CA130805) (University of Rochester); National Cancer Institute/National Institutes of Health (CA62006 and CA165923) (Yale); Association pour la Recherche contre le Cancer, Fondation de France, AFSSET, and a donation from Faberge employees (Engela); European Commission (QLK4-CT-2000-00422 and FOOD-CT-2006–023103), Spanish Ministry of Health (CIBERESP, PI11/01810, RCESP C03/09, RTICESP C03/10, and RTIC RD06/0020/0095), Rio Hortega (CM13/00232), Agència de Gestió d’Ajuts Universitaris i de Recerca–Generalitat de Catalunya (Catalonian Government, 2009SGR1465), National Institutes of Health (contract NO1-CO-12400), Italian Ministry of Education, University and Research (PRIN 2007 prot. 2007WEJLZB, PRIN 2009 prot. 20092ZELR2), Italian Association for Cancer Research (IG grant 11855/2011); Federal Office for Radiation Protection (StSch4261 and StSch4420), José Carreras Leukemia Foundation (DJCLS-R04/08), German Federal Ministry for Education and Research (BMBF-01-EO-1303), Health Research Board, Ireland and Cancer Research Ireland, and Czech Republic MH CZ - DRO (MMCI, 00209805) (EpiLymph); National Cancer Institute/National Institutes of Health (CA51086), European Community (Europe Against Cancer Programme), and Italian Alliance Against Cancer (Lega Italiana per la Lotta contro i Tumori) (Italy, multicenter); Italian Association for Cancer Research (Italy, Aviano-Milan); Italian Association for Cancer Research (IG 10068) (Italy, Aviano-Naples); Swedish Cancer Society (2009/659), Stockholm County Council (20110209), Strategic Research Program in Epidemiology at Karolinska Institut, Swedish Cancer Society (02 6661), Danish Cancer Research Foundation, Lundbeck Foundation (R19-A2364), Danish Cancer Society (DP 08-155), National Cancer Institute/National Institutes of Health (5R01 CA69669-02), and Plan Denmark (SCALE); Leukaemia & Lymphoma Research, UK (United Kingdom); and Australian National Health and Medical Research Council (ID990920), Cancer Council NSW, and University of Sydney Faculty of Medicine (New South Wales). We thank the following individuals for their substantial contributions to this project: Aaron D. Norman, Dennis P. Robinson, and Priya Ramar (Mayo Clinic College of Medicine) for their work at the InterLymph Data Coordinating Center in organizing, collating, harmonizing, and documenting of the data from the participating studies in the InterLymph Consortium; Michael Spriggs, Peter Hui, and Bill Wheeler (Information Management Services, Inc) for their programming support; and Noelle Richa Siegfried and Emily Smith (RTI International) for project coordination. References 1. Roman E Smith AG . Epidemiology of lymphomas. Histopathology . 2011; 58( 1): 4– 14. Google Scholar CrossRef Search ADS PubMed  2. Smith A Howell D Patmore R Jack A Roman E . Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer . 2011; 105( 11): 1684– 1692. Google Scholar CrossRef Search ADS PubMed  3. 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Medical History, Lifestyle, Family History, and Occupational Risk Factors for Marginal Zone Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

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Oxford University Press
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Published by Oxford University Press 2014.
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1052-6773
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1745-6614
DOI
10.1093/jncimonographs/lgu011
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25174026
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Abstract

Abstract Background Marginal zone lymphoma (MZL), comprised of nodal, extranodal, and splenic subtypes, accounts for 5%–10% of non-Hodgkin lymphoma cases. A detailed evaluation of the independent effects of risk factors for MZL and its subtypes has not been conducted. Methods Data were pooled from 1052 MZL cases (extranodal [EMZL] = 633, nodal [NMZL] = 157, splenic [SMZL] = 140) and 13766 controls from 12 case–control studies. Adjusted unconditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). Results Novel findings for MZL subtypes include increased risk for B-cell activating autoimmune conditions (EMZL OR = 6.40, 95% CI = 4.24 to 9.68; NMZL OR = 7.80, 95% CI = 3.32 to 18.33; SMZL OR = 4.25, 95% CI = 1.49 to 12.14), hepatitis C virus seropositivity (EMZL OR = 5.29, 95% CI = 2.48 to 11.28), self-reported peptic ulcers (EMZL OR = 1.83, 95% CI = 1.35 to 2.49), asthma without other atopy (SMZL OR = 2.28, 95% CI = 1.23 to 4.23), family history of hematologic cancer (EMZL OR = 1.90, 95% CI = 1.37 to 2.62) and of non-Hodgkin lymphoma (NMZL OR = 2.82, 95% CI = 1.33 to 5.98), permanent hairdye use (SMZL OR = 6.59, 95% CI = 1.54 to 28.17), and occupation as a metalworker (NMZL OR = 3.56, 95% CI = 1.67 to 7.58). Reduced risks were observed with consumption of any alcohol (EMZL fourth quartile OR = 0.48, 95% CI = 0.28 to 0.82) and lower consumption of wine (NMZL first to third quartile ORs < 0.45) compared with nondrinkers, and occupation as a teacher (EMZL OR = 0.58, 95% CI = 0.37 to 0.88). Conclusion Our results provide new data suggesting etiologic heterogeneity across MZL subtypes although a common risk of MZL associated with B-cell activating autoimmune conditions was found. There are more than 40 major non-Hodgkin lymphoma (NHL) subtypes of which marginal zone lymphoma (MZL), an indolent subtype, accounts for approximately 5%–10% of cases (1,2). MZL is comprised of three distinct diseases, extranodal MZL (EMZL) of mucosa-associated lymphoid tissue, splenic MZL (SMZL), and nodal MZL (NMZL) (3,4). EMZL was first recognized in the early 1980s and included in the 1994 Revised European-American Lymphoma (REAL) classification (5) and in 2001, nodal and splenic MZL were added to the World Health Organization (WHO) classification (4). Differences in incidence of MZL across anatomic sites have been observed by age at diagnosis, sex, and race/ethnicity, suggesting that host and environmental factors related to MZL risk and susceptibility are heterogeneous across MZL subtypes (6). However, no large epidemiological studies of MZL subtypes have been previously published. There is a limited understanding of the etiology and risk factors associated with MZL development, due to the rarity, particularly of SMZL and NMZL. Other than autoimmune conditions, hepatitis C virus (HCV), Helicobacter pylori, and several less common bacterial infections, few risk factors have been identified (7,8). EMZL is the most common MZL subtype accounting for about 8% of all NHL and 70% of MZL (9). It typically affects the gastrointestinal tract, primarily the stomach (85%) (9). Other involved sites include the skin, salivary glands, thyroid, and lung. EMZL is associated with chronic antigenic stimulation including infections and autoimmune diseases (7,10). Reported causes of EMZL include H pylori infection for EMZL of the stomach, Chlamydia psittaci for ocular EMZL, and Borrelia burgdorferi for skin EMZL, Sjogren’s syndrome (SS) for salivary gland EMZL, and Hashimoto’s thyroiditis for thyroid EMZL (9) Antigenic effects are not site-specific, however, and there are geographic variations in prevalence of EMZL types. SMZL and NMZL account for about 20% and 10% of MZL, respectively (2% or less of all NHL) (11). SMZL has been associated with HCV infection and a tropical SMZL has been identified in regions of the world endemic for malaria (12). NMZL is the least well understood MZL and like SMZL, has been associated with HCV infection (13). To advance our understanding of the etiology of MZL, we investigated associations with lifestyle, medical history, family history, and occupational risk factors in a pooled analysis of data from 12 case–control studies from Europe, North America, and Australia as part of the International Lymphoma Epidemiology Consortium (InterLymph) NHL Subtypes Project. Methods Study Population Detailed methodology for the InterLymph NHL Subtypes Project is provided elsewhere in this issue. Studies eligible for inclusion met the following criteria: 1) case–control design, with incident, histologically confirmed cases of MZL and 2) availability of individual-level data for risk factors of interest by December 31, 2011. Contributing studies were approved by local ethics review committees. All participants provided informed consent before interview. NHL Subtype Ascertainment and Harmonization Cases were classified as MZL according to the WHO classification (3,4) and, where possible, into MZL subtypes according to the hierarchical classification of the InterLymph Pathology Working Group (Table 1) (14,15). Most studies had at least one expert hematopathologist confirm the diagnoses. The study review procedures and rules for NHL subtype classification were reviewed by an interdisciplinary team of pathologists and epidemiologists. Table 1. Characteristics of the case–control studies and participants included in the pooled analyses of marginal zone lymphoma, the InterLymph NHL Subtypes Project*   Controls  Cases  Total    No. (%)  No. (%)  No.  Total  13766 (92.9)  1052 (7.1)  14818  Study         North America          British Columbia  845 (6.1)  101 (9.6)  946    Mayo Clinic  1314 (9.5)  68 (6.5)  1382    NCI-SEER  1055 (7.7)  106 (10.1)  1161    Nebraska (newer)  533 (3.9)  35 (3.3)  568    UCSF2  457 (3.3)  187 (17.8)  644    University of Rochester  139 (1.0)  24 (2.3)  163    Yale  717 (5.2)  40 (3.8)  757   Europe          Engela  722 (5.2)  20 (1.9)  742    EpiLymph  2460 (17.9)  138 (13.1)  2598    Italy (Aviano-Naples)  504 (3.7)  14 (1.3)  518    SCALE  3187 (23.2)  117 (11.1)  3304    United Kingdom  1139 (8.3)  141 (13.4)  1280   Australia          New South Wales  694 (5.0)  61 (5.8)  755  Region         North America  5060 (36.8)  561 (53.3)  5621   Northern Europe  6542 (47.5)  343 (32.6)  6885   Southern Europe  1470 (10.7)  87 (8.3)  1557   Australia  694 (5.0)  61 (5.8)  755  Design         Population-based  9673 (70.3)  847 (80.5)  10520   Hospital-based  4093 (29.7)  205 (19.5)  4298  Age         <30  769 (5.6)  19 (1.8)  788   30–39  1133 (8.2)  49 (4.7)  1182   40–49  1974 (14.3)  137 (13.0)  2111   50–59  3323 (24.1)  265 (25.2)  3588   60–69  3835 (27.9)  316 (30.0)  4151   70–79  2474 (18.0)  224 (21.3)  2698   ≥80  258 (1.9)  39 (3.7)  297   Missing  0 (0.0)  3 (0.3)  3  Sex         Men  7206 (52.3)  492 (46.8)  7698   Women  6560 (47.7)  560 (53.2)  7120  Race/ethnicity         White, non-Hispanic  12854 (93.4)  917 (87.2)  13771   Black  199 (1.4)  20 (1.9)  219   Asian  189 (1.4)  52 (4.9)  241   Hispanic  121 (0.9)  27 (2.6)  148   Other/unknown/missing  403 (2.9)  36 (3.4)  439  Socioeconomic status         Low  4771 (34.7)  385 (36.6)  5156   Medium  4532 (32.9)  333 (31.7)  4865   High  4216 (30.6)  322 (30.6)  4538   Other/missing  247 (1.8)  12 (1.1)  259  NHL subclass         World Health Organization  —  1052 (100)  14818   Working Formulation  —  0 (0.0)  0  InterLymph hierarchical classification (14)         B-cell    1052 (100)     MZL    1052 (100)     SMZL    140 (13.3)  140   EMZL    633 (60.2)  633   NMZL    157 (14.9)  157   MZL, NOS    120 (11.4)  120   Missing    2 (0.2)  13768  Lymphoma site, detail         Not collected    134 (12.7)  134   Nodal    151 (14.4)  151   Extranodal lymphatic          Spleen    139 (13.2)  139    Other    6 (0.6)  6   Extranodal non-lymphatic          Stomach    125 (11.9)  125    Eye/orbit    70 (6.7)  70    Skin    61 (5.8)  61    Parotid or salivary gland    61 (5.8)  61    Intestine/colon/rectum    40 (3.8)  40    Thyroid    6 (0.6)  6    All other, specified    182 (17.3)  182    Site unknown    34 (3.2)  34   Systemic    42 (4.0)  42   Unknown/unclassifiable    1 (0.1)  1    Controls  Cases  Total    No. (%)  No. (%)  No.  Total  13766 (92.9)  1052 (7.1)  14818  Study         North America          British Columbia  845 (6.1)  101 (9.6)  946    Mayo Clinic  1314 (9.5)  68 (6.5)  1382    NCI-SEER  1055 (7.7)  106 (10.1)  1161    Nebraska (newer)  533 (3.9)  35 (3.3)  568    UCSF2  457 (3.3)  187 (17.8)  644    University of Rochester  139 (1.0)  24 (2.3)  163    Yale  717 (5.2)  40 (3.8)  757   Europe          Engela  722 (5.2)  20 (1.9)  742    EpiLymph  2460 (17.9)  138 (13.1)  2598    Italy (Aviano-Naples)  504 (3.7)  14 (1.3)  518    SCALE  3187 (23.2)  117 (11.1)  3304    United Kingdom  1139 (8.3)  141 (13.4)  1280   Australia          New South Wales  694 (5.0)  61 (5.8)  755  Region         North America  5060 (36.8)  561 (53.3)  5621   Northern Europe  6542 (47.5)  343 (32.6)  6885   Southern Europe  1470 (10.7)  87 (8.3)  1557   Australia  694 (5.0)  61 (5.8)  755  Design         Population-based  9673 (70.3)  847 (80.5)  10520   Hospital-based  4093 (29.7)  205 (19.5)  4298  Age         <30  769 (5.6)  19 (1.8)  788   30–39  1133 (8.2)  49 (4.7)  1182   40–49  1974 (14.3)  137 (13.0)  2111   50–59  3323 (24.1)  265 (25.2)  3588   60–69  3835 (27.9)  316 (30.0)  4151   70–79  2474 (18.0)  224 (21.3)  2698   ≥80  258 (1.9)  39 (3.7)  297   Missing  0 (0.0)  3 (0.3)  3  Sex         Men  7206 (52.3)  492 (46.8)  7698   Women  6560 (47.7)  560 (53.2)  7120  Race/ethnicity         White, non-Hispanic  12854 (93.4)  917 (87.2)  13771   Black  199 (1.4)  20 (1.9)  219   Asian  189 (1.4)  52 (4.9)  241   Hispanic  121 (0.9)  27 (2.6)  148   Other/unknown/missing  403 (2.9)  36 (3.4)  439  Socioeconomic status         Low  4771 (34.7)  385 (36.6)  5156   Medium  4532 (32.9)  333 (31.7)  4865   High  4216 (30.6)  322 (30.6)  4538   Other/missing  247 (1.8)  12 (1.1)  259  NHL subclass         World Health Organization  —  1052 (100)  14818   Working Formulation  —  0 (0.0)  0  InterLymph hierarchical classification (14)         B-cell    1052 (100)     MZL    1052 (100)     SMZL    140 (13.3)  140   EMZL    633 (60.2)  633   NMZL    157 (14.9)  157   MZL, NOS    120 (11.4)  120   Missing    2 (0.2)  13768  Lymphoma site, detail         Not collected    134 (12.7)  134   Nodal    151 (14.4)  151   Extranodal lymphatic          Spleen    139 (13.2)  139    Other    6 (0.6)  6   Extranodal non-lymphatic          Stomach    125 (11.9)  125    Eye/orbit    70 (6.7)  70    Skin    61 (5.8)  61    Parotid or salivary gland    61 (5.8)  61    Intestine/colon/rectum    40 (3.8)  40    Thyroid    6 (0.6)  6    All other, specified    182 (17.3)  182    Site unknown    34 (3.2)  34   Systemic    42 (4.0)  42   Unknown/unclassifiable    1 (0.1)  1  EMZL = extranodal marginal zone lymphoma; MZL = marginal zone lymphoma; NCI-SEER = National Cancer Institute-Surveillance, Epidemiology, and End Results; NHL = non-Hodgkin lymphoma; NMZL = nodal marginal zone lymphoma; NOS = not otherwise specified; SCALE = Scandinavian Lymphoma Etiology Study SMZL = splenic marginal zone lymphoma; UCSF = University of California, San Francisco. View Large Cases also were classified according to primary site. In most studies, primary site was recorded where known, regardless of disease stage. Initially, lymphoma site was categorized as nodal, extranodal lymphatic (spleen, Waldeyer’s ring, thymus), or extranodal extra-lymphatic (16). Specific primary sites (eg, stomach, eye) were recorded (Table 1). Cases were classified as systemic if disease was widespread or primary site was bone marrow, blood, or cerebrospinal fluid and no other site was listed. Risk Factor Ascertainment and Harmonization Each study collected data on putative NHL risk factors in a standardized, structured format by in-person or telephone interviews and/or self-administered questionnaires. Risk factors with data from at least four studies were selected for analysis. Each variable was harmonized and data were reviewed for consistency among related variables; details are provided elsewhere in this issue. Statistical Analysis Analyses were conducted using SAS software, version 9.2 (SAS Institute Inc, Cary, NC). Odds ratios (ORs) for MZL and each MZL subtype were computed as estimates of relative risk in unconditional logistic regression models adjusted for age, race/ethnicity, sex, and study (referred to as “basic adjusted models”). Statistical significance was evaluated using a nested likelihood ratio test, with P values less than .05 identifying putatively influential factors. Interstudy heterogeneity was evaluated conducting a separate logistic regression within each study and then quantifying the variability of the coefficients by the H statistic (17). Effect modification and confounding were evaluated for each risk factor. To address potential confounding, ORs were evaluated in a series of models adjusted for one other risk factor. A model then was fit that included all putative risk factors with missing categories created for each factor, followed by a forward step-wise logistic regression (“final model”). In these specific analyses, there was no evidence of confounding. Thus, the ORs are presented from the basic adjusted models. To facilitate comparisons across studies, findings are presented in the text for several uncommon factors with five or fewer exposed persons and in the tables to balance our presentation of MZL subtypes. Exploratory analyses conducted by EMZL primary sites were constrained due to small numbers of exposed cases within groups, usually less than three, and reported in brief in the text and in Supplementary Table 2, available online. Because controls for most original studies were frequency-matched by age and sex to all cases, not just MZL, we conducted sensitivity analyses using a subset of controls frequency-matched to MZL cases by age and sex. Results were similar, thus the full set of controls was used to increase statistical power. Results A total of 1052 MZL cases diagnosed from 1995 to 2008 and 13766 controls were included in these analyses (Table 1). A slight majority of the cases were from studies conducted in North America. Both cases and controls were largely non-Hispanic white although the proportion of minorities was greater among cases. Compared with controls, cases were somewhat older, a majority 60 years or older at diagnosis, and comprised of slightly more women than men. EMZL was the most common subtype (60%) and stomach is the most commonly reported extranodal site. All MZL Factors associated with increased MZL risk overall included: SS and systemic lupus erythematosus (SLE), as well as B-cell activating immune conditions overall; HCV seropositivity; peptic ulcers; asthma without other atopy; first-degree relative with a hematological malignancy (any or several specific types); decreasing years since quit smoking (the only smoking factor of 16 smoking-related variables analyzed); hair–dye use among women; and occupations as general carpenters, general laborers, painters, and metalworkers (Table 2). Factors inversely associated with MZL included increased recreational sun exposure, consumption of any type of alcohol and wine consumption, and occupation as a teacher. No associations were observed with body mass index, physical activity, blood transfusions, atopy/allergy variables other than asthma, number of siblings, menstrual and reproductive factors among women, and living or working on a farm. There also was no evidence of meaningful interstudy heterogeneity of effects. Table 2. Odds ratios (ORs) and 95% confidence intervals (CIs) for personal medical history, family history, lifestyle factors, and occupation associated with marginal zone lymphoma*   Controls  Cases      Factors  No. (%)  No. (%)  OR (95% CI)  P  Medical conditions  Autoimmune conditions   Sjögren syndrome    No  7374 (97.3)  582 (94.0)  1.00 (referent)  <.001    Yes  9 (0.1)  24 (3.9)  38.38 (17.04 to 86.48)      SLE    No  11904 (98.2)  873 (97.3)  1.00 (referent)  <.001    Yes  25 (0.2)  11 (1.2)  6.57 (3.11 to 13.86)      History of autoimmune disease†    None  13158 (95.6)  972 (92.4)  1.00 (referent)  <.001    B-cell activation  125 (0.9)  45 (4.3)  5.75 (3.97 to 8.33)      T-cell activation  471 (3.4)  33 (3.1)  1.05 (0.72 to 1.52)      Both  12 (0.1)  2 (0.2)  2.78 (0.60 to 12.77)    Other medical conditions           HCV infection    Seronegative  5259 (68.4)  354 (82.1)  1.00 (referent)  .001    Seropositive  95 (1.2)  14 (3.2)  3.04 (1.65 to 5.60)     Ulcer    No  9478 (81.3)  734 (78.7)  1.00 (referent)  .001    Yes  781 (6.7)  76 (8.1)  1.56 (1.21 to 2.03)     Asthma and other atopic conditions‡    No  10939 (80.3)  751 (73.1)  1.00 (referent)  .103    Asthma w/o other atopy  435 (3.2)  45 (4.4)  1.42 (1.03 to 1.97)      Asthma and allergy, hay fever, or eczema  762 (5.6)  56 (5.4)  0.93 (0.70 to 1.25)    Family history, at least one first degree           Any hematologic malignancy    No  8519 (86.2)  676 (77.3)  1.00 (referent)  <.001    Yes  492 (5.0)  78 (8.9)  1.73 (1.33 to 2.25)     Any hematologic malignancy, male relative    No  7940 (88.0)  672 (81.0)  1.00 (referent)  <.001    Yes  230 (2.5)  43 (5.2)  2.00 (1.41 to 2.83)     Any hematologic malignancy, female relative    No  7936 (87.9)  679 (81.8)  1.00 (referent)  .034    Yes  234 (2.6)  36 (4.3)  1.52 (1.05 to 2.21)     HL    No  7625 (89.5)  690 (84.6)  1.00 (referent)  .010    Yes  41 (0.5)  11 (1.3)  2.73 (1.36 to 5.50)     HL, male relative    No  7642 (89.7)  694 (85.0)  1.00 (referent)  .028    Yes  24 (0.3)  7 (0.9)  2.99 (1.23 to 7.28)     HL, female relative    No  7110 (91.1)  666 (85.8)  1.00 (referent)  .186    Yes  18 (0.2)  4 (0.5)  2.27 (0.74 to 6.92)     NHL    No  8085 (88.2)  703 (82.3)  1.00 (referent)  .020    Yes  205 (2.2)  31 (3.6)  1.65 (1.10 to 2.46)     NHL, male relative    No  8339 (92.4)  713 (85.9)  1.00 (referent)  .048    Yes  93 (1.0)  15 (1.8)  1.85 (1.04 to 3.27)     NHL, female relative    No  8061 (89.3)  699 (84.2)  1.00 (referent)  .153    Yes  109 (1.2)  16 (1.9)  1.52 (0.88 to 2.63)     Leukemia§    No  7930 (87.9)  678 (81.7)  1.00 (referent)  .010    Yes  240 (2.7)  37 (4.5)  1.66 (1.15 to 2.38)     Leukemia, male relative    No  8039 (89.1)  695 (83.7)  1.00 (referent)  .062    Yes  131 (1.5)  20 (2.4)  1.64 (1.00 to 2.67)     Leukemia, female relative    No  8067 (89.4)  698 (84.1)  1.00 (referent)  .069    Yes  103 (1.1)  17 (2.0)  1.69 (0.99 to 2.89)     Multiple myeloma||    No  7631 (89.6)  699 (85.7)  1.00 (referent)  .387    Yes  35 (0.4)  2 (0.2)  0.55 (0.13 to 2.37)    Lifestyle factors¶           Recreational sun exposure (h/wk)    Quartile 1 (low)  2234 (20.6)  198 (27.3)  1.00 (referent)  .001    Quartile 2  2332 (21.6)  122 (16.9)  0.66 (0.52 to 0.84)      Quartile 3  2159 (20.0)  152 (21.0)  0.78 (0.62 to 0.97)      Quartile 4 (high)  2983 (27.6)  155 (21.4)  0.68 (0.54 to 0.85)     History of cigarette smoking     No  5463 (42.3)  390 (41.0)  1.00 (referent)  .191    Yes  6531 (50.5)  480 (50.5)  1.10 (0.95 to 1.28)     Years since quit cigarette smoking    Nonsmoker  5463 (42.3)  390 (41.0)  1.00 (referent)  .018    Former, >25 y  1250 (9.7)  112 (11.8)  1.07 (0.84 to 1.36)      Former, 16–25 y  1075 (8.3)  78 (8.2)  0.96 (0.74 to 1.25)      Former, 6–15 y  1064 (8.2)  70 (7.4)  1.00 (0.76 to 1.32)      Former, <5 y   559 (4.3)  48 (5.0)  1.62 (1.17 to 2.24)      Former, unknown years  59 (0.5)  8 (0.8)  3.24 (1.49 to 7.05)      Current smoker  2448 (18.9)  157 (16.5)  1.13 (0.92 to 1.39)     Any type of alcohol (g/wk)    Nondrinker  2121 (17.3)  225 (25.3)  1.00 (referent)  .017    Quartile 1 (low)  1384 (11.3)  141 (15.8)  0.76 (0.59 to 0.98)      Quartile 2  1258 (10.3)  114 (12.8)  0.78 (0.60 to 1.02)      Quartile 3  1108 (9.1)  73 (8.2)  0.60 (0.44 to 0.82)      Quartile 4 (high)  888 (7.3)  48 (5.4)  0.61 (0.42 to 0.88)      Drinker, grams unknown  1079 (8.8)  68 (7.6)  0.96 (0.59 to 1.57)     Wine (g/wk)    Nondrinker  2121 (17.3)  225 (25.3)  1.00 (referent)  .002    Quartile 1 (low)  1223 (10.0)  126 (14.2)  0.77 (0.59 to 1.00)      Quartile 2  981 (8.0)  79 (8.9)  0.62 (0.46 to 0.84)      Quartile 3  1119 (9.2)  77 (8.7)  0.60 (0.44 to 0.80)      Quartile 4 (high)  643 (5.3)  24 (2.7)  0.59 (0.37 to 0.95)      Drinker, grams unknown  1079 (8.8)  68 (7.6)  0.97 (0.60 to 1.58)      Drinker, liquor and beer only   672 (5.5)  70 (7.9)  1.03 (0.75 to 1.41)     Ever used hair dyes (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .330    Ever hair dye  2412 (38.1)  181 (41.1)  1.17 (0.85 to 1.61)     Type of hair dye used (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .078    Temporary only   64 (1.0)  3 (0.7)  0.49 (0.15 to 1.67)      Permanent  2053 (32.4)  161 (36.6)  1.28 (0.92 to 1.78)      Ever hair dye, type unknown  295 (4.7)  17 (3.9)  0.67 (0.32 to 1.41)     Color of hair dye used (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .672    Light  735 (11.6)  53 (12.0)  1.23 (0.82 to 1.84)      Dark  1368 (21.6)  109 (24.8)  1.19 (0.84 to 1.69)      Ever hair dye, color unknown  309 (4.9)  19 (4.3)  0.91 (0.44 to 1.89)     Total years of hair dye use (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .196    ≤8 y  921 (14.5)  64 (14.5)  1.16 (0.79 to 1.71)      9–19 y  677 (10.7)  41 (9.3)  0.96 (0.63 to 1.47)      ≥20 y  770 (12.1)  76 (7.3)  1.40 (0.97 to 2.03)      Duration unknown  44 (0.69)  0 (0)  —     Used hair dyes prior to 1980 (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .255    Ever hair dye use, before 1980  895 (14.1)  77 (17.5)  1.44 (0.95 to 2.19)      Hair dye use, only during or after 1980  990 (15.6)  58 (13.2)  1.33 (0.86 to 2.06)      Hair dye use, period unknown  527 (8.3)  46 (10.5)  0.78 (0.45 to 1.35)     Physical activity    None  716 (10.1)  54 (10.5)  1.00 (referent)  .982    Mild  474 (6.7)  45 (8.8)  1.04 (0.66 to 1.63)      Moderate  934 (13.2)  80 (15.6)  0.96 (0.64 to 1.43)      Vigorous  3037 (43.0)  198 (38.7)  0.99 (0.71 to 1.37)    Occupation           Painter    No  8015 (98.2)  624 (97.2)  1.00 (referent)  .083    Yes  135 (1.7)  15 (2.3)  1.68 (0.97 to 2.92)     Teacher    No  7350 (90.0)  603 (93.9)  1.00 (referent)  <.001    Yes  800 (9.8)  36 (5.6)  0.50 (0.35 to 0.70)     General carpenter#    No  7362 (98.8)  587 (97.5)  1.00 (referent)  .017    Yes  60 (0.8)  12 (2.0)  2.34 (1.23 to 4.45)     General unspecified laborer    No  7708 (94.4)  589 (91.7)  1.00 (referent)  .069    Yes  442 (5.4)  50 (7.8)  1.35 (0.99 to 1.84)     Metal worker    No  7693 (94.2)  598 (93.1)  1.00 (referent)  .140    Yes  457 (5.6)  41 (6.4)  1.30 (0.93 to 1.83)      Controls  Cases      Factors  No. (%)  No. (%)  OR (95% CI)  P  Medical conditions  Autoimmune conditions   Sjögren syndrome    No  7374 (97.3)  582 (94.0)  1.00 (referent)  <.001    Yes  9 (0.1)  24 (3.9)  38.38 (17.04 to 86.48)      SLE    No  11904 (98.2)  873 (97.3)  1.00 (referent)  <.001    Yes  25 (0.2)  11 (1.2)  6.57 (3.11 to 13.86)      History of autoimmune disease†    None  13158 (95.6)  972 (92.4)  1.00 (referent)  <.001    B-cell activation  125 (0.9)  45 (4.3)  5.75 (3.97 to 8.33)      T-cell activation  471 (3.4)  33 (3.1)  1.05 (0.72 to 1.52)      Both  12 (0.1)  2 (0.2)  2.78 (0.60 to 12.77)    Other medical conditions           HCV infection    Seronegative  5259 (68.4)  354 (82.1)  1.00 (referent)  .001    Seropositive  95 (1.2)  14 (3.2)  3.04 (1.65 to 5.60)     Ulcer    No  9478 (81.3)  734 (78.7)  1.00 (referent)  .001    Yes  781 (6.7)  76 (8.1)  1.56 (1.21 to 2.03)     Asthma and other atopic conditions‡    No  10939 (80.3)  751 (73.1)  1.00 (referent)  .103    Asthma w/o other atopy  435 (3.2)  45 (4.4)  1.42 (1.03 to 1.97)      Asthma and allergy, hay fever, or eczema  762 (5.6)  56 (5.4)  0.93 (0.70 to 1.25)    Family history, at least one first degree           Any hematologic malignancy    No  8519 (86.2)  676 (77.3)  1.00 (referent)  <.001    Yes  492 (5.0)  78 (8.9)  1.73 (1.33 to 2.25)     Any hematologic malignancy, male relative    No  7940 (88.0)  672 (81.0)  1.00 (referent)  <.001    Yes  230 (2.5)  43 (5.2)  2.00 (1.41 to 2.83)     Any hematologic malignancy, female relative    No  7936 (87.9)  679 (81.8)  1.00 (referent)  .034    Yes  234 (2.6)  36 (4.3)  1.52 (1.05 to 2.21)     HL    No  7625 (89.5)  690 (84.6)  1.00 (referent)  .010    Yes  41 (0.5)  11 (1.3)  2.73 (1.36 to 5.50)     HL, male relative    No  7642 (89.7)  694 (85.0)  1.00 (referent)  .028    Yes  24 (0.3)  7 (0.9)  2.99 (1.23 to 7.28)     HL, female relative    No  7110 (91.1)  666 (85.8)  1.00 (referent)  .186    Yes  18 (0.2)  4 (0.5)  2.27 (0.74 to 6.92)     NHL    No  8085 (88.2)  703 (82.3)  1.00 (referent)  .020    Yes  205 (2.2)  31 (3.6)  1.65 (1.10 to 2.46)     NHL, male relative    No  8339 (92.4)  713 (85.9)  1.00 (referent)  .048    Yes  93 (1.0)  15 (1.8)  1.85 (1.04 to 3.27)     NHL, female relative    No  8061 (89.3)  699 (84.2)  1.00 (referent)  .153    Yes  109 (1.2)  16 (1.9)  1.52 (0.88 to 2.63)     Leukemia§    No  7930 (87.9)  678 (81.7)  1.00 (referent)  .010    Yes  240 (2.7)  37 (4.5)  1.66 (1.15 to 2.38)     Leukemia, male relative    No  8039 (89.1)  695 (83.7)  1.00 (referent)  .062    Yes  131 (1.5)  20 (2.4)  1.64 (1.00 to 2.67)     Leukemia, female relative    No  8067 (89.4)  698 (84.1)  1.00 (referent)  .069    Yes  103 (1.1)  17 (2.0)  1.69 (0.99 to 2.89)     Multiple myeloma||    No  7631 (89.6)  699 (85.7)  1.00 (referent)  .387    Yes  35 (0.4)  2 (0.2)  0.55 (0.13 to 2.37)    Lifestyle factors¶           Recreational sun exposure (h/wk)    Quartile 1 (low)  2234 (20.6)  198 (27.3)  1.00 (referent)  .001    Quartile 2  2332 (21.6)  122 (16.9)  0.66 (0.52 to 0.84)      Quartile 3  2159 (20.0)  152 (21.0)  0.78 (0.62 to 0.97)      Quartile 4 (high)  2983 (27.6)  155 (21.4)  0.68 (0.54 to 0.85)     History of cigarette smoking     No  5463 (42.3)  390 (41.0)  1.00 (referent)  .191    Yes  6531 (50.5)  480 (50.5)  1.10 (0.95 to 1.28)     Years since quit cigarette smoking    Nonsmoker  5463 (42.3)  390 (41.0)  1.00 (referent)  .018    Former, >25 y  1250 (9.7)  112 (11.8)  1.07 (0.84 to 1.36)      Former, 16–25 y  1075 (8.3)  78 (8.2)  0.96 (0.74 to 1.25)      Former, 6–15 y  1064 (8.2)  70 (7.4)  1.00 (0.76 to 1.32)      Former, <5 y   559 (4.3)  48 (5.0)  1.62 (1.17 to 2.24)      Former, unknown years  59 (0.5)  8 (0.8)  3.24 (1.49 to 7.05)      Current smoker  2448 (18.9)  157 (16.5)  1.13 (0.92 to 1.39)     Any type of alcohol (g/wk)    Nondrinker  2121 (17.3)  225 (25.3)  1.00 (referent)  .017    Quartile 1 (low)  1384 (11.3)  141 (15.8)  0.76 (0.59 to 0.98)      Quartile 2  1258 (10.3)  114 (12.8)  0.78 (0.60 to 1.02)      Quartile 3  1108 (9.1)  73 (8.2)  0.60 (0.44 to 0.82)      Quartile 4 (high)  888 (7.3)  48 (5.4)  0.61 (0.42 to 0.88)      Drinker, grams unknown  1079 (8.8)  68 (7.6)  0.96 (0.59 to 1.57)     Wine (g/wk)    Nondrinker  2121 (17.3)  225 (25.3)  1.00 (referent)  .002    Quartile 1 (low)  1223 (10.0)  126 (14.2)  0.77 (0.59 to 1.00)      Quartile 2  981 (8.0)  79 (8.9)  0.62 (0.46 to 0.84)      Quartile 3  1119 (9.2)  77 (8.7)  0.60 (0.44 to 0.80)      Quartile 4 (high)  643 (5.3)  24 (2.7)  0.59 (0.37 to 0.95)      Drinker, grams unknown  1079 (8.8)  68 (7.6)  0.97 (0.60 to 1.58)      Drinker, liquor and beer only   672 (5.5)  70 (7.9)  1.03 (0.75 to 1.41)     Ever used hair dyes (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .330    Ever hair dye  2412 (38.1)  181 (41.1)  1.17 (0.85 to 1.61)     Type of hair dye used (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .078    Temporary only   64 (1.0)  3 (0.7)  0.49 (0.15 to 1.67)      Permanent  2053 (32.4)  161 (36.6)  1.28 (0.92 to 1.78)      Ever hair dye, type unknown  295 (4.7)  17 (3.9)  0.67 (0.32 to 1.41)     Color of hair dye used (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .672    Light  735 (11.6)  53 (12.0)  1.23 (0.82 to 1.84)      Dark  1368 (21.6)  109 (24.8)  1.19 (0.84 to 1.69)      Ever hair dye, color unknown  309 (4.9)  19 (4.3)  0.91 (0.44 to 1.89)     Total years of hair dye use (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .196    ≤8 y  921 (14.5)  64 (14.5)  1.16 (0.79 to 1.71)      9–19 y  677 (10.7)  41 (9.3)  0.96 (0.63 to 1.47)      ≥20 y  770 (12.1)  76 (7.3)  1.40 (0.97 to 2.03)      Duration unknown  44 (0.69)  0 (0)  —     Used hair dyes prior to 1980 (women only)    Never hair dye  856 (13.5)  55 (12.5)  1.00 (referent)  .255    Ever hair dye use, before 1980  895 (14.1)  77 (17.5)  1.44 (0.95 to 2.19)      Hair dye use, only during or after 1980  990 (15.6)  58 (13.2)  1.33 (0.86 to 2.06)      Hair dye use, period unknown  527 (8.3)  46 (10.5)  0.78 (0.45 to 1.35)     Physical activity    None  716 (10.1)  54 (10.5)  1.00 (referent)  .982    Mild  474 (6.7)  45 (8.8)  1.04 (0.66 to 1.63)      Moderate  934 (13.2)  80 (15.6)  0.96 (0.64 to 1.43)      Vigorous  3037 (43.0)  198 (38.7)  0.99 (0.71 to 1.37)    Occupation           Painter    No  8015 (98.2)  624 (97.2)  1.00 (referent)  .083    Yes  135 (1.7)  15 (2.3)  1.68 (0.97 to 2.92)     Teacher    No  7350 (90.0)  603 (93.9)  1.00 (referent)  <.001    Yes  800 (9.8)  36 (5.6)  0.50 (0.35 to 0.70)     General carpenter#    No  7362 (98.8)  587 (97.5)  1.00 (referent)  .017    Yes  60 (0.8)  12 (2.0)  2.34 (1.23 to 4.45)     General unspecified laborer    No  7708 (94.4)  589 (91.7)  1.00 (referent)  .069    Yes  442 (5.4)  50 (7.8)  1.35 (0.99 to 1.84)     Metal worker    No  7693 (94.2)  598 (93.1)  1.00 (referent)  .140    Yes  457 (5.6)  41 (6.4)  1.30 (0.93 to 1.83)    * Basic model adjusted for age, sex, race/ethnicity, and study. For exposures with more than two groups, ie, exposed and unexposed, the P value is the P for trend. HCV = hepatitis c virus; HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma; SLE = systemic lupus erythematosus. † Includes self-reported history of specific autoimmune diseases occurring ≥2 years prior to diagnosis/interview (except the New South Wales study, which did not ascertain date of onset). Autoimmune diseases were classified according to whether they are primarily mediated by B-cell or T-cell responses. B-cell activating diseases included Hashimoto thyroiditis, hemolytic anemia, myasthenia gravis, pernicious anemia, rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus erythematosus. T-cell activating diseases included celiac disease, immune thrombocytopenic purpura, inflammatory bowel disorder (Crohn’s disease, ulcerative colitis), multiple sclerosis, polymyositis or dermatomyositis, psoriasis, sarcoidosis, systemic sclerosis or scleroderma, and type 1 diabetes. ‡ Atopic disorders include asthma, eczema, hay fever, or other allergies, excluding drug allergies. § Based on International Classification of Diseases (ICD)-9 and ICD10 classification. || Not presented by sex of relative due to small number of exposed cases. ¶ Recreational sun exposure (hours per week, study-specific quartiles available upon request; alcohol consumption in grams of ethanol per week (alcohol: <44.40, 44.40–110.68, 110.69–251.99, ≥252.00, beer: <12.90, 12.90–39.85, 39.86–111.61, ≥111.62, liquor: <6.99, 6.99–23.85, 23.85–83.99, ≥84.00; wine: <14.10, 14.10–55.16, 55.17–167.99, ≥168.00). # An International Standard of Occupations (ISCO) category that includes woodworkers. View Large Exploratory analyses were next conducted by sex (data not shown). Results generally were comparable by sex (P heterogeneity > .05), although for selected risk factors, the exposure prevalence and/or risk estimates suggested some variability. Specifically, autoimmune conditions were reported by 10.2% of women and 4.6% of men with MZL, with stronger effects of B-cell activated immune conditions in women (OR = 6.69, 95% confidence interval [CI] = 4.38 to 10.23) than men (OR = 3.56, 95% CI = 1.57 to 8.06) mainly due to SS (women: 6.1% cases, 0.2% controls, OR = 34.7, 95% CI = 15.0 to 79.8; men: 2.1% cases, 0 controls) and SLE (women: 2.1% cases, 0.2% controls, OR = 7.46, 95% CI = 3.34 to 16.6; 0 men). History of peptic ulcers had a stronger and statistically significant effect in men (OR = 1.79, 95% CI = 1.28 to 2.50) than women (OR = 1.31, 95% CI = 0.87 to 1.97). Women were more likely to report a family history than were men (any hematological malignancy; women: OR = 1.98, 95% CI = 1.40 to 2.78; men: OR = 1.48, 95% CI = 0.98 to 2.24) with the exception of a family history of NHL (women: OR = 1.28, 95% CI = 0.72 to 2.30; men: OR = 2.21, 95% CI = 1.27 to 3.86). MZL Subtypes Factors that were significantly associated with MZL were next evaluated for the subtypes of EMZL (N = 633), NMZL (N = 157), and SMZL (N = 140) (Tables 3–5). Risk for all three subtypes was increased with B-cell activating autoimmune conditions (EMZL OR = 6.40, 95% CI = 4.24 to 9.68; NMZL OR = 7.80, 95% CI = 3.32 to 18.33; SMZL OR = 4.25, 95% CI = 1.49 to 12.14; Table 3), particularly SS and SLE. HCV seropositivity (OR = 5.29, 95% CI = 2.48 to 11.28) and peptic ulcers (OR = 1.83, 95% CI = 1.35 to 2.49) were associated with EMZL risk, whereas asthma without other atopy was associated with SMZL (OR = 2.28, 95% CI = 1.23 to 4.23). There were null associations of HCV serostatus, peptic ulcers, and asthma without other atopy with NMZL risk. Table 3. Odds ratios (ORs) and 95% confidence intervals (CIs) for personal medical history and family history associated with marginal zone lymphoma subtypes*     EMZL (n = 633)      NMZL (n = 157)      SMZL (n = 140)      Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)  P  Ctrls/Ca  OR (95% CI)  P  Autoimmune medical conditions   Sjögren syndrome    No  6536/358  1.00 (referent)  .000  4199/122  1.00 (referent)  <.001  5363/18  1.00 (referent)  .805    Yes  9/19  40.25 (17.5 to 92.6)    4/5  141 (25.01 to 800)    8/0  —     SLE    No  11904/543  1.00 (referent)  <.001  7434/63  1.00 (referent)  .026  9893/81  1.00 (referent)  .231    Yes  25/8  8.44 (3.58 to 19.91)    23/2  9.24 (1.95 to 43.74)    23/1  4.61 (0.59 to 35.87)     Autoimmune disease‡    None  13158/575  1.00 (referent)  <.001  8594/143  1.00 (referent)  <.001  12468/134  1.00 (referent)  .126    B-cell activation  125/34  6.40 (4.24 to 9.68)    89/7  7.80 (3.32 to 18.33)    122/4  4.25 (1.49 to 12.14)      T-cell activation  471/23  1.08 (0.69 to 1.67)    242/6  1.48 (0.62 to 3.54)    447/2  0.70 (0.17 to 2.87)      Both  12/1  2.07 (0.26 to 16.32)    11/1  11.67 (1.33 to 103)    12/0  —    Other medical conditions   HCV infection    Seronegative  5259/211  1.00 (referent)  <.001  2951/31  1.00 (referent)  .250  3410/64  1.00 (referent)  .864    Seropositive  95/10  5.29 (2.48 to 11.28)    48/1  4.36 (0.54 to 35.38)    93/1  0.84 (0.11 to 6.28)     Ulcer    No  9478/430  1.00 (referent)  <.001  4979/122  1.00 (referent)  .827  9478/113  1.00 (referent)  .682    Yes  781/53  1.83 (1.35 to 2.49)    478/7  1.09 (0.49 to 2.43)    781/11  1.15 (0.61 to 2.17)     Asthma and other atopic conditions§    No  10939/467  1.00 (referent)  .171  6531/101  1.00 (referent)  .862  10288/114  1.00 (referent)  .011    Asthma no other atopy  435/28  1.50 (1.00 to 2.24)    294/3  0.77 (0.24 to 2.50)    404/12  2.28 (1.23 to 4.23)      Asthma, other atopy  762/39  1.04 (0.74 to 1.47)    496/11  1.10 (0.57 to 2.13)    727/4  0.46 (0.17 to 1.26)        EMZL (n = 633)      NMZL (n = 157)      SMZL (n = 140)      Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)  P  Ctrls/Ca  OR (95% CI)  P  Autoimmune medical conditions   Sjögren syndrome    No  6536/358  1.00 (referent)  .000  4199/122  1.00 (referent)  <.001  5363/18  1.00 (referent)  .805    Yes  9/19  40.25 (17.5 to 92.6)    4/5  141 (25.01 to 800)    8/0  —     SLE    No  11904/543  1.00 (referent)  <.001  7434/63  1.00 (referent)  .026  9893/81  1.00 (referent)  .231    Yes  25/8  8.44 (3.58 to 19.91)    23/2  9.24 (1.95 to 43.74)    23/1  4.61 (0.59 to 35.87)     Autoimmune disease‡    None  13158/575  1.00 (referent)  <.001  8594/143  1.00 (referent)  <.001  12468/134  1.00 (referent)  .126    B-cell activation  125/34  6.40 (4.24 to 9.68)    89/7  7.80 (3.32 to 18.33)    122/4  4.25 (1.49 to 12.14)      T-cell activation  471/23  1.08 (0.69 to 1.67)    242/6  1.48 (0.62 to 3.54)    447/2  0.70 (0.17 to 2.87)      Both  12/1  2.07 (0.26 to 16.32)    11/1  11.67 (1.33 to 103)    12/0  —    Other medical conditions   HCV infection    Seronegative  5259/211  1.00 (referent)  <.001  2951/31  1.00 (referent)  .250  3410/64  1.00 (referent)  .864    Seropositive  95/10  5.29 (2.48 to 11.28)    48/1  4.36 (0.54 to 35.38)    93/1  0.84 (0.11 to 6.28)     Ulcer    No  9478/430  1.00 (referent)  <.001  4979/122  1.00 (referent)  .827  9478/113  1.00 (referent)  .682    Yes  781/53  1.83 (1.35 to 2.49)    478/7  1.09 (0.49 to 2.43)    781/11  1.15 (0.61 to 2.17)     Asthma and other atopic conditions§    No  10939/467  1.00 (referent)  .171  6531/101  1.00 (referent)  .862  10288/114  1.00 (referent)  .011    Asthma no other atopy  435/28  1.50 (1.00 to 2.24)    294/3  0.77 (0.24 to 2.50)    404/12  2.28 (1.23 to 4.23)      Asthma, other atopy  762/39  1.04 (0.74 to 1.47)    496/11  1.10 (0.57 to 2.13)    727/4  0.46 (0.17 to 1.26)    * Ca = cases; Ctrls = controls; EMZL = extranodal marginal zone lymphoma; HCV = hepatitis c virus; NMZL = nodal marginal zone lymphoma; SLE = systemic lupus erythematosus; SMZL = splenic marginal zone lymphoma. † Basic model adjusted for age, sex, race/ethnicity, and study. For exposures with more than two categories, ie, exposed and unexposed, the P value is the P for trend. ‡ Includes self-reported history of specific autoimmune diseases occurring ≥2 years prior to diagnosis/interview (except the New South Wales study, which did not ascertain date of onset). Autoimmune diseases were classified according to whether they are primarily mediated by B-cell or T-cell responses. B-cell activating diseases included Hashimoto thyroiditis, hemolytic anemia, myasthenia gravis, pernicious anemia, rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus erythematosus. T-cell activating diseases included celiac disease, immune thrombocytopenic purpura, inflammatory bowel disorder (Crohn’s disease, ulcerative colitis), multiple sclerosis, polymyositis or dermatomyositis, psoriasis, sarcoidosis, systemic sclerosis or scleroderma, and type 1 diabetes. § Atopic disorders include asthma, eczema, hay fever, or other allergies, excluding drug allergies. View Large Table 4. Odds ratios (ORs) and 95% confidence intervals (CIs) for family history of hematologic malignancies associated with subtypes of marginal zone lymphoma     EMZL      NMZL      SMZL    Family history, at least one first degree  Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)†  P  Any hematologic malignancy   No  8519/357  1.00 (referent)  <.001  6928/96  1.00 (referent)  .23  8016/112  1.00 (referent)  .69   Yes  492/49  1.90 (1.37 to 2.62)    443/13  1.48 (0.80 to 2.74)    457/7  1.18 (0.54 to 2.56)    Any hematologic malignancy, male relative   No  7940/352  1.00 (referent)  <.001  6330/99  1.00 (referent)  .44  7419/110  1.00 (referent)  .31   Yes  230/27  2.20 (1.44 to 3.37)    200/6  1.44 (0.60 to 3.45)    213/5  1.66 (0.66 to 4.16)    Any hematologic malignancy, female relative   No  7936/356  1.00 (referent)  .04  6315/97  1.00 (referent)  .18  7416/113  1.00 (referent)  .64   Yes  234/23  1.65 (1.05 to 2.60)    215/8  1.74 (0.81 to 3.76)    216/2  0.73 (0.18 to 3.00)    HL†   No  7625/362  1.00 (referent)  .06  6496/103  1.00 (referent)  .25  7090/113  1.00 (referent)  .60   Yes  41/6  2.59 (1.06 to 6.30)    34/2  2.73 (0.59 to 12.62)    38/1  1.90 (0.24 to 13.62)    NHL‡   No  8085/376  1.00 (referent)  .16  6454/98  1.00 (referent)  .01  7557/115  1.00 (referent)  .24   Yes  205/15  1.52 (0.87 to 2.65)    196/9  2.82 (1.33 to 5.98)    195/1  0.37 (0.05 to 2.65)    NHL, male relative   No  8339/378  1.00 (referent)  .08  6702/104  1.00 (referent)  .12  7803/118  1.00 (referent)  .12   Yes  93/8  2.06 (0.97 to 4.41)    90/4  2.60 (0.87 to 7.79)    91/0  —    NHL, female relative   No  8061/371  1.00 (referent)  .44  6427/100  1.00 (referent)  .05  7531/114  1.00 (referent)  .71   Yes  109/8  1.36 (0.64 to 2.87)    103/5  3.00 (1.12 to 7.98)    101/1  0.70 (0.10 to 5.11)    Leukemia§   No  7930/355  1.00 (referent)  .005  6323/102  1.00 (referent)  .55  7404/111  1.00 (referent)  .75   Yes  240/24  2.00 (1.28 to 3.13)    207/3  0.71 (0.22 to 2.32)    228/4  1.18 (0.43 to 3.25)    Leukemia, male relative   No  8039/366  1.00 (referent)  .04  6423/104  1.00 (referent)  .38  7510/112  1.00 (referent)  .48   Yes  131/13  1.96 (1.08 to 3.55)    107/1  0.45 (0.06 to 3.39)    122/3  1.56 (0.48 to 5.05)    Leukemia, female relative   No  8067/368  1.00 (referent)  .06  6436/103  1.00 (referent)  .99  7532/114  1.00 (referent)  .75   Yes  103/11  1.97 (1.03 to 3.77)    94/2  0.99 (0.23 to 4.23)    100/1  0.73 (0.10 to 5.35)    MM‡   No  7631/368  1.00 (referent)  .03  6496/104  1.00 (referent)  .88  7103/113  1.00 (referent)  .30   Yes  35/0  —    34/1  1.17 (0.15 to 9.41)    25/1  3.61 (0.46 to 28.20)        EMZL      NMZL      SMZL    Family history, at least one first degree  Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)†  P  Ctrls/Ca  OR (95% CI)†  P  Any hematologic malignancy   No  8519/357  1.00 (referent)  <.001  6928/96  1.00 (referent)  .23  8016/112  1.00 (referent)  .69   Yes  492/49  1.90 (1.37 to 2.62)    443/13  1.48 (0.80 to 2.74)    457/7  1.18 (0.54 to 2.56)    Any hematologic malignancy, male relative   No  7940/352  1.00 (referent)  <.001  6330/99  1.00 (referent)  .44  7419/110  1.00 (referent)  .31   Yes  230/27  2.20 (1.44 to 3.37)    200/6  1.44 (0.60 to 3.45)    213/5  1.66 (0.66 to 4.16)    Any hematologic malignancy, female relative   No  7936/356  1.00 (referent)  .04  6315/97  1.00 (referent)  .18  7416/113  1.00 (referent)  .64   Yes  234/23  1.65 (1.05 to 2.60)    215/8  1.74 (0.81 to 3.76)    216/2  0.73 (0.18 to 3.00)    HL†   No  7625/362  1.00 (referent)  .06  6496/103  1.00 (referent)  .25  7090/113  1.00 (referent)  .60   Yes  41/6  2.59 (1.06 to 6.30)    34/2  2.73 (0.59 to 12.62)    38/1  1.90 (0.24 to 13.62)    NHL‡   No  8085/376  1.00 (referent)  .16  6454/98  1.00 (referent)  .01  7557/115  1.00 (referent)  .24   Yes  205/15  1.52 (0.87 to 2.65)    196/9  2.82 (1.33 to 5.98)    195/1  0.37 (0.05 to 2.65)    NHL, male relative   No  8339/378  1.00 (referent)  .08  6702/104  1.00 (referent)  .12  7803/118  1.00 (referent)  .12   Yes  93/8  2.06 (0.97 to 4.41)    90/4  2.60 (0.87 to 7.79)    91/0  —    NHL, female relative   No  8061/371  1.00 (referent)  .44  6427/100  1.00 (referent)  .05  7531/114  1.00 (referent)  .71   Yes  109/8  1.36 (0.64 to 2.87)    103/5  3.00 (1.12 to 7.98)    101/1  0.70 (0.10 to 5.11)    Leukemia§   No  7930/355  1.00 (referent)  .005  6323/102  1.00 (referent)  .55  7404/111  1.00 (referent)  .75   Yes  240/24  2.00 (1.28 to 3.13)    207/3  0.71 (0.22 to 2.32)    228/4  1.18 (0.43 to 3.25)    Leukemia, male relative   No  8039/366  1.00 (referent)  .04  6423/104  1.00 (referent)  .38  7510/112  1.00 (referent)  .48   Yes  131/13  1.96 (1.08 to 3.55)    107/1  0.45 (0.06 to 3.39)    122/3  1.56 (0.48 to 5.05)    Leukemia, female relative   No  8067/368  1.00 (referent)  .06  6436/103  1.00 (referent)  .99  7532/114  1.00 (referent)  .75   Yes  103/11  1.97 (1.03 to 3.77)    94/2  0.99 (0.23 to 4.23)    100/1  0.73 (0.10 to 5.35)    MM‡   No  7631/368  1.00 (referent)  .03  6496/104  1.00 (referent)  .88  7103/113  1.00 (referent)  .30   Yes  35/0  —    34/1  1.17 (0.15 to 9.41)    25/1  3.61 (0.46 to 28.20)    * Ca = cases; Ctrls = controls; EMZL = extranodal marginal zone lymphoma; HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma; MM = multiple myeloma NMZL = nodal marginal zone lymphoma; SMZL = splenic marginal zone lymphoma. † Basic model adjusted for age, sex, race/ethnicity, and study. For exposures with more than two categories, ie, exposed and unexposed, the P value is the P for trend. ‡ Not presented by sex of relative due to small number of exposed cases; all P values were >.10. § Based on International Classification of Diseases (ICD)-9 and ICD10 classification. View Large Table 5. Odds ratios (ORs) and 95% confidence intervals (CIs) for lifestyle factors and occupation associated with subtypes of marginal zone lymphoma*     EMZL      NMZL      SMZL    Lifestyle factors†  Ctrls/Ca  OR (95% CI)‡  P  Ctrls/Ca  OR (95% CI)‡  P  Ctrls/Ca  OR (95% CI)‡  P  Recreational sun exposure (h/wk)   Quartile 1 (low)  2234/105  1.00 (referent)  .14  1311/12  1.00 (referent)  .84  2059/34  1.00 (referent)  .33   Quartile 2  2332/72  0.74 (0.54 to 1.00)    1343/11  0.86 (0.37 to 1.98)    2160/18  0.59 (0.33 to 1.08)     Quartile 3  2159/88  0.92 (0.68 to 1.23)    1367/12  0.92 (0.40 to 2.14)    1975/28  0.80 (0.47 to 1.35)     Quartile 4 (high)  2983/96  0.76 (0.56 to 1.01)    1394/16  1.21 (0.54 to 2.72)    2799/25  0.70 (0.40 to 1.22)    History of cigarette smoking    No  5463/235  1.00 (referent)  .49  3355/58  1.00 (referent)  .82  5141/55  1.00 (referent)  .95   Yes  6531/275  1.07 (0.89 to 1.29)    3821/57  0.96 (0.64 to 1.42)    6137/68  1.01 (0.69 to 1.48)    Years since quit cigarette smoking   Never smoker  5463/235  1.00 (referent)  .05  3355/58  1.00 (referent)  .74  5141/55  1.00 (referent)  .53   Former, >25 y   1250/68  1.10 (0.82 to 1.48)    881/30  1.01 (0.57 to 1.78)    1156/10  0.69 (0.35 to 1.39)     Former, 16–25 y   1075/43  0.91 (0.65 to 1.29)    658/8  0.59 (0.27 to 1.28)    1013/18  1.46 (0.84 to 2.55)     Former, 6-15 y  1064/41  0.99 (0.70 to 1.41)    1631/0  1.03 (0.50 to 2.11)    971/9  0.86 (0.42 to 1.77)     Former, <5 y  559/29  1.55 (1.03 to 2.33)    278/4  1.58 (0.54 to 4.67)    531/7  1.57 (0.70 to 3.54)     Former, unknown years  59/8  3.58 (1.65 to 7.78)    23/0  —    48/0  —     Current smoker  2448/83  1.01 (0.77 to 1.32)    1282/15  1.14 (0.62 to 2.09)    2342/22  1.00 (0.59 to 1.68)    Any alcohol (g/wk)   Nondrinker  2121/112  1.00 (referent)  .01  1883/46  1.00 (referent)  .09  1855/42  1.00 (referent)  .38   Quartile 1 (low)  1384/95  0.93 (0.68 to 1.27)    976/22  0.50 (0.29 to 0.88)    992/13  0.59 (0.30 to 1.16)     Quartile 2  1258/68  0.91 (0.64 to 1.29)    729/12  0.41 (0.21 to 0.83)    1011/13  0.51 (0.26 to 1.01)     Quartile 3  1108/33  0.55 (0.36 to 0.84)    589/14  0.66 (0.34 to 1.30)    904/16  0.76 (0.39 to 1.48)     Quartile 4 (high)  888/19  0.48 (0.28 to 0.82)    487/7  0.78 (0.32 to 1.89)    801/12  0.75 (0.36 to 1.59)     Drinker, grams unknown  1079/52  1.15 (0.64 to 2.08)    1079/3  1.01 (0.14 to 7.18)    1079/10  0.65 (0.21 to 1.98)    Wine (g/wk)   Nondrinker  2121/112  1.00 (referent)  .09  1883/46  1.00 (referent)  .003  1855/42  1.00 (referent)  .63   Quartile 1 (low)  1223/82  0.93 (0.67 to 1.29)    792/14  0.38 (0.20 to 0.72)    919/13  0.57 (0.28 to 1.16)     Quartile 2  981/42  0.61 (0.41 to 0.92)    507/10  0.37 (0.17 to 0.78)    691/13  0.73 (0.36 to 1.48)     Quartile 3  1119/42  0.65 (0.43 to 0.98)    614/12  0.45 (0.22 to 0.90)    963/14  0.58 (0.30 to 1.13)     Quartile 4 (high)  643/14  0.70 (0.37 to 1.31)    415/4  1.06 (0.33 to 3.42)    624/6  0.67 (0.26 to 1.69)     Drinker, grams unknown  1079/52  1.18 (0.65 to 2.14)    1079/3  1.02 (0.14 to 7.39)    1079/10  0.63 (0.21 to 1.95)     Liquor, beer only   672/36  1.07 (0.70 to 1.65)    1453/5  1.36 (0.69 to 2.67)    511/8  0.65 (0.28 to 1.47)    Ever used hairdye (women only)   Never hair dye  856/36  1.00 (referent)  .84  856/10  1.00 (referent)  .60  658/2  1.00 (referent)  .001   Ever hair dye  2412/100  0.96 (0.64 to 1.43)    2412/27  0.82 (0.39 to 1.73)    1893/30  6.54 (1.53 to 27.85)    Type of hairdye used (women only)   Never hair dye  856/36  1.00 (referent)  .29  856/10  1.00 (referent)  .86  658/2  1.00 (referent)  .01   Temporary only   64/2  0.41 (0.09 to 1.80)    64/1  0.46 (0.06 to 3.89)    52/0  —     Permanent  2053/88  1.06 (0.70 to 1.61)    2053/21  0.87 (0.39 to 1.94)    1549/28  6.59 (1.54 to 28.17)     Type unknown  295/10  0.55 (0.21 to 1.43)    295/5  0.70 (0.18 to 2.73)    292/2  5.93 (0.56 to 63.09)    Color of hairdye used (women only)   Never hair dye  856/36  1.00 (referent)  .92  856/10  1.00 (referent)  .73  658/2  1.00 (referent)  .004   Light  735/26  0.85 (0.50 to 1.45)    735/5  0.63 (0.20 to 1.93)    539/13  9.69 (2.12 to 44.34)     Dark  1368/62  1.00 (0.65 to 1.55)    1368/18  0.98 (0.43 to 2.26)    1047/15  5.30 (1.19 to 23.66)     Color unknown  309/12  1.02 (0.39 to 2.70)    309/4  0.59 (0.12 to 2.77)    307/2  4.53 (0.44 to 46.94)    Used hair dyes before 1980 (women only)   Never hair dye  856/36  1.00 (referent)  .92  856/10  1.00 (referent)  .61  658/2  1.00 (referent)  .001   Use before 1980  735/26  0.85 (0.50 to 1.45)    895/9  0.55 (0.20 to 1.51)    601/16  14.85 (1.94 to 114)     Use only during or after 1980  1368/62  1.00 (0.65 to 1.55)    990/7  0.67 (0.23 to 1.90)    766/8  7.05 (0.86 to 58.04)     Use, period unknown  309/12  1.02 (0.39 to 2.70)    1527/1  1.52 (0.12 to 5.69)    526/6  2.34 (0.31 to 17.48)    Physical activity   None  716/25  1.00 (referent)  .84  716/5  1.00 (referent)  .95  674/16  1.00 (referent)  .06   Mild  474/29  0.84 (0.47 to 1.49)    474/7  0.77 (0.23 to 2.55)    425/8  1.14 (0.41 to 3.20)     Moderate  934/55  0.85 (0.50 to 1.43)    934/14  0.79 (0.27 to 2.36)    902/9  0.57 (0.22 to 1.53)     Vigorous  3037/110  0.80 (0.50 to 1.28)    3037/18  0.73 (0.26 to 2.08)    2443/23  0.44 (0.22 to 0.90)    Occupation   Painter    No  8015/330  1.00 (referent)  .97  6914/78  1.00 (referent)  .29  7300/113  1.00 (referent)  .50    Yes  135/4  1.02 (0.37 to 2.83)    110/2  2.43 (0.57 to 10.40)    133/3  1.54 (0.47 to 5.00)     Teacher    No  7350/310  1.00 (referent)  .007  6369/75  1.00 (referent)  .16  6769/112  1.00 (referent)  .01    Yes  800/24  0.58 (0.37 to 0.88)    655/5  0.54 (0.22 to 1.36)    664/4  0.33 (0.12 to 0.91)     General carpenter    No  7362/293  1.00 (referent)  .43  6255/76  1.00 (referent)  .69  7362/113  1.00 (referent)  .10    Yes  60/4  1.55 (0.55 to 4.39)    41/1  1.56 (0.20 to 11.93)    60/3  3.21 (0.95 to 10.88)     General unspecified laborer    No  7708/314  1.00 (referent)  .92  6678/73  1.00 (referent)  .29  7040/103  1.00 (referent)  .03    Yes  442/20  0.98 (0.61 to 1.56)    346/7  1.58 (0.70 to 3.56)    393/13  2.10 (1.15 to 3.84)     Metal worker    No  7693/320  1.00 (referent)  .91  6647/71  1.00 (referent)  .004  6992/108  1.00 (referent)  .74    Yes  457/14  1.03 (0.59 to 1.81)    377/9  3.56 (1.67 to 7.58)    441/8  1.14 (0.54 to 2.39)        EMZL      NMZL      SMZL    Lifestyle factors†  Ctrls/Ca  OR (95% CI)‡  P  Ctrls/Ca  OR (95% CI)‡  P  Ctrls/Ca  OR (95% CI)‡  P  Recreational sun exposure (h/wk)   Quartile 1 (low)  2234/105  1.00 (referent)  .14  1311/12  1.00 (referent)  .84  2059/34  1.00 (referent)  .33   Quartile 2  2332/72  0.74 (0.54 to 1.00)    1343/11  0.86 (0.37 to 1.98)    2160/18  0.59 (0.33 to 1.08)     Quartile 3  2159/88  0.92 (0.68 to 1.23)    1367/12  0.92 (0.40 to 2.14)    1975/28  0.80 (0.47 to 1.35)     Quartile 4 (high)  2983/96  0.76 (0.56 to 1.01)    1394/16  1.21 (0.54 to 2.72)    2799/25  0.70 (0.40 to 1.22)    History of cigarette smoking    No  5463/235  1.00 (referent)  .49  3355/58  1.00 (referent)  .82  5141/55  1.00 (referent)  .95   Yes  6531/275  1.07 (0.89 to 1.29)    3821/57  0.96 (0.64 to 1.42)    6137/68  1.01 (0.69 to 1.48)    Years since quit cigarette smoking   Never smoker  5463/235  1.00 (referent)  .05  3355/58  1.00 (referent)  .74  5141/55  1.00 (referent)  .53   Former, >25 y   1250/68  1.10 (0.82 to 1.48)    881/30  1.01 (0.57 to 1.78)    1156/10  0.69 (0.35 to 1.39)     Former, 16–25 y   1075/43  0.91 (0.65 to 1.29)    658/8  0.59 (0.27 to 1.28)    1013/18  1.46 (0.84 to 2.55)     Former, 6-15 y  1064/41  0.99 (0.70 to 1.41)    1631/0  1.03 (0.50 to 2.11)    971/9  0.86 (0.42 to 1.77)     Former, <5 y  559/29  1.55 (1.03 to 2.33)    278/4  1.58 (0.54 to 4.67)    531/7  1.57 (0.70 to 3.54)     Former, unknown years  59/8  3.58 (1.65 to 7.78)    23/0  —    48/0  —     Current smoker  2448/83  1.01 (0.77 to 1.32)    1282/15  1.14 (0.62 to 2.09)    2342/22  1.00 (0.59 to 1.68)    Any alcohol (g/wk)   Nondrinker  2121/112  1.00 (referent)  .01  1883/46  1.00 (referent)  .09  1855/42  1.00 (referent)  .38   Quartile 1 (low)  1384/95  0.93 (0.68 to 1.27)    976/22  0.50 (0.29 to 0.88)    992/13  0.59 (0.30 to 1.16)     Quartile 2  1258/68  0.91 (0.64 to 1.29)    729/12  0.41 (0.21 to 0.83)    1011/13  0.51 (0.26 to 1.01)     Quartile 3  1108/33  0.55 (0.36 to 0.84)    589/14  0.66 (0.34 to 1.30)    904/16  0.76 (0.39 to 1.48)     Quartile 4 (high)  888/19  0.48 (0.28 to 0.82)    487/7  0.78 (0.32 to 1.89)    801/12  0.75 (0.36 to 1.59)     Drinker, grams unknown  1079/52  1.15 (0.64 to 2.08)    1079/3  1.01 (0.14 to 7.18)    1079/10  0.65 (0.21 to 1.98)    Wine (g/wk)   Nondrinker  2121/112  1.00 (referent)  .09  1883/46  1.00 (referent)  .003  1855/42  1.00 (referent)  .63   Quartile 1 (low)  1223/82  0.93 (0.67 to 1.29)    792/14  0.38 (0.20 to 0.72)    919/13  0.57 (0.28 to 1.16)     Quartile 2  981/42  0.61 (0.41 to 0.92)    507/10  0.37 (0.17 to 0.78)    691/13  0.73 (0.36 to 1.48)     Quartile 3  1119/42  0.65 (0.43 to 0.98)    614/12  0.45 (0.22 to 0.90)    963/14  0.58 (0.30 to 1.13)     Quartile 4 (high)  643/14  0.70 (0.37 to 1.31)    415/4  1.06 (0.33 to 3.42)    624/6  0.67 (0.26 to 1.69)     Drinker, grams unknown  1079/52  1.18 (0.65 to 2.14)    1079/3  1.02 (0.14 to 7.39)    1079/10  0.63 (0.21 to 1.95)     Liquor, beer only   672/36  1.07 (0.70 to 1.65)    1453/5  1.36 (0.69 to 2.67)    511/8  0.65 (0.28 to 1.47)    Ever used hairdye (women only)   Never hair dye  856/36  1.00 (referent)  .84  856/10  1.00 (referent)  .60  658/2  1.00 (referent)  .001   Ever hair dye  2412/100  0.96 (0.64 to 1.43)    2412/27  0.82 (0.39 to 1.73)    1893/30  6.54 (1.53 to 27.85)    Type of hairdye used (women only)   Never hair dye  856/36  1.00 (referent)  .29  856/10  1.00 (referent)  .86  658/2  1.00 (referent)  .01   Temporary only   64/2  0.41 (0.09 to 1.80)    64/1  0.46 (0.06 to 3.89)    52/0  —     Permanent  2053/88  1.06 (0.70 to 1.61)    2053/21  0.87 (0.39 to 1.94)    1549/28  6.59 (1.54 to 28.17)     Type unknown  295/10  0.55 (0.21 to 1.43)    295/5  0.70 (0.18 to 2.73)    292/2  5.93 (0.56 to 63.09)    Color of hairdye used (women only)   Never hair dye  856/36  1.00 (referent)  .92  856/10  1.00 (referent)  .73  658/2  1.00 (referent)  .004   Light  735/26  0.85 (0.50 to 1.45)    735/5  0.63 (0.20 to 1.93)    539/13  9.69 (2.12 to 44.34)     Dark  1368/62  1.00 (0.65 to 1.55)    1368/18  0.98 (0.43 to 2.26)    1047/15  5.30 (1.19 to 23.66)     Color unknown  309/12  1.02 (0.39 to 2.70)    309/4  0.59 (0.12 to 2.77)    307/2  4.53 (0.44 to 46.94)    Used hair dyes before 1980 (women only)   Never hair dye  856/36  1.00 (referent)  .92  856/10  1.00 (referent)  .61  658/2  1.00 (referent)  .001   Use before 1980  735/26  0.85 (0.50 to 1.45)    895/9  0.55 (0.20 to 1.51)    601/16  14.85 (1.94 to 114)     Use only during or after 1980  1368/62  1.00 (0.65 to 1.55)    990/7  0.67 (0.23 to 1.90)    766/8  7.05 (0.86 to 58.04)     Use, period unknown  309/12  1.02 (0.39 to 2.70)    1527/1  1.52 (0.12 to 5.69)    526/6  2.34 (0.31 to 17.48)    Physical activity   None  716/25  1.00 (referent)  .84  716/5  1.00 (referent)  .95  674/16  1.00 (referent)  .06   Mild  474/29  0.84 (0.47 to 1.49)    474/7  0.77 (0.23 to 2.55)    425/8  1.14 (0.41 to 3.20)     Moderate  934/55  0.85 (0.50 to 1.43)    934/14  0.79 (0.27 to 2.36)    902/9  0.57 (0.22 to 1.53)     Vigorous  3037/110  0.80 (0.50 to 1.28)    3037/18  0.73 (0.26 to 2.08)    2443/23  0.44 (0.22 to 0.90)    Occupation   Painter    No  8015/330  1.00 (referent)  .97  6914/78  1.00 (referent)  .29  7300/113  1.00 (referent)  .50    Yes  135/4  1.02 (0.37 to 2.83)    110/2  2.43 (0.57 to 10.40)    133/3  1.54 (0.47 to 5.00)     Teacher    No  7350/310  1.00 (referent)  .007  6369/75  1.00 (referent)  .16  6769/112  1.00 (referent)  .01    Yes  800/24  0.58 (0.37 to 0.88)    655/5  0.54 (0.22 to 1.36)    664/4  0.33 (0.12 to 0.91)     General carpenter    No  7362/293  1.00 (referent)  .43  6255/76  1.00 (referent)  .69  7362/113  1.00 (referent)  .10    Yes  60/4  1.55 (0.55 to 4.39)    41/1  1.56 (0.20 to 11.93)    60/3  3.21 (0.95 to 10.88)     General unspecified laborer    No  7708/314  1.00 (referent)  .92  6678/73  1.00 (referent)  .29  7040/103  1.00 (referent)  .03    Yes  442/20  0.98 (0.61 to 1.56)    346/7  1.58 (0.70 to 3.56)    393/13  2.10 (1.15 to 3.84)     Metal worker    No  7693/320  1.00 (referent)  .91  6647/71  1.00 (referent)  .004  6992/108  1.00 (referent)  .74    Yes  457/14  1.03 (0.59 to 1.81)    377/9  3.56 (1.67 to 7.58)    441/8  1.14 (0.54 to 2.39)    * Ca = cases; Ctrls = controls; EMZL = extranodal marginal zone lymphoma; NMZL = nodal marginal zone lymphoma; SMZL = splenic marginal zone lymphoma. † Recreational sun exposure (hours per week, study-specific quartiles available upon request; alcohol consumption in g of ethanol per week (alcohol: <44.40, 44.40–110.68, 110.69–251.99, ≥252.00, beer: <12.90, 12.90–39.85, 39.86–111.61, ≥111.62, liquor: <6.99, 6.99–23.85, 23.85–83.99, ≥84.00; wine: <14.10, 14.10–55.16, 55.17–167.99, ≥168.00). ‡ c model adjusted for age, sex, race/ethnicity, and study. For exposures with more than two categories, ie, exposed and unexposed, the P value is the P for trend. View Large EMZL was associated with family history of any hematologic cancer (OR = 1.90, 95% CI = 1.37 to 2.62, Table 4), particularly leukemia (OR = 2.00, 95% CI = 1.28 to 5.13), whereas NMZL was associated with a family history of NHL (OR = 2.82, 95% CI = 1.33 to 5.98). Although the magnitude of the ORs suggested increased risk of SMZL with a family history of several specific hematologic cancers, estimates were imprecise. Associations between lifestyle factors and MZL subtypes were heterogeneous (Table 5). Ever smoking of cigarettes was not associated with EMZL, NMZL, or SMZL. However, compared with never smokers, risk of EMZL was elevated for those who quit less than 5 years before diagnosis/interview (OR = 1.55, 95% CI = 1.03 to 2.33) but was not elevated for longer duration of quitting or for current smokers. Alcohol consumption was inversely associated with EMZL risk (fourth quartile vs nondrinkers, OR = 0.48, 95% CI = 0.28 to 0.82). In contrast, NMZL risk was decreased for lower levels of consumption of any alcohol and particularly wine, whereas there was no association for the highest quartile of intake. Consumption of any alcohol or wine was not associated with SMZL. Among women, SMZL risk was increased with hairdye use including ever use (OR = 6.54, 95% CI = 1.53 to 27.85), use of permanent dyes (OR = 6.59, 95% CI = 1.54 to 28.17), and light color (OR = 9.69, 95% CI = 2.12 to 44.34) (Table 5). Further analyses of hair–dye characteristics for SMZL risk (Supplementary Table 1, available online) showed that permanent dyes, regardless of color, were associated with increased risk, although risk was greater for light (>10-fold) than for dark (>5.5-fold) color dyes and greatest for use before 1980 (light permanent OR ~19; dark permanent OR ~10), acknowledging small numbers of exposed women. Associations for hairdye use factors with risk of EMZL and of NMZL were null. Occupation as a teacher was inversely associated with EMZL (OR = 0.58, 95% CI = 0.37 to 0.88) and SMZL (OR = 0.33, 95% CI = 0.12 to 0.91) risk. Occupation as a general laborer was associated with increased SMZL risk (OR = 2.10, 95% CI = 1.15 to 3.84) and as a metalworker with increased NMZL risk (OR = 3.56, 95% CI = 1.67 to 7.58). Exploratory analyses (Supplementary Table 2, available online) were conducted by the common EMZL primary sites, stomach, eye/orbit, skin, and parotid/salivary gland. Increased risk of EMZL of the stomach, skin, and especially the parotid/salivary gland was associated with autoimmune conditions. Specifically, parotid EMZL was associated with B-cell activating autoimmune conditions (OR = 40.2, 95% CI = 20.1 to 80.4), SS (OR = 506, 95% CI = 165 to 1554), SLE (OR = 27.6, 95% CI = 5.4 to 141), and myositis (OR = 41.5, 95% CI = 7.08 to 243), whereas stomach EMZL was associated with SLE (OR = 14.2, 95% CI = 2.99 to 67.3) and skin EMZL with hemolytic anemia (OR = 23, 95% CI = 1.91 to 277). Other medical conditions associated with increased risk of skin EMZL were atopy and hayfever with other atopy (OR = 1.74, 95% CI = 1.01 to 3.01; OR = 2.24, 95% CI = 1.11 to 4.54, respectively). Risk of stomach EMZL was increased for those with peptic ulcer (OR = 3.97, 95% CI = 2.38 to 6.64), whereas risk of eye/orbit EMZL was decreased for those with eczema (OR = 0.23, 95% CI = 0.06 to 0.96). Family history of any hematologic cancer was associated with a greater than threefold increased risk of skin EMZL and Hodgkin lymphoma with a nearly 20-fold increased risk. Occupation as a teacher was associated with a decreased risk of stomach EMZL (OR = 0.12, 95% CI = 0.02 to 0.88). Occupationally related increased risks unique to the analyses by site were a nearly ninefold increased risk of EMZL of the eye/orbit and a greater than sevenfold risk of parotid/salivary gland among bakers, and a 25-fold increase risk of skin EMZL among petroleum workers. Alcohol consumption was related with decreased risks of stomach, eye/orbit, and parotid/salivary gland. Recognizing that most of these analyses were based on few exposed cases, often less than three, results require confirmation and should be interpreted conservatively. Discussion Our large pooled analysis of MZL from 12 case–control studies conducted on three continents and including more than 1000 cases and 13000 controls has allowed for the first time a broad evaluation of a number of potential epidemiological risk factors for MZL subtypes and across all MZL. The study size and extensive risk factor data enabled multivariable modeling to evaluate confounding among risk factors, facilitated the detailed assessment of MZL subtypes, and enabled exploratory analyses of MZL by sex. Although several MZL findings presented here are consistent with results from smaller previous pooled analyses within InterLymph, including family history (18), autoimmune disease (19), atopy (20), hairdye (21), HCV (22), and recreational sun exposure (23), our larger sample size, simultaneous assessment of multiple exposures, and systematic assessment of MZL subtypes highlight the potential heterogeneity of risk factors across MZL subtypes including several specific autoimmune conditions, peptic ulcers, HCV seropositivity, family history of hematological malignancies, hairdye use in women, and alcohol consumption, particularly wine. Despite the large total number of MZL cases, results from analyses of NMZL and SMZL were based on a relatively small number of cases and thus should be interpreted cautiously. Associations between family history and EMZL and NMZL subtypes observed in these analyses are new, however, the patterns are consistent with our overall MZL results and previously published results for NHL (24) and MZL (18). Inherited genetic factors may explain some MZL risk (18) although other shared environmental factors within families, particularly among siblings also may contribute to the observed effects (24). Small differential effects by sex of the case and of the relative with cancer could be due to potential recall bias between men and women and between cases and controls (25). The inverse association between alcohol consumption, particularly for wine, has not been published previously for MZL and MZL subtypes although a recent meta-analysis of published NHL studies provides some support for a general association (26). Compared with nondrinkers, ORs tended to decrease with increased consumption for MZL and EMZL, whereas for NMZL, the ORs for increasing consumption were not linear, although CIs for point estimates overlapped. Whether other unmeasured underlying lifestyle behaviors may be confounding this association and contributing to the seemingly different subtype patterns is uncertain. Body mass index, physical activity, socio-economic status (SES), and smoking showed weak associations with MZL and MZL subtypes and did not alter the observed alcohol association. The most novel result was the strong and consistent increased risk of SMZL with regular hairdye use. However, as hairdye use was available for only about 20% of SMZL cases and there were few exposed participants in some categories of use, results should be considered hypothesis generating. The associations with various hairdye characteristics including type, color, and period of use increase the plausibility of a relationship. An earlier InterLymph analysis of hairdye that did not assess MZL subtypes found no association with MZL overall (21) consistent with our overall MZL results. The pattern of association suggests that exposure to chemicals in hairdye may confer an increased SMZL risk. If true, specific chemicals and the biological mechanisms that increase risk for some subtypes and MZL of the spleen, but not other nodal or extranodal sites, remain to be elucidated. The observed associations with SS and SLE that were stronger among women, for EMZL and NMZL, are consistent with data from previous case–control and cohort studies (19,27,28). Lymphomagenesis in autoimmune disease is most well studied for SS, yet the complex process remains unclear with chronic antigenic stimulation, mutations, and translocations all playing a role (29,30). Clarifying common biological pathways in autoimmune disease and lymphomagenesis might help to improve treatment results for autoimmune conditions and simultaneously prevent their progression to MZL. Data presented here support or confirm associations of several infectious conditions with MZL subtypes. History of peptic ulcers was assessed as a proxy for H. pylori infection and the increased risks, specifically for EMZL of the stomach, are consistent with other published data (10) and with an H. pylori infectious etiology. Further, the strong association between HCV seropositivity and EMZL in our analyses is consistent with a reported causative role for HCV in MZL, particularly EMZL mucosa-associated lymphoid tissue [reviewed in (31)]. There were no data to explore the role of other putative infectious agents including B. burgdorferi and C. psittaci. In our subtype analyses, the increased risk of EMZL and SMZL observed for asthma without atopic conditions was previously reported for MZL (20). These results contrast with those from other NHL subtypes that showed inverse associations (20) and are inconsistent with the premise that factors hypothesized to contribute to a tumor protective immune milieu, that is, allergy, atopy and the environmental factors, number of siblings, and farm living, confer a reduced risk (32). This inconsistency in reported associations between asthma and lymphoma remain to be clarified but could be associated with reverse causality given results from a lymphoma case–control study that showed an inverse association between lymphoma stage and serum immunoglobulin levels as well as an increase in IgE levels from pre- to posttreatment (33). The asthma association also may be partly explained by differences in host immunological response and airway immunopathology between atopic and nonatopic asthmatics (34,35). The atopy association is complex and whether these immune-related differences may contribute to variability in pathogenesis of lymphoma subtypes requires further study. Occupational associations with MZL and MZL subtypes are understudied and associations for metalworkers, general laborers, and carpenters are novel to our analyses. Related occupational exposures to solvents and other chemicals that have some or limited evidence of being associated with NHL (36,37) may explain these findings. In contrast, we did not confirm an increased risk of ocular MZL that previously was reported among animal breeders/slaughterers (38). Also, the inverse association of teaching with MZL, EMZL, and SMZL in our study contrasted with results from a Singapore study that showed increased NHL risk among teachers but did not assess NHL subtypes (39). Exposure to infectious agents was proposed for both the teaching and animal-related occupational associations but based on the hygiene hypothesis, this explanation also would support an inverse association, as we found for teachers. Given the inconsistency in results and weak evidence for most occupationally related exposures, further careful study of work-place exposures is warranted. This study is the first to broadly examine the association between a number of known and suspected risk factors for NHL with MZL and MZL subtypes and assess them in a multivariable setting. Our results provide some intriguing novel findings that emphasize the etiological heterogeneity across NHL subtypes but also across MZL subtypes. The large sample size also allowed for exploration of effects by sex for MZL, although sex-stratified analyses by MZL subtype were not possible. The number of statistical tests conducted and the small number of exposed in some analyses may have resulted in chance findings, so novel results require follow-up. Additionally, recall bias, misclassification of exposures and conditions, and selection bias may have occurred. Misclassification of MZL including primary site, also may have biased our results, particularly for NMZL, the most difficult MZL subtype to diagnose (40). Our use of the InterLymph NHL classification (14,15), combined with site information, helped to diminish additional misclassification when harmonizing data across studies. Finally, including populations from different regions and continents allowed us to estimate effects with greater power than in individual studies and enhances the generalizability of our findings. Our novel findings by subtype require confirmation and larger studies are needed to assess the exploratory results by sex and by primary site of EMZL. However, these results may provide important clues to better define populations at high risk of MZL and are useful for hypothesis generating to inform future research. Studies are warranted to further elucidate lymphomagenesis of MZL and MZL subtypes. Funding This pooled analysis was supported by the Intramural Research Program of the National Cancer Institute/National Institutes of Health and National Cancer Institute/National Institutes of Health (R01 CA14690, U01 CA118444, and R01 CA92153-S1). InterLymph annual meetings during 2010–2013 were supported by the Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute/National Institutes of Health (2010–2013); Lymphoma Coalition (2010–2013); National Institutes of Health Office of Rare Diseases Research (2010); National Cancer Institute/National Institutes of Health (R13 CA159842 01) (2011); University of Cagliari, Provincial Administration of Cagliari, Banca di Credito Sardo, and Consorzio Industriale Sardo, Italy (2011); Intramural Research Program of the National Cancer Institute/National Institutes of Health (2012); and Faculté de Médecine de Dijon, Institut de Veille Sanitaire, Registre des hémopathies malignes de Côte d’Or, INSERM, Institut National du Cancer, Université de Bourgogne, Groupe Ouest Est d’Etude des Leucémies et Autres Maladies du Sang (GOELAMS), l’Institut Bergonié, The Lymphoma Study Association (LYSA), Registre Régional des Hémopathies de Basse Normandie, and the City of Dijon, France (2013). Meeting space at the 2013 Annual Meeting of the American Association for Cancer Research (AACR) was provided by the Molecular Epidemiology Group (MEG) of the AACR. Pooling of the occupation data was supported by the National Cancer Institute/National Institutes of Health (R03CA125831). Individual studies were supported by: the Canadian Institutes for Health Research (CIHR), Canadian Cancer Society, and Michael Smith Foundation for Health Research (British Columbia); Intramural Research Program of the National Cancer Institute/National Institutes of Health (Iowa/Minnesota); National Cancer Institute/National Institutes of Health (N01-CP-ES-11027) (Kansas); National Cancer Institute/National Institutes of Health (R01 CA50850) (Los Angeles); National Cancer Institute/National Institutes of Health (R01 CA92153 and P50 CA97274), Lymphoma Research Foundation (164738), and the Henry J. Predolin Foundation (Mayo Clinic); Intramural Research Program of the National Cancer Institute/National Institutes of Health and Public Health Service (contracts N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, and N02-PC-71105) (NCI-SEER); National Cancer Institute/National Institutes of Health (R01CA100555 and R03CA132153) and American Institute for Cancer Research (99B083) (Nebraska [newer]); National Cancer Institute/National Institutes of Health (N01-CP-95618) and State of Nebraska Department of Health (LB-506) (Nebraska [older]); National Cancer Institute/National Institutes of Health (R01CA45614, RO1CA154643-01A1, and R01CA104682) (UCSF1); National Cancer Institute/National Institutes of Health (CA143947, CA150037, R01CA087014, R01CA104682, RO1CA122663, and RO1CA154643-01A1) (UCSF2); National Heart Lung and Blood Institute/National Institutes of Health (hematology training grant award T32 HL007152), National Center for Research Resources/National Institutes of Health (UL 1 RR024160), and National Cancer Institute/National Institutes of Health (K23 CA102216 and P50 CA130805) (University of Rochester); National Cancer Institute/National Institutes of Health (CA62006 and CA165923) (Yale); Association pour la Recherche contre le Cancer, Fondation de France, AFSSET, and a donation from Faberge employees (Engela); European Commission (QLK4-CT-2000-00422 and FOOD-CT-2006–023103), Spanish Ministry of Health (CIBERESP, PI11/01810, RCESP C03/09, RTICESP C03/10, and RTIC RD06/0020/0095), Rio Hortega (CM13/00232), Agència de Gestió d’Ajuts Universitaris i de Recerca–Generalitat de Catalunya (Catalonian Government, 2009SGR1465), National Institutes of Health (contract NO1-CO-12400), Italian Ministry of Education, University and Research (PRIN 2007 prot. 2007WEJLZB, PRIN 2009 prot. 20092ZELR2), Italian Association for Cancer Research (IG grant 11855/2011); Federal Office for Radiation Protection (StSch4261 and StSch4420), José Carreras Leukemia Foundation (DJCLS-R04/08), German Federal Ministry for Education and Research (BMBF-01-EO-1303), Health Research Board, Ireland and Cancer Research Ireland, and Czech Republic MH CZ - DRO (MMCI, 00209805) (EpiLymph); National Cancer Institute/National Institutes of Health (CA51086), European Community (Europe Against Cancer Programme), and Italian Alliance Against Cancer (Lega Italiana per la Lotta contro i Tumori) (Italy, multicenter); Italian Association for Cancer Research (Italy, Aviano-Milan); Italian Association for Cancer Research (IG 10068) (Italy, Aviano-Naples); Swedish Cancer Society (2009/659), Stockholm County Council (20110209), Strategic Research Program in Epidemiology at Karolinska Institut, Swedish Cancer Society (02 6661), Danish Cancer Research Foundation, Lundbeck Foundation (R19-A2364), Danish Cancer Society (DP 08-155), National Cancer Institute/National Institutes of Health (5R01 CA69669-02), and Plan Denmark (SCALE); Leukaemia & Lymphoma Research, UK (United Kingdom); and Australian National Health and Medical Research Council (ID990920), Cancer Council NSW, and University of Sydney Faculty of Medicine (New South Wales). 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Journal

JNCI Monographs – Oxford University Press

Published: Aug 30, 2014

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